RARE DISEASE
Tularemia
Tularemia
Tularemia
Drug discovery
2
drugs
With orphan designations
Overview
Tularemia, caused by Francisella tularensis, is a highly infectious zoonotic disease transmitted through arthropod bites, animal contact, or aerosol exposure. It manifests as ulceroglandular, glandular, oculoglandular, oropharyngeal, typhoidal, or pneumonic forms, with fever, lymphadenopathy, and systemic symptoms. Severe cases (particularly pneumonic/typhoidal) have fatality rates up to 60% if untreated, but early antibiotic therapy reduces mortality to <2% [5][6][10]. It is a Tier 1 bioterrorism agent due to low infectious dose and airborne spread potential.
Population
Highest incidence in males (63% of cases), children aged 5–9, and adults ≥65 in the south-central U.S. (Arkansas, Kansas, Missouri, Oklahoma) [2][4][17].
Elevated risk among American Indian/Alaska Native populations (incidence 5× higher than whites) and individuals with outdoor/occupational exposures (hunting, landscaping) [2][7][12].
Burden
U.S. incidence rose 56% (2011–2022), averaging 205 annual cases; global re-emergence reported in Europe (Sweden, Finland) and Asia [2][7][19].
Low mortality (<2% with treatment) but high morbidity: 10–15% relapse rates, prolonged hospitalization for severe pneumonia/meningitis [1][3][6].
Economic/public health burden from delayed diagnosis, diverse presentations, and required biosafety measures for laboratory handling [5][12][19].
Therapies
Severe cases: Gentamicin (preferred IV/IM) or streptomycin for 10–14 days [1][6][8].
Mild/moderate cases: Ciprofloxacin (500 mg PO BID) or doxycycline (100 mg PO BID) for 14–21 days; levofloxacin is an alternative [1][3][10].
Prophylaxis: Doxycycline (100 mg BID) or ciprofloxacin (500 mg BID) for 14 days post-exposure [18].
Categories: rare infectious diseases
Research Papers
996 drug discovery papers about Tularemia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
996 drug discovery papers about Tularemia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2024-05-01 | Tularemia-associated hyperinflammation regulation by Natural Killer T cell subsets
Abstract Inflammation is critical for effective clearance of viral and bacterial challenges, while simultaneously a mechanism utilized by many highly infectious pathogens to cause disease. The bacterium Francisella tularensis (Ft), the causative agent of human tularemia, elicits a cytokine storm, in which the immune system over-responds to the presence of the bacterium causing a dysregulated release of proinflammatory and regulatory cytokines. Without treatment, tularemia mortality can be as high as 30%, with inhalation of as few as 10 CFUs inducing respiratory tularemia. Natural Killer T (NKT) cells are innate-like T lymphocytes with a diverse array of regulatory functions. NKT cells are activated very early following Ft infection suggesting a critical role in the innate immune response in tularemia. NKT cells are categorized into two distinct subsets, types I and II, with a yet to be defined understanding of their individual characteristics in regulating inflammation. Through a combination of in vitro and in vivo techniques, we have observed a cooperative suppression of inflammation when both subsets of NKT cells are present. This phenotypic suppression is disrupted when each subtype responds individually to Ft. The cellular mechanism controlling this interdependence of function will yield a better understanding of NKT-regulated inflammation in tularemia, and more broadly characterize their involvement and potential therapeutic application for a number of NIH priority pathogens.
2023-01-05 | Group 2 Innate Lymphoid Cells Are Detrimental to the Control of Infection with Francisella tularensis.
Abstract Innate lymphoid cells (ILCs) are capable of rapid response to a wide variety of immune challenges, including various respiratory pathogens. Despite this, their role in the immune response against the lethal intracellular bacterium Francisella tularensis is not yet known. In this study, we demonstrate that infection of the airways with F. tularensis results in a significant reduction in lung type 2 ILCs (ILC2s) in mice. Conversely, the expansion of ILC2s via treatment with the cytokine IL-33, or by adoptive transfer of ILC2s, resulted in significantly enhanced bacterial burdens in the lung, liver, and spleen, suggesting that ILC2s may favor severe infection. Indeed, specific reduction of ILC2s in a transgenic mouse model results in a reduction in lung bacterial burden. Using an in vitro culture system, we show that IFN-γ from the live vaccine strain–infected lung reduces ILC2 numbers, suggesting that this cytokine in the lung environment is mechanistically important in reducing ILC2 numbers during infection. Finally, we show Ab-mediated blockade of IL-5, of which ILC2s are a major innate source, reduces bacterial burden postinfection, suggesting that IL-5 production by ILC2s may play a role in limiting protective immunity. Thus, overall, we highlight a negative role for ILC2s in the control of infection with F. tularensis. Our work therefore highlights the role of ILC2s in determining the severity of potentially fatal airway infections and raises the possibility of interventions targeting innate immunity during infection with F. tularensis to benefit the host.
2022-08-01 | Structural and biophysical properties of FopA, a major outer membrane protein of Francisella tularensis
Francisella tularensis is an extremely infectious pathogen and a category A bioterrorism agent. It causes the highly contagious zoonosis, Tularemia. Currently, FDA approved vaccines against tularemia are unavailable. F . tularensis outer membrane protein A (FopA) is a well-studied virulence determinant and protective antigen against tularemia. It is a major outer membrane protein (Omp) of F . tularensis . However, FopA-based therapeutic intervention is hindered due to lack of complete structural information for membrane localized mature FopA. In our study, we established recombinant expression, monodisperse purification, crystallization and X-ray diffraction (~6.5 Å) of membrane localized mature FopA. Further, we performed bioinformatics and biophysical experiments to unveil its structural organization in the outer membrane. FopA consists of 393 amino acids and has less than 40% sequence identity to known bacterial Omps. Using comprehensive sequence alignments and structure predictions together with existing partial structural information, we propose a two-domain organization for FopA. Circular dichroism spectroscopy and heat modifiability assay confirmed FopA has a β-barrel domain consistent with alphafold2’s prediction of an eight stranded β-barrel at the N-terminus. Small angle X-ray scattering (SAXS) and native-polyacrylamide gel electrophoresis revealed FopA purified in detergent micelles is predominantly dimeric. Molecular density derived from SAXS at 31 Å shows putative dimeric N-terminal β-barrels surrounded by detergent corona and connected to C-terminal domains via flexible linker. Disorder analysis predicts N- and C-terminal domains are interspersed by a long intrinsically disordered region and alphafold2 predicts this region to be largely unstructured. Taken together, we propose a dimeric, two-domain organization of FopA in the outer membrane: the N-terminal β-barrel is membrane embedded, provides dimerization interface and tethers to membrane extrinsic C-terminal domain via long flexible linker. Structure determination of membrane localized mature FopA is essential to understand its role in pathogenesis and develop anti-tularemia therapeutics. Our results pave the way towards it.
2022-04-09 | Structural and biophysical properties of FopA, a major outer membrane protein of Francisella tularensis
Abstract Francisella tularensis is an extremely infectious pathogen and a category A bioterrorism agent. It causes the highly contagious zoonosis, Tularemia. Currently, FDA approved vaccines against tularemia are unavailable. F. tularensis outer membrane protein A (FopA) is a well-studied virulence determinant and protective antigen against tularemia. It is a major outer membrane protein (Omp) of F. tularensis . However, FopA-based therapeutic intervention is hindered due to lack of complete structural information for membrane localized mature FopA. In our study, we established recombinant expression, monodisperse purification, crystallization and X-ray diffraction (∼6.5 Å) of membrane localized mature FopA. Further, we performed bioinformatics and biophysical experiments to unveil its structural organization in the outer membrane. FopA consists of 393 amino acids and has less than 40% sequence identity to known bacterial Omps. Using comprehensive sequence alignments and structure predictions together with existing partial structural information, we propose a two-domain organization for FopA. Circular dichroism spectroscopy and heat modifiability assay confirmed FopA has a β-barrel domain consistent with alphafold2’s prediction of an eight stranded β-barrel at the N-terminus. Small angle X-ray scattering (SAXS) and native-polyacrylamide gel electrophoresis revealed FopA purified in detergent micelles is predominantly dimeric. Molecular density derived from SAXS at 31 Å shows putative dimeric N-terminal β-barrels surrounded by detergent corona and connected to C-terminal domains via flexible linker. Disorder analysis predicts N- and C-terminal domains are interspersed by a long intrinsically disordered region and alphafold2 predicts this region to be largely unstructured. Taken together, we propose a dimeric, two-domain organization of FopA in the outer membrane: the N-terminal β-barrel is membrane embedded, provides dimerization interface and tethers to membrane extrinsic C-terminal domain via long flexible linker. Structure determination of membrane localized mature FopA is essential to understand its role in pathogenesis and develop anti-tularemia therapeutics. Our results pave the way towards it.
2020-04-29 | Investigation of the role of Band 3 in red blood cell invasion by Francisella tularensis.
Francisella tularensis is a pathogenic gram-negative bacterium and the causative agent of the disease tularemia. As an intracellular pathogen, F. tularensis can infect and replicate within cells of the immune system, such as macrophages as well as non-immune cells including hepatocytes and epithelial cells. In all of the aforementioned cases, uptake is facilitated by the endocytic machinery and cytoskeletal rearrangements of the host cell. F. tularensis is also capable of invading erythrocytes - cells that are incapable of endocytosis or phagocytosis. Therefore, it quite likely that red blood cell invasion occurs through a distinct mechanism. Unlike the cytoskeleton of the nucleated host cells, erythrocytes are supported through a meshwork of spectrin filaments that are tethered by small actin bundles. We previously showed that actin rearrangement is not required for invasion. However, treatment of red blood cells with a snake venom that inhibits the activity of spectrin abrogates erythrocyte invasion. This venom acts through binding and inactivating Band 3, an anion transporter that complexes with spectrin. We therefore hypothesized that interaction with Band 3 is required for erythrocyte invasion. To test this, we generated Fab fragments from monoclonal and polyclonal antibodies specific to Band 3. These fragments will be used to treat erythrocytes during in vitro assays to determine the role of Band 3 during red blood cell invasion by F. tularensis. (Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence and 1R15HL147135).
small molecules
2026-09-23 | Prostaglandin D2 production in obese mice is associated with reduced lung inflammation and improved control of Francisella tularensis and Bordetella pertussis infection.
Obesity is a risk factor for severe respiratory viral infections, but its impact on bacterial respiratory diseases remains unclear and is sometimes paradoxical. Herein, we demonstrate that diet-induced obese, male C57BL/6J mice exhibited increased resistance to pulmonary infection with Francisella tularensis and Bordetella pertussis compared with lean controls. This enhanced protection in obese mice was associated with early production of the lipid mediator prostaglandin D2 (PGD2), reduced prostaglandin E2 levels, attenuated pulmonary inflammation and decreased lung cell death. Using in vitro models, we found that PGD2 and its metabolites, PGJ2 and 15-deoxy-PGJ2, suppressed macrophage inflammatory responses and limited replication of both F. tularensis and B. pertussis. In studies using the highly virulent F. tularensis SchuS4 strain, antagonism of the PGD2 receptor DP2 increased bacterial burden in macrophages in vitro, and activation of both PGD2 receptors (DP1 and DP2) in lean mice reduced bacterial loads and lung inflammation in vivo. Together, these data indicate that PGD2 signaling promotes bacterial control and limits inflammation during these bacterial infections. The association between early PGD2 production and enhanced resistance to F. tularensis and B. pertussis in obese mice suggests that modulation of PGD2 signaling may contribute to obesity-associated protection and represents a potential host-directed therapeutic strategy to improve protection of these infections.
2026-08-29 | Tularemia in pediatric patients in Sivas Province: a 15-year clinical experience
Tularemia is a clinically important yet often underrecognized cause of persistent cervical lymphadenopathy in children living in endemic regions, and delayed diagnosis may lead to prolonged morbidity, inappropriate antibiotic use, and unnecessary invasive procedures. This study aimed to evaluate the clinical, laboratory, and radiological features, treatment approaches, and outcomes of pediatric tularemia in an endemic region, and to identify distinguishing characteristics between confirmed and suspected cases. A retrospective study was conducted at a tertiary referral center between 2011 and 2025, including pediatric patients evaluated for suspected tularemia. Cases were classified as tularemia positive or negative (control) based on microbiological and serological criteria. Demographic, clinical, laboratory, and radiological data, along with treatment approaches, were compared between groups. Statistical analyses were performed using appropriate tests according to data distribution, with p < 0.05 considered statistically significant. A total of 71 patients were included (31 tularemia, 40 controls). Rural residence was significantly more common among patients with tularemia (80.0% vs. 55.0%, p = 0.029). Submandibular lymphadenopathy (60.7% vs. 34.7%), nodal necrosis (25.8% vs. 2.5%), and hypoechoic lymph nodes (30.0% vs. 10.0%) were observed more frequently in the tularemia group, whereas conglomerated lymph nodes were more common among tularemia-negative patients (17.2% vs. 47.5%) (all p < 0.05). Patients with tularemia had higher leukocyte, neutrophil, lymphocyte, platelet counts, erythrocyte sedimentation rate levels, and lower albumin concentrations (all p < 0.05). Aminoglycosides were the most frequently administered antimicrobial agents after diagnosis (64.5%), whereas beta-lactam antibiotics were commonly prescribed before tularemia was recognized (74.2%). Surgical intervention was required in more than half of the patients (58.1%). Reactive (60%) and EBV-associated lymphadenopathy (12.5%) constituted the most common final diagnoses among tularemia-negative cases. Tularemia should be considered in children with cervical lymphadenopathy and oropharyngeal symptoms in endemic regions, particularly those with rural residence. Submandibular involvement, necrotic and hypoechoic lymph nodes, and a lower tendency for conglomeration may help distinguish tularemia from other causes of cervical lymphadenopathy. Early recognition and appropriate antimicrobial therapy may reduce the need for surgical intervention.
2026-07-15 | Aminoglycosides: Is there an effective alternative in severe tularaemia? A case series.
Severe pulmonary tularaemia is rare, and evidence guiding optimal antimicrobial treatment remains limited. Although aminoglycosides are commonly recommended, their toxicity profile and practical limitations may complicate treatments. The purpose of this case series was to describe clinical outcomes in adult patients with severe pulmonary tularaemia caused by Francisella tularensis who were treated with fluoroquinolones or tetracyclines.; METHODS: We retrospectively describe six adult patients with severe pulmonary tularaemia. Clinical presentation, antimicrobial treatment, and clinical and radiological outcomes were reviewed, with a focus on response to targeted therapy with fluoroquinolones or tetracyclines.; RESULTS: All six patients achieved complete clinical and radiological recovery following targeted antimicrobial therapy with either fluoroquinolones or tetracyclines despite severe pulmonary disease.; CONCLUSION: This case series provides consistent real-world evidence that fluoroquinolones and tetracyclines can achieve favourable outcomes in severe pulmonary tularaemia. These findings highlight their potential role as alternative treatment strategies and contribute meaningful data to the ongoing discussion on optimal antimicrobial management of tularaemia.
2026-07-14 | Pulmonary tularemia leading to a relapse of tularemia orchitis in a patient on TNF-alpha inhibitor.
Tularemia represents a zoonotic infection that poses particular diagnostic and therapeutic challenges in immunocompromised patients. We present a rare case of tularemia orchitis in a patient receiving tumor necrosis factor alpha (TNF alpha) inhibitor treatment. We conducted a case analysis of a 71-year-old farmer receiving adalimumab for psoriatic arthritis who developed sequential pulmonary and genitourinary manifestations of tularemia. Clinical presentation, laboratory findings, microbiological identification through culture and polymerase chain reaction testing, imaging studies, and histopathological examination were documented. Treatment response and clinical follow-up were monitored throughout the disease course. The patient initially presented with pneumonic tularemia confirmed by positive blood cultures. Following apparent clinical resolution with doxycycline therapy, he developed orchitis 3 months later requiring unilateral orchiectomy. Polymerase chain reaction testing confirmed Francisella tularensis as the causative pathogen in testicular tissue. Histological examination revealed dense inflammatory infiltration with histiocytes, neutrophils, and T‑lymphocytes. Combination therapy with doxycycline and ciprofloxacin achieved clinical remission, although fluoroquinolone-induced peripheral neuropathy necessitated treatment modification. Patients receiving tumor necrosis factor alpha inhibitors demonstrate increased susceptibility to tularemia manifestations and potential disease relapse. The blood-testis barrier may limit antibiotic penetration, contributing to treatment failure with monotherapy. Enhanced clinical awareness and consideration of combination antimicrobial therapy may be warranted in immunocompromised patients with tularemia, particularly those residing in endemic regions.
2026-06-20 | Severe pneumonic tularemia following inhalational exposure with acute respiratory distress syndrome and multiorgan failure.
A man in his early 70s presented with septic shock and severe ARDS, likely after aerosolising Francisella tularensis Initial empirical treatment for community-acquired pneumonia with ceftriaxone failed, resulting in clinical deterioration with stage 3 acute kidney injury requiring dialysis and necrotising pneumonia. After pneumonic tularaemia was identified, antimicrobial therapy was transitioned to renally dosed levofloxacin, along with aggressive ICU support including prone positioning and tube thoracostomy. The patient ultimately made a full recovery, returning to his functional baseline one month after discharge.This case underscores the importance of eliciting environmental exposures in patients with severe, culture-negative pneumonia unresponsive to beta-lactams, as this should prompt consideration of inhalational tularaemia. It also highlights how pathogen-induced cytokine storm can drive catastrophic multiorgan failure and supports fluoroquinolones as a safe and effective first-line alternative to aminoglycosides in the setting of renal failure.
vaccines
2026-09-29 | Immunopeptidomics reveals conserved and abundant Francisella tularensis proteins as immunogenic CD4 T cell antigens in mice.
Human tularemia is caused by infection with the intracellular bacterium Francisella tularensis. The ability of the bacterium to cause a severe pneumonic form of the disease has led to concerns in the field of biodefense and efforts to develop a vaccine. F. tularensis LVS provides partial protection against fully virulent strains, with CD4+ T cells playing a significant role in this protection, however the recognized bacterial antigens remain largely unknown. To identify these antigens, we screened MHC class II peptides presented by infected dendritic cells using mass spectrometry-based immunopeptidomics. We identified 57 MHC-II peptides from 23 different F. tularensis LVS proteins. Most of these proteins were highly expressed in the bacterial proteome. Subsequent screening for IFN-γ responses identified ten peptides as immunogenic epitopes of CD4+ T cells following immunization of mice with F. tularensis LVS, thereby revealing previously unknown specificity and breadth of the induced immune responses. Five epitopes, derived from the antigens FTL_1678, DacD, DnaK, FTL_1498, and MinD, represented the dominant epitopes that elicited a response in at least 80% of immunizations. Finally, a peptide vaccine containing these epitopes proved to be immunogenic in mice and contributed to the early control of bacterial replication following challenge with the virulent F. tularensis FSC200 strain, although this alone was insufficient to ensure complete protection. Using immunopeptidomics, we have thus identified several immunogenic CD4+ T cell epitopes and antigens of F. tularensis LVS. Beyond their potential role in the protective immune response, the identified epitopes may also enable the development of tools for characterizing antigen-specific CD4+ T cells in vaccination studies or T cell biology research.
2026-09-15 | Biopolymer-Antigen Conjugate Vaccines for Prevention of Tularemia
Abstract Francisella tularensis, the causative agent of tularemia, is a facultative intracellular pathogen categorized as a tier I bioterrorism agent. The current live vaccine strain (LVS) vaccine poses safety and virulence concerns, advocating the need for a safer alternative. In this study, we demonstrated a combination of antigens FopA, Tul4, SucB, and DnaK conjugated to biopolymer particles (BPs) as a multivalent subunit vaccine that not only induces LVS and SchuS4-specific antibody titers but also confers protective immunity with differential cytokine profiles upon LVS challenge. This multivalent vaccine conferred 80% survival in mice, with antibodies of opsonizing ability and rapid recovery from weight loss. The production of these biopolymer conjugate vaccines was achieved in one step inside engineered Escherichia coli and is not only cost-effective but also leads to thermostable formulations, eliminating the need for cold-chain transport and storage. E. coli fermentation-based production avoids the need for high-containment facilities. Collectively, the FopA-BP-Tul4, SucB-BP, and Dnak-BP combined formulations hold the promise for the development of a robust subunit vaccine for the prevention of tularemia.
2026-08-14 | Transcriptional analyses of peripheral blood lymphocytes obtained shortly after primary immunization discriminate vaccines against Francisella tularensis.
The high virulence and pathogenesis of Francisella tularensis (Ft), responsible for tularemia, made it a target for bioweapon development during the "Cold War." This prompted investigation of vaccines, starting with an older vaccine candidate denoted Ft live vaccine strain (LVS). LVS has limited efficacy against aerosol challenge with Ft subsp. Tularensis (Type A), the most virulent subtype. However, no vaccines, including LVS, have been licensed in the U.S. Animal studies indicate that Ft vaccines induce protective T-cell-mediated immune responses. In previous studies, analyses of leukocytes from vaccinated animals that were restimulated in vitro facilitated screening and selection of vaccines for more extensive in vivo evaluation. These studies demonstrated that a novel live attenuated vaccine strain derived from Type A Ft, denoted ΔclpB, was protective against aerosol challenge in animal models. In this study, we focused on evaluating immune responses immediately after vaccination of Fischer 344 rats with LVS and ΔclpB using multiple analytical approaches. While humoral immune responses were comparable between the two vaccines, we identified multiple differences in immune responses by analyses of peripheral blood leukocytes by flow cytometry and by relative gene expression. In particular, vaccination with LVS or ΔclpB resulted in differential expression of multiple genes at selected time points. Gene expression, in turn, predicted activation or inhibition of multiple biological pathways. These results suggest that immune responses shortly after primary vaccination may discriminate vaccines with different degrees of in vivo protection that could potentially be used as correlates of protection and extrapolate efficacy from animals to people.
2026-07-27 | Potential Roles of Gamma-Delta T Cells in a Bacterial Immun-Ization Model.
Background/Objective: Francisella tularensis is a highly infectious intracellular pathogen that causes severe pulmonary tularemia following aerosol exposure, yet no licensed vaccine exists. Because infection initiates at the respiratory mucosa, understanding mechanisms of protective pulmonary immunity is critical for mucosal vaccine development. This study investigated the role of lung-resident γδ T cells following intranasal immunization with inactivated F. tularensis (iFt) and subsequent lethal challenge with live vaccine strain (LVS). Methods: Mice were intranasally immunized with iFt and later challenged with lethal LVS. Pulmonary immune responses were evaluated using flow cytometry and cytokine analysis. Recruitment of γδ and αβ T cells, production of IL-17 and IFN-γ, neutrophil infiltration, and γδ T cell memory phenotypes were assessed in naïve and immunized mice following infection. Results: Primary LVS infection induced rapid recruitment of γδ T cells to the lung beginning on Day 2 post-infection, preceding significant αβ T cell accumulation. Increased pulmonary IL-17 and IFN-γ correlated with expansion of IL-17- and IFN-γ-associated γδ T cell populations. Following iFt immunization, mice demonstrated enhanced survival after lethal LVS challenge, accompanied by early increases in pulmonary IL-17 and IL-17 producing γδ T cells. Immunized mice also exhibited expansion of effector memory and central memory γδ T cell populations associated with IL-17 production. Conclusions: These findings identify IL-17 producing γδ T cells as contributors to early mucosal immunity following intranasal vaccination against F. tularensis and suggest that targeting lung-resident γδ T cells may support the development of next-generation mucosal vaccines against respiratory pathogens.
2026-06-21 | Designing of a conserved subunit multiepitope vaccine candidate against Francisella tularensis Schu S4 using immunoinformatics.
Francisella tularensis Schu S4 is the most virulent strain responsible for tularemia, a highly infectious zoonotic disease. Despite its potential as a pathogen of concern, no effective vaccine has been developed for this pathogen. In this study, two multi-epitope subunit vaccine candidates were designed targeting the virulence factors DacD and DsbA to reduce disease severity caused by F. tularensis Schu S4. Using a comprehensive immunoinformatics approach, the most efficient B- and T-cell epitopes were identified from conserved sequences and linked with adjuvants and linkers to generate two vaccine constructs. These constructs were modeled, refined, and validated through molecular docking against Toll-Like Receptors (TLRs) and MHC alleles, followed by 200 ns molecular dynamics simulations. Their immunogenic potential and expression efficiency were further evaluated through immune simulations and computational cloning into the pET30a( +) vector. Both the constructed vaccine candidates, TulaVac1 and TulaVac2, showed high antigenicity, immunogenicity, stability, and solubility. The epitope conservancy was nearly 100%, with global population coverage rates of 73.19% and 99.74% for MHC class I and II epitopes, respectively. Docking analyses revealed six CTL epitopes with binding energies of ≤ -9.0 kcal/mol, while vaccine-TLR and MHC docking suggested superior performance of TulaVac1. MM/GBSA analysis yielded favorable binding energies ranging from - 87.22 to - 161.30 kcal/mol, MD simulations confirmed the stable interaction for 200 ns, and immune simulations showed robust immune responses with satisfactory codon adaptation. These findings position TulaVac1 and TulaVac2 as promising candidates for effective prophylaxis against tularemia.
proteins
2025-12-17 | Activation of B1 B cells by F. tularensis atypical LPS depends on classical complement and C3a.
Francisella tularensis (Ft), a Gram-negative bacterium that causes tularemia, possesses a non-inflammatory atypical LPS (LPSFt) that is highly immunogenic through unknown mechanism. We previously showed that immunization with LPSFt, a type 2 T-independent (TI) antigen, elicits protective LPSFt-specific IgM (IgMFt) and IgG3Ft by B1 cells in a mechanism dependent on the IL-5 produced by innate lymphoid cells type 2 (ILC2). Here, we examined the role of complement in the B1 cells' response against LPSFt. C3-/-, C1q-/- and C4-/- mice immunized with LPSFt failed to produce IgMFt and IgG3Ft. In contrast, the response of Cfb-/- and Mbl1/Mbl2-/- mice was comparable to that of WT mice. Thus, activation of the classical complement cascade, but not the alternative or the Mannose Binding Lectin pathway, is required for activation of B1 cells and production of LPSFt-specific antibodies. Complement activation generates the C3d fragment, which opsonizes antigens for recognition by complement receptor-2 (CR2), and the C3a and C5a anaphylatoxins. Our results show that C3d opsonized LPSFt and that the response to immunization was dependent on CR2 expression by B1 cells. Importantly, the response to LPSFt immunization was also drastically decreased in C3ar1-/-, but not in C5ar1-/- mice. C3a induced IL-5 in ILC2, which supported B1 cells activation. Decreased antibody production in C3ar1-/- and Cr2-/- mice correlated with increased susceptibility to tularemia. Together, these results demonstrate that the high immunogenicity of LPSFt depends on two effector mechanisms triggered by activation of the classical complement pathway: 1) tagging of LPSFt with C3d fragment, leading to its interaction with CR2 expressed by B1 cells; 2) production of the anaphylatoxin C3a that stimulated IL-5 secretion by ILC2. Our study increases our understanding of the B1 cells' response to TI-2 antigens and identifies two complement effector mechanisms that can be harnessed for therapeutic interventions.
2025-10-21 | De Novo Design of High‐Affinity Miniprotein Binders Targeting Francisella Tularensis Virulence Factor
Abstract Francisella tularensis poses considerable public health risk due to its high infectivity and potential for bioterrorism. Francisella‐like lipoprotein (Flpp3), a key virulence factor unique to Francisella, plays critical roles in infection and immune evasion, making it a promising target for therapeutic development. However, the lack of well‐defined binding pockets and structural information on native interactions has hindered structure‐guided ligand discovery against Flpp3. Here, we used a combination of physics‐based and deep‐learning methods to design high‐affinity miniprotein binders targeting two distinct sites on Flpp3. We identified four binders for site I with binding affinities ranging between 24–110 nM. For the second site, an initial binder showed a dissociation constant ( K D ) of 81 nM, and subsequent site saturation mutagenesis yielded variants with sub‐nanomolar affinities. Circular dichroism confirmed the topology of designed miniproteins. The X‐ray crystal structure of Flpp3 in complex with a site I binder is nearly identical to the design model (Cα root‐mean‐square deviation (RMSD): 0.9 Å). These designed miniproteins provide research tools to explore the roles of Flpp3 in tularemia and should enable the development of new therapeutic candidates.
2025-07-09 | De novo design of high-affinity miniprotein binders targeting Francisella tularensis virulence factor.
Francisella tularensis poses considerable public health risk due to its high infectivity and potential for bioterrorism. Francisella-like lipoprotein (Flpp3), a key virulence factor unique to Francisella, plays critical roles in infection and immune evasion, making it a promising target for therapeutic development. However, the lack of well-defined binding pockets and structural information on native interactions has hindered structure-guided ligand discovery against Flpp3. Here, we used a combination of physics-based and deep-learning methods to design high-affinity miniprotein binders targeting two distinct sites on Flpp3. We identified four binders for site I with binding affinities ranging between 24-110 nM. For the second site, an initial binder showed a dissociation constant (K D ) of 81 nM, and subsequent site saturation mutagenesis yielded variants with sub-nanomolar affinities. Circular dichroism confirmed the topology of designed miniproteins. The X-ray crystal structure of Flpp3 in complex with a site I binder is nearly identical to the design model (Cα root-mean-square deviation: 0.9 Å). These designed miniproteins provide research tools to explore the roles of Flpp3 in tularemia and should enable the development of new therapeutic candidates.
2025-07-02 | Treatment of bacterial biothreat agents with a novel purified bioactive lactoferrin affects both growth and biofilm formation.
Lactoferrin is known to exhibit broad spectrum activity against a multitude of bacteria, fungi, and viruses due to its multi-functional mode of action. Recently, Lactea Therapeutics and its affiliates have developed a novel, patent-pending technology to purify naturally derived bovine lactoferrin (Lactea Lf) for use as a medical countermeasure that was not previously available. To assess the efficacy of Lactea Lf against biothreat pathogens, we performed biofilm inhibition assays and generated dose-response curves against Burkholderia pseudomallei, Burkholderia mallei, and Francisella tularensis for proof-of-principle studies. Here, we show that Lactea Lf can significantly inhibit biofilm and decrease the overall growth in a dose dependent manner for all Burkholderia species tested. Of note, Lactea Lf was found to completely inhibit biofilm formation by virulent B. pseudomallei without observing complete growth inhibition. The growth of F. tularensis was also significantly inhibited when cultured in the presence of Lactea Lf and appeared more sensitive to treatment when compared to B. pseudomallei. Based on these results, a pneumonic infection model using the F. tularensis LVS strain was performed prophylactically administering Lactea Lf and continuing treatment post challenge. No protection was observed in this model which prompted biodistribution studies using fluorescent tagged Lactea Lf. These experiments revealed that therapeutic material was mainly confined to the NALT region following intranasal delivery and then quickly dispersed or inactivated suggesting that future formulation and delivery method could be addressed to increase in vivo treatment efficacy. Taken together, these data support that Lactea Lf is a potentially new candidate for further studies as a broad-spectrum antimicrobial medical countermeasure with efficacy against several high priority biodefense-related bacterial pathogens.
2023-04-03 | IL-12p40 is essential but not sufficient for Francisella tularensis LVS clearance in chronically infected mice.
IL-12p40 plays an important role in F. tularensis Live Vaccine Strain (LVS) clearance that is independent of its functions as a part of the heterodimeric cytokines IL-12p70 or IL-23. In contrast to WT, p35, or p19 knockout (KO) mice, p40 KO mice infected with LVS develop a chronic infection that does not resolve. Here, we further evaluated the role of IL-12p40 in F. tularensis clearance. Despite reduced IFN-γ production, primed splenocytes from p40 KO and p35 KO mice appeared functionally similar to those from WT mice during in vitro co-culture assays of intramacrophage bacterial growth control. Gene expression analysis revealed a subset of genes that were upregulated in re-stimulated WT and p35 KO splenocytes, but not p40 KO splenocytes, and thus are candidates for involvement in F. tularensis clearance. To directly evaluate a potential mechanism for p40 in F. tularensis clearance, we reconstituted protein levels in LVS-infected p40 KO mice using either intermittent injections of p40 homodimer (p80) or treatment with a p40-producing lentivirus construct. Although both delivery strategies yielded readily detectable levels of p40 in sera and spleens, neither treatment had a measurable impact on LVS clearance by p40 KO mice. Taken together, these studies demonstrate that clearance of F. tularensis infection depends on p40, but p40 monomers and/or dimers alone are not sufficient.
other
2026-09-26 | A Tularemia cluster in Manisa, Türkiye: clinical characteristics and investigation of a probable waterborne source
Abstract Background Tularemia is a re-emerging zoonotic disease caused by Francisella tularensis. In Türkiye, water-associated transmission is an important epidemiological pattern and oropharyngeal disease is common. This study aimed to describe the clinical characteristics of a tularemia cluster identified in Manisa, western Türkiye, and to evaluate the epidemiological and environmental findings supporting a probable waterborne source. Methods This retrospective, observational, two-center study included 13 adult patients with clinically compatible tularemia and a single positive microagglutination test (MAT) titer of ≥ 1:160 diagnosed between January and May 2025. Demographic, epidemiological, clinical, laboratory, radiological, cytopathological, treatment, and outcome data were retrospectively collected. Twelve patients from Alaşehir reported natural spring-water consumption within the same local area, whereas one patient resided in Demirci and had a separate exposure history. Following recognition of the cluster, an environmental investigation was conducted under the coordination of the Provincial Directorate of Health. Results Thirteen patients were included. The median age was 33 years (range, 21–73 years), and eight (61.5%) were female. Twelve patients (92.3%) resided in rural Alaşehir and reported natural spring-water consumption within the same local area; one patient resided in Demirci and was not epidemiologically linked to that exposure. The oropharyngeal form was the most common presentation (10/13, 76.9%), followed by the glandular form (3/13, 23.1%). Cervical lymphadenopathy was present in all patients, and imaging frequently demonstrated necrosis, liquefaction, abscess formation, or surrounding soft-tissue involvement. Before referral, most patients had received antimicrobial therapy that was ineffective against tularemia. Because this was a selected tertiary-care referral cohort with persistent symptoms and/or complicated lymphadenopathy, treatment was individualized according to disease duration and clinical response; drainage was required in selected patients. All patients achieved clinical recovery. A stored natural spring-water sample obtained from a household in Alaşehir was reported culture-positive for F. tularensis by the National Reference Laboratory. Molecular confirmation or typing linking the environmental finding to the human cases was not available. Conclusions This cluster highlights the importance of considering tularemia in patients with persistent cervical lymphadenopathy and tonsillopharyngitis unresponsive to beta-lactam antibiotics, particularly in rural settings with natural spring-water exposure. The shared exposure among the Alaşehir cases and the culture-positive environmental sample support a probable waterborne source; however, the absence of direct microbiological confirmation of the human cases and molecular linkage prevents definitive attribution of the transmission chain.
2026-07-28 | MAIT17 Cells and IL-17-Driven iBALT Formation Protect Against Pulmonary Tularemia 2267799
Abstract Introduction Here we demonstrate that respiratory infection with Francisella tularensis induces the formation of induced bronchus-associated lymphoid tissue (iBALT) as a protective mechanism against pulmonary tularemia-like disease in mice. While semi-invariant natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are abundant at the lung mucosa, their roles in infectious diseases remain poorly understood. Pulmonary tularemia, the most severe form of tularemia, arises from respiratory infection with F. tularensis. Using C57BL/6 mice infected with the live vaccine strain (LVS) of F. tularensis to model tularemia-like disease, we previously showed that NKT cells exacerbate disease, as NKT-deficient CD1d⁻/⁻ mice were protected. Notably, protected CD1d⁻/⁻ mice developed iBALT structures in the lungs, which were absent in C57BL/6 mice. Methods Molecular immunology methods. Results Respiratory LVS infection in CD1d⁻/⁻ mice induced a robust expansion of IL-17-producing MAIT17 cells and a decrease in regulatory T cells in the lungs compared to C57BL/6 mice. Single-cell RNA sequencing revealed a gene signature in MAIT cells linked to factors that drive iBALT formation. Supporting this notion, adoptive transfer of LVS-activated lung MAIT cells from infected CD1d⁻/⁻ mice conferred protection against tularemia-like disease in RAG2⁻/⁻ recipients, while splenic MAIT cells did not despite the fact that both populations homed to the lungs after transfer. Lung-derived MAIT cells were enriched in IL-17-producing MAIT17 cells, whereas splenic MAIT cells predominantly consisted of interferon-gamma-producing MAIT1 cells. Last, IL-17 was identified as critical for iBALT development during respiratory LVS infection in CD1d⁻/⁻ mice. Conclusion In summary, our findings establish MAIT cells as central mediators of IL-17-dependent protection against pulmonary tularemia-like disease and underscore the potential protective role of iBALT in disease resistance. Funding Source NIH AI137082, VA Merit BX001610, VA SRCS BX004595 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
2026-03-28 | Tularemia: Historical Perspectives and Current Challenges of a Re-Emerging Zoonosis.
Tularemia is a plague-like, potentially fatal zoonosis caused by the coccobacillus Francisella tularensis. It was discovered at the beginning of the last century in the United States and was soon recognized in Japan and in the former Soviet Union as the cause of clinical conditions that had been known for one and two centuries, respectively. More than 250 animal species are susceptible to infection, with rodents and lagomorphs serving as key reservoirs, and several vectors may transmit the disease, mainly ticks and mosquitoes. Humans are incidental hosts and are infected primarily by two F. tularensis subspecies, tularensis and holarctica: the former is more severe and is found almost exclusively in North America, whereas the latter is distributed throughout the Northern Hemisphere, mainly in Europe and Asia. Tularemia is highly infectious; therefore, diagnostic cultures should be handled in biosafety level 3 laboratories. Nevertheless, interhuman transmission is exceedingly rare. Although tularemia is relatively uncommon, it shows a re-emerging pattern at the global level, particularly in Europe. As with plague, mitigation may be more effectively achieved through a One Health approach. Neither approved vaccines nor therapeutic antibodies are currently available, whereas aminoglycoside, tetracycline, and quinolone antibiotics are effective. Owing to its high infectivity, its ease of transmission by inhalation, its clinical severity, with a prolonged and debilitating course, and its potential lethality, F. tularensis has long been considered a potential biological weapon, particularly if antibiotic-resistant strains were used. Although natural antibiotic resistance has not been described to date, research programs aimed at obtaining resistant strains have been conducted. It has been suggested that the disease was already present in the Middle East during the second millennium BC; should this hypothesis be confirmed by paleogenomic studies, plague and tularemia would have coexisted for more than three millennia, with plague masking the less severe tularemia. Many challenges related to tularemia are still unresolved.
2026-01-21 | Behind the COVID-19 Curtain: A Rare Case of Autochthonous Pneumonic Tularemia in Portugal.
The presence of Francisella tularensis has been well documented in Portugal; however, reports of human infection remain rare. We report the case of a 63-year-old woman presenting with pneumonia and SARS-CoV-2 infection. The relapsing course of infection, partial response to fluoroquinolone and macrolide antibiotics, and epidemiological background led to the suspicion of an underlying zoonotic disease. Serology later confirmed F. tularensis infection, and the patient improved under directed therapy. To the best of our knowledge, this is the first case of autochthonous pneumonic tularemia reported in Portugal.
2026-01-01 | MODERN ASPECTS OF TULAREMIA EPIDEMIOLOGY IN THE RUSSIAN FEDERATION
The analysis of the incidence of tularemia in the Russian Federation in 2024 was conducted, including age and gender characteristics, occupational and social structure of patients, clinical forms and severity of the disease. Based on this research, the modern clinical and epidemiological features of tularemia were identified and the relevance of this infection was confirmed.
antibodies
2024-05-01 | Tularemia-associated hyperinflammation regulation by Natural Killer T cell subsets
Abstract Inflammation is critical for effective clearance of viral and bacterial challenges, while simultaneously a mechanism utilized by many highly infectious pathogens to cause disease. The bacterium Francisella tularensis (Ft), the causative agent of human tularemia, elicits a cytokine storm, in which the immune system over-responds to the presence of the bacterium causing a dysregulated release of proinflammatory and regulatory cytokines. Without treatment, tularemia mortality can be as high as 30%, with inhalation of as few as 10 CFUs inducing respiratory tularemia. Natural Killer T (NKT) cells are innate-like T lymphocytes with a diverse array of regulatory functions. NKT cells are activated very early following Ft infection suggesting a critical role in the innate immune response in tularemia. NKT cells are categorized into two distinct subsets, types I and II, with a yet to be defined understanding of their individual characteristics in regulating inflammation. Through a combination of in vitro and in vivo techniques, we have observed a cooperative suppression of inflammation when both subsets of NKT cells are present. This phenotypic suppression is disrupted when each subtype responds individually to Ft. The cellular mechanism controlling this interdependence of function will yield a better understanding of NKT-regulated inflammation in tularemia, and more broadly characterize their involvement and potential therapeutic application for a number of NIH priority pathogens.
2023-01-05 | Group 2 Innate Lymphoid Cells Are Detrimental to the Control of Infection with Francisella tularensis.
Abstract Innate lymphoid cells (ILCs) are capable of rapid response to a wide variety of immune challenges, including various respiratory pathogens. Despite this, their role in the immune response against the lethal intracellular bacterium Francisella tularensis is not yet known. In this study, we demonstrate that infection of the airways with F. tularensis results in a significant reduction in lung type 2 ILCs (ILC2s) in mice. Conversely, the expansion of ILC2s via treatment with the cytokine IL-33, or by adoptive transfer of ILC2s, resulted in significantly enhanced bacterial burdens in the lung, liver, and spleen, suggesting that ILC2s may favor severe infection. Indeed, specific reduction of ILC2s in a transgenic mouse model results in a reduction in lung bacterial burden. Using an in vitro culture system, we show that IFN-γ from the live vaccine strain–infected lung reduces ILC2 numbers, suggesting that this cytokine in the lung environment is mechanistically important in reducing ILC2 numbers during infection. Finally, we show Ab-mediated blockade of IL-5, of which ILC2s are a major innate source, reduces bacterial burden postinfection, suggesting that IL-5 production by ILC2s may play a role in limiting protective immunity. Thus, overall, we highlight a negative role for ILC2s in the control of infection with F. tularensis. Our work therefore highlights the role of ILC2s in determining the severity of potentially fatal airway infections and raises the possibility of interventions targeting innate immunity during infection with F. tularensis to benefit the host.
2022-08-01 | Structural and biophysical properties of FopA, a major outer membrane protein of Francisella tularensis
Francisella tularensis is an extremely infectious pathogen and a category A bioterrorism agent. It causes the highly contagious zoonosis, Tularemia. Currently, FDA approved vaccines against tularemia are unavailable. F . tularensis outer membrane protein A (FopA) is a well-studied virulence determinant and protective antigen against tularemia. It is a major outer membrane protein (Omp) of F . tularensis . However, FopA-based therapeutic intervention is hindered due to lack of complete structural information for membrane localized mature FopA. In our study, we established recombinant expression, monodisperse purification, crystallization and X-ray diffraction (~6.5 Å) of membrane localized mature FopA. Further, we performed bioinformatics and biophysical experiments to unveil its structural organization in the outer membrane. FopA consists of 393 amino acids and has less than 40% sequence identity to known bacterial Omps. Using comprehensive sequence alignments and structure predictions together with existing partial structural information, we propose a two-domain organization for FopA. Circular dichroism spectroscopy and heat modifiability assay confirmed FopA has a β-barrel domain consistent with alphafold2’s prediction of an eight stranded β-barrel at the N-terminus. Small angle X-ray scattering (SAXS) and native-polyacrylamide gel electrophoresis revealed FopA purified in detergent micelles is predominantly dimeric. Molecular density derived from SAXS at 31 Å shows putative dimeric N-terminal β-barrels surrounded by detergent corona and connected to C-terminal domains via flexible linker. Disorder analysis predicts N- and C-terminal domains are interspersed by a long intrinsically disordered region and alphafold2 predicts this region to be largely unstructured. Taken together, we propose a dimeric, two-domain organization of FopA in the outer membrane: the N-terminal β-barrel is membrane embedded, provides dimerization interface and tethers to membrane extrinsic C-terminal domain via long flexible linker. Structure determination of membrane localized mature FopA is essential to understand its role in pathogenesis and develop anti-tularemia therapeutics. Our results pave the way towards it.
2022-04-09 | Structural and biophysical properties of FopA, a major outer membrane protein of Francisella tularensis
Abstract Francisella tularensis is an extremely infectious pathogen and a category A bioterrorism agent. It causes the highly contagious zoonosis, Tularemia. Currently, FDA approved vaccines against tularemia are unavailable. F. tularensis outer membrane protein A (FopA) is a well-studied virulence determinant and protective antigen against tularemia. It is a major outer membrane protein (Omp) of F. tularensis . However, FopA-based therapeutic intervention is hindered due to lack of complete structural information for membrane localized mature FopA. In our study, we established recombinant expression, monodisperse purification, crystallization and X-ray diffraction (∼6.5 Å) of membrane localized mature FopA. Further, we performed bioinformatics and biophysical experiments to unveil its structural organization in the outer membrane. FopA consists of 393 amino acids and has less than 40% sequence identity to known bacterial Omps. Using comprehensive sequence alignments and structure predictions together with existing partial structural information, we propose a two-domain organization for FopA. Circular dichroism spectroscopy and heat modifiability assay confirmed FopA has a β-barrel domain consistent with alphafold2’s prediction of an eight stranded β-barrel at the N-terminus. Small angle X-ray scattering (SAXS) and native-polyacrylamide gel electrophoresis revealed FopA purified in detergent micelles is predominantly dimeric. Molecular density derived from SAXS at 31 Å shows putative dimeric N-terminal β-barrels surrounded by detergent corona and connected to C-terminal domains via flexible linker. Disorder analysis predicts N- and C-terminal domains are interspersed by a long intrinsically disordered region and alphafold2 predicts this region to be largely unstructured. Taken together, we propose a dimeric, two-domain organization of FopA in the outer membrane: the N-terminal β-barrel is membrane embedded, provides dimerization interface and tethers to membrane extrinsic C-terminal domain via long flexible linker. Structure determination of membrane localized mature FopA is essential to understand its role in pathogenesis and develop anti-tularemia therapeutics. Our results pave the way towards it.
2020-04-29 | Investigation of the role of Band 3 in red blood cell invasion by Francisella tularensis.
Francisella tularensis is a pathogenic gram-negative bacterium and the causative agent of the disease tularemia. As an intracellular pathogen, F. tularensis can infect and replicate within cells of the immune system, such as macrophages as well as non-immune cells including hepatocytes and epithelial cells. In all of the aforementioned cases, uptake is facilitated by the endocytic machinery and cytoskeletal rearrangements of the host cell. F. tularensis is also capable of invading erythrocytes - cells that are incapable of endocytosis or phagocytosis. Therefore, it quite likely that red blood cell invasion occurs through a distinct mechanism. Unlike the cytoskeleton of the nucleated host cells, erythrocytes are supported through a meshwork of spectrin filaments that are tethered by small actin bundles. We previously showed that actin rearrangement is not required for invasion. However, treatment of red blood cells with a snake venom that inhibits the activity of spectrin abrogates erythrocyte invasion. This venom acts through binding and inactivating Band 3, an anion transporter that complexes with spectrin. We therefore hypothesized that interaction with Band 3 is required for erythrocyte invasion. To test this, we generated Fab fragments from monoclonal and polyclonal antibodies specific to Band 3. These fragments will be used to treat erythrocytes during in vitro assays to determine the role of Band 3 during red blood cell invasion by F. tularensis. (Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence and 1R15HL147135).
small molecules
2026-09-23 | Prostaglandin D2 production in obese mice is associated with reduced lung inflammation and improved control of Francisella tularensis and Bordetella pertussis infection.
Obesity is a risk factor for severe respiratory viral infections, but its impact on bacterial respiratory diseases remains unclear and is sometimes paradoxical. Herein, we demonstrate that diet-induced obese, male C57BL/6J mice exhibited increased resistance to pulmonary infection with Francisella tularensis and Bordetella pertussis compared with lean controls. This enhanced protection in obese mice was associated with early production of the lipid mediator prostaglandin D2 (PGD2), reduced prostaglandin E2 levels, attenuated pulmonary inflammation and decreased lung cell death. Using in vitro models, we found that PGD2 and its metabolites, PGJ2 and 15-deoxy-PGJ2, suppressed macrophage inflammatory responses and limited replication of both F. tularensis and B. pertussis. In studies using the highly virulent F. tularensis SchuS4 strain, antagonism of the PGD2 receptor DP2 increased bacterial burden in macrophages in vitro, and activation of both PGD2 receptors (DP1 and DP2) in lean mice reduced bacterial loads and lung inflammation in vivo. Together, these data indicate that PGD2 signaling promotes bacterial control and limits inflammation during these bacterial infections. The association between early PGD2 production and enhanced resistance to F. tularensis and B. pertussis in obese mice suggests that modulation of PGD2 signaling may contribute to obesity-associated protection and represents a potential host-directed therapeutic strategy to improve protection of these infections.
2026-08-29 | Tularemia in pediatric patients in Sivas Province: a 15-year clinical experience
Tularemia is a clinically important yet often underrecognized cause of persistent cervical lymphadenopathy in children living in endemic regions, and delayed diagnosis may lead to prolonged morbidity, inappropriate antibiotic use, and unnecessary invasive procedures. This study aimed to evaluate the clinical, laboratory, and radiological features, treatment approaches, and outcomes of pediatric tularemia in an endemic region, and to identify distinguishing characteristics between confirmed and suspected cases. A retrospective study was conducted at a tertiary referral center between 2011 and 2025, including pediatric patients evaluated for suspected tularemia. Cases were classified as tularemia positive or negative (control) based on microbiological and serological criteria. Demographic, clinical, laboratory, and radiological data, along with treatment approaches, were compared between groups. Statistical analyses were performed using appropriate tests according to data distribution, with p < 0.05 considered statistically significant. A total of 71 patients were included (31 tularemia, 40 controls). Rural residence was significantly more common among patients with tularemia (80.0% vs. 55.0%, p = 0.029). Submandibular lymphadenopathy (60.7% vs. 34.7%), nodal necrosis (25.8% vs. 2.5%), and hypoechoic lymph nodes (30.0% vs. 10.0%) were observed more frequently in the tularemia group, whereas conglomerated lymph nodes were more common among tularemia-negative patients (17.2% vs. 47.5%) (all p < 0.05). Patients with tularemia had higher leukocyte, neutrophil, lymphocyte, platelet counts, erythrocyte sedimentation rate levels, and lower albumin concentrations (all p < 0.05). Aminoglycosides were the most frequently administered antimicrobial agents after diagnosis (64.5%), whereas beta-lactam antibiotics were commonly prescribed before tularemia was recognized (74.2%). Surgical intervention was required in more than half of the patients (58.1%). Reactive (60%) and EBV-associated lymphadenopathy (12.5%) constituted the most common final diagnoses among tularemia-negative cases. Tularemia should be considered in children with cervical lymphadenopathy and oropharyngeal symptoms in endemic regions, particularly those with rural residence. Submandibular involvement, necrotic and hypoechoic lymph nodes, and a lower tendency for conglomeration may help distinguish tularemia from other causes of cervical lymphadenopathy. Early recognition and appropriate antimicrobial therapy may reduce the need for surgical intervention.
2026-07-15 | Aminoglycosides: Is there an effective alternative in severe tularaemia? A case series.
Severe pulmonary tularaemia is rare, and evidence guiding optimal antimicrobial treatment remains limited. Although aminoglycosides are commonly recommended, their toxicity profile and practical limitations may complicate treatments. The purpose of this case series was to describe clinical outcomes in adult patients with severe pulmonary tularaemia caused by Francisella tularensis who were treated with fluoroquinolones or tetracyclines.; METHODS: We retrospectively describe six adult patients with severe pulmonary tularaemia. Clinical presentation, antimicrobial treatment, and clinical and radiological outcomes were reviewed, with a focus on response to targeted therapy with fluoroquinolones or tetracyclines.; RESULTS: All six patients achieved complete clinical and radiological recovery following targeted antimicrobial therapy with either fluoroquinolones or tetracyclines despite severe pulmonary disease.; CONCLUSION: This case series provides consistent real-world evidence that fluoroquinolones and tetracyclines can achieve favourable outcomes in severe pulmonary tularaemia. These findings highlight their potential role as alternative treatment strategies and contribute meaningful data to the ongoing discussion on optimal antimicrobial management of tularaemia.
2026-07-14 | Pulmonary tularemia leading to a relapse of tularemia orchitis in a patient on TNF-alpha inhibitor.
Tularemia represents a zoonotic infection that poses particular diagnostic and therapeutic challenges in immunocompromised patients. We present a rare case of tularemia orchitis in a patient receiving tumor necrosis factor alpha (TNF alpha) inhibitor treatment. We conducted a case analysis of a 71-year-old farmer receiving adalimumab for psoriatic arthritis who developed sequential pulmonary and genitourinary manifestations of tularemia. Clinical presentation, laboratory findings, microbiological identification through culture and polymerase chain reaction testing, imaging studies, and histopathological examination were documented. Treatment response and clinical follow-up were monitored throughout the disease course. The patient initially presented with pneumonic tularemia confirmed by positive blood cultures. Following apparent clinical resolution with doxycycline therapy, he developed orchitis 3 months later requiring unilateral orchiectomy. Polymerase chain reaction testing confirmed Francisella tularensis as the causative pathogen in testicular tissue. Histological examination revealed dense inflammatory infiltration with histiocytes, neutrophils, and T‑lymphocytes. Combination therapy with doxycycline and ciprofloxacin achieved clinical remission, although fluoroquinolone-induced peripheral neuropathy necessitated treatment modification. Patients receiving tumor necrosis factor alpha inhibitors demonstrate increased susceptibility to tularemia manifestations and potential disease relapse. The blood-testis barrier may limit antibiotic penetration, contributing to treatment failure with monotherapy. Enhanced clinical awareness and consideration of combination antimicrobial therapy may be warranted in immunocompromised patients with tularemia, particularly those residing in endemic regions.
2026-06-20 | Severe pneumonic tularemia following inhalational exposure with acute respiratory distress syndrome and multiorgan failure.
A man in his early 70s presented with septic shock and severe ARDS, likely after aerosolising Francisella tularensis Initial empirical treatment for community-acquired pneumonia with ceftriaxone failed, resulting in clinical deterioration with stage 3 acute kidney injury requiring dialysis and necrotising pneumonia. After pneumonic tularaemia was identified, antimicrobial therapy was transitioned to renally dosed levofloxacin, along with aggressive ICU support including prone positioning and tube thoracostomy. The patient ultimately made a full recovery, returning to his functional baseline one month after discharge.This case underscores the importance of eliciting environmental exposures in patients with severe, culture-negative pneumonia unresponsive to beta-lactams, as this should prompt consideration of inhalational tularaemia. It also highlights how pathogen-induced cytokine storm can drive catastrophic multiorgan failure and supports fluoroquinolones as a safe and effective first-line alternative to aminoglycosides in the setting of renal failure.
vaccines
2026-09-29 | Immunopeptidomics reveals conserved and abundant Francisella tularensis proteins as immunogenic CD4 T cell antigens in mice.
Human tularemia is caused by infection with the intracellular bacterium Francisella tularensis. The ability of the bacterium to cause a severe pneumonic form of the disease has led to concerns in the field of biodefense and efforts to develop a vaccine. F. tularensis LVS provides partial protection against fully virulent strains, with CD4+ T cells playing a significant role in this protection, however the recognized bacterial antigens remain largely unknown. To identify these antigens, we screened MHC class II peptides presented by infected dendritic cells using mass spectrometry-based immunopeptidomics. We identified 57 MHC-II peptides from 23 different F. tularensis LVS proteins. Most of these proteins were highly expressed in the bacterial proteome. Subsequent screening for IFN-γ responses identified ten peptides as immunogenic epitopes of CD4+ T cells following immunization of mice with F. tularensis LVS, thereby revealing previously unknown specificity and breadth of the induced immune responses. Five epitopes, derived from the antigens FTL_1678, DacD, DnaK, FTL_1498, and MinD, represented the dominant epitopes that elicited a response in at least 80% of immunizations. Finally, a peptide vaccine containing these epitopes proved to be immunogenic in mice and contributed to the early control of bacterial replication following challenge with the virulent F. tularensis FSC200 strain, although this alone was insufficient to ensure complete protection. Using immunopeptidomics, we have thus identified several immunogenic CD4+ T cell epitopes and antigens of F. tularensis LVS. Beyond their potential role in the protective immune response, the identified epitopes may also enable the development of tools for characterizing antigen-specific CD4+ T cells in vaccination studies or T cell biology research.
2026-09-15 | Biopolymer-Antigen Conjugate Vaccines for Prevention of Tularemia
Abstract Francisella tularensis, the causative agent of tularemia, is a facultative intracellular pathogen categorized as a tier I bioterrorism agent. The current live vaccine strain (LVS) vaccine poses safety and virulence concerns, advocating the need for a safer alternative. In this study, we demonstrated a combination of antigens FopA, Tul4, SucB, and DnaK conjugated to biopolymer particles (BPs) as a multivalent subunit vaccine that not only induces LVS and SchuS4-specific antibody titers but also confers protective immunity with differential cytokine profiles upon LVS challenge. This multivalent vaccine conferred 80% survival in mice, with antibodies of opsonizing ability and rapid recovery from weight loss. The production of these biopolymer conjugate vaccines was achieved in one step inside engineered Escherichia coli and is not only cost-effective but also leads to thermostable formulations, eliminating the need for cold-chain transport and storage. E. coli fermentation-based production avoids the need for high-containment facilities. Collectively, the FopA-BP-Tul4, SucB-BP, and Dnak-BP combined formulations hold the promise for the development of a robust subunit vaccine for the prevention of tularemia.
2026-08-14 | Transcriptional analyses of peripheral blood lymphocytes obtained shortly after primary immunization discriminate vaccines against Francisella tularensis.
The high virulence and pathogenesis of Francisella tularensis (Ft), responsible for tularemia, made it a target for bioweapon development during the "Cold War." This prompted investigation of vaccines, starting with an older vaccine candidate denoted Ft live vaccine strain (LVS). LVS has limited efficacy against aerosol challenge with Ft subsp. Tularensis (Type A), the most virulent subtype. However, no vaccines, including LVS, have been licensed in the U.S. Animal studies indicate that Ft vaccines induce protective T-cell-mediated immune responses. In previous studies, analyses of leukocytes from vaccinated animals that were restimulated in vitro facilitated screening and selection of vaccines for more extensive in vivo evaluation. These studies demonstrated that a novel live attenuated vaccine strain derived from Type A Ft, denoted ΔclpB, was protective against aerosol challenge in animal models. In this study, we focused on evaluating immune responses immediately after vaccination of Fischer 344 rats with LVS and ΔclpB using multiple analytical approaches. While humoral immune responses were comparable between the two vaccines, we identified multiple differences in immune responses by analyses of peripheral blood leukocytes by flow cytometry and by relative gene expression. In particular, vaccination with LVS or ΔclpB resulted in differential expression of multiple genes at selected time points. Gene expression, in turn, predicted activation or inhibition of multiple biological pathways. These results suggest that immune responses shortly after primary vaccination may discriminate vaccines with different degrees of in vivo protection that could potentially be used as correlates of protection and extrapolate efficacy from animals to people.
2026-07-27 | Potential Roles of Gamma-Delta T Cells in a Bacterial Immun-Ization Model.
Background/Objective: Francisella tularensis is a highly infectious intracellular pathogen that causes severe pulmonary tularemia following aerosol exposure, yet no licensed vaccine exists. Because infection initiates at the respiratory mucosa, understanding mechanisms of protective pulmonary immunity is critical for mucosal vaccine development. This study investigated the role of lung-resident γδ T cells following intranasal immunization with inactivated F. tularensis (iFt) and subsequent lethal challenge with live vaccine strain (LVS). Methods: Mice were intranasally immunized with iFt and later challenged with lethal LVS. Pulmonary immune responses were evaluated using flow cytometry and cytokine analysis. Recruitment of γδ and αβ T cells, production of IL-17 and IFN-γ, neutrophil infiltration, and γδ T cell memory phenotypes were assessed in naïve and immunized mice following infection. Results: Primary LVS infection induced rapid recruitment of γδ T cells to the lung beginning on Day 2 post-infection, preceding significant αβ T cell accumulation. Increased pulmonary IL-17 and IFN-γ correlated with expansion of IL-17- and IFN-γ-associated γδ T cell populations. Following iFt immunization, mice demonstrated enhanced survival after lethal LVS challenge, accompanied by early increases in pulmonary IL-17 and IL-17 producing γδ T cells. Immunized mice also exhibited expansion of effector memory and central memory γδ T cell populations associated with IL-17 production. Conclusions: These findings identify IL-17 producing γδ T cells as contributors to early mucosal immunity following intranasal vaccination against F. tularensis and suggest that targeting lung-resident γδ T cells may support the development of next-generation mucosal vaccines against respiratory pathogens.
2026-06-21 | Designing of a conserved subunit multiepitope vaccine candidate against Francisella tularensis Schu S4 using immunoinformatics.
Francisella tularensis Schu S4 is the most virulent strain responsible for tularemia, a highly infectious zoonotic disease. Despite its potential as a pathogen of concern, no effective vaccine has been developed for this pathogen. In this study, two multi-epitope subunit vaccine candidates were designed targeting the virulence factors DacD and DsbA to reduce disease severity caused by F. tularensis Schu S4. Using a comprehensive immunoinformatics approach, the most efficient B- and T-cell epitopes were identified from conserved sequences and linked with adjuvants and linkers to generate two vaccine constructs. These constructs were modeled, refined, and validated through molecular docking against Toll-Like Receptors (TLRs) and MHC alleles, followed by 200 ns molecular dynamics simulations. Their immunogenic potential and expression efficiency were further evaluated through immune simulations and computational cloning into the pET30a( +) vector. Both the constructed vaccine candidates, TulaVac1 and TulaVac2, showed high antigenicity, immunogenicity, stability, and solubility. The epitope conservancy was nearly 100%, with global population coverage rates of 73.19% and 99.74% for MHC class I and II epitopes, respectively. Docking analyses revealed six CTL epitopes with binding energies of ≤ -9.0 kcal/mol, while vaccine-TLR and MHC docking suggested superior performance of TulaVac1. MM/GBSA analysis yielded favorable binding energies ranging from - 87.22 to - 161.30 kcal/mol, MD simulations confirmed the stable interaction for 200 ns, and immune simulations showed robust immune responses with satisfactory codon adaptation. These findings position TulaVac1 and TulaVac2 as promising candidates for effective prophylaxis against tularemia.
proteins
2025-12-17 | Activation of B1 B cells by F. tularensis atypical LPS depends on classical complement and C3a.
Francisella tularensis (Ft), a Gram-negative bacterium that causes tularemia, possesses a non-inflammatory atypical LPS (LPSFt) that is highly immunogenic through unknown mechanism. We previously showed that immunization with LPSFt, a type 2 T-independent (TI) antigen, elicits protective LPSFt-specific IgM (IgMFt) and IgG3Ft by B1 cells in a mechanism dependent on the IL-5 produced by innate lymphoid cells type 2 (ILC2). Here, we examined the role of complement in the B1 cells' response against LPSFt. C3-/-, C1q-/- and C4-/- mice immunized with LPSFt failed to produce IgMFt and IgG3Ft. In contrast, the response of Cfb-/- and Mbl1/Mbl2-/- mice was comparable to that of WT mice. Thus, activation of the classical complement cascade, but not the alternative or the Mannose Binding Lectin pathway, is required for activation of B1 cells and production of LPSFt-specific antibodies. Complement activation generates the C3d fragment, which opsonizes antigens for recognition by complement receptor-2 (CR2), and the C3a and C5a anaphylatoxins. Our results show that C3d opsonized LPSFt and that the response to immunization was dependent on CR2 expression by B1 cells. Importantly, the response to LPSFt immunization was also drastically decreased in C3ar1-/-, but not in C5ar1-/- mice. C3a induced IL-5 in ILC2, which supported B1 cells activation. Decreased antibody production in C3ar1-/- and Cr2-/- mice correlated with increased susceptibility to tularemia. Together, these results demonstrate that the high immunogenicity of LPSFt depends on two effector mechanisms triggered by activation of the classical complement pathway: 1) tagging of LPSFt with C3d fragment, leading to its interaction with CR2 expressed by B1 cells; 2) production of the anaphylatoxin C3a that stimulated IL-5 secretion by ILC2. Our study increases our understanding of the B1 cells' response to TI-2 antigens and identifies two complement effector mechanisms that can be harnessed for therapeutic interventions.
2025-10-21 | De Novo Design of High‐Affinity Miniprotein Binders Targeting Francisella Tularensis Virulence Factor
Abstract Francisella tularensis poses considerable public health risk due to its high infectivity and potential for bioterrorism. Francisella‐like lipoprotein (Flpp3), a key virulence factor unique to Francisella, plays critical roles in infection and immune evasion, making it a promising target for therapeutic development. However, the lack of well‐defined binding pockets and structural information on native interactions has hindered structure‐guided ligand discovery against Flpp3. Here, we used a combination of physics‐based and deep‐learning methods to design high‐affinity miniprotein binders targeting two distinct sites on Flpp3. We identified four binders for site I with binding affinities ranging between 24–110 nM. For the second site, an initial binder showed a dissociation constant ( K D ) of 81 nM, and subsequent site saturation mutagenesis yielded variants with sub‐nanomolar affinities. Circular dichroism confirmed the topology of designed miniproteins. The X‐ray crystal structure of Flpp3 in complex with a site I binder is nearly identical to the design model (Cα root‐mean‐square deviation (RMSD): 0.9 Å). These designed miniproteins provide research tools to explore the roles of Flpp3 in tularemia and should enable the development of new therapeutic candidates.
2025-07-09 | De novo design of high-affinity miniprotein binders targeting Francisella tularensis virulence factor.
Francisella tularensis poses considerable public health risk due to its high infectivity and potential for bioterrorism. Francisella-like lipoprotein (Flpp3), a key virulence factor unique to Francisella, plays critical roles in infection and immune evasion, making it a promising target for therapeutic development. However, the lack of well-defined binding pockets and structural information on native interactions has hindered structure-guided ligand discovery against Flpp3. Here, we used a combination of physics-based and deep-learning methods to design high-affinity miniprotein binders targeting two distinct sites on Flpp3. We identified four binders for site I with binding affinities ranging between 24-110 nM. For the second site, an initial binder showed a dissociation constant (K D ) of 81 nM, and subsequent site saturation mutagenesis yielded variants with sub-nanomolar affinities. Circular dichroism confirmed the topology of designed miniproteins. The X-ray crystal structure of Flpp3 in complex with a site I binder is nearly identical to the design model (Cα root-mean-square deviation: 0.9 Å). These designed miniproteins provide research tools to explore the roles of Flpp3 in tularemia and should enable the development of new therapeutic candidates.
2025-07-02 | Treatment of bacterial biothreat agents with a novel purified bioactive lactoferrin affects both growth and biofilm formation.
Lactoferrin is known to exhibit broad spectrum activity against a multitude of bacteria, fungi, and viruses due to its multi-functional mode of action. Recently, Lactea Therapeutics and its affiliates have developed a novel, patent-pending technology to purify naturally derived bovine lactoferrin (Lactea Lf) for use as a medical countermeasure that was not previously available. To assess the efficacy of Lactea Lf against biothreat pathogens, we performed biofilm inhibition assays and generated dose-response curves against Burkholderia pseudomallei, Burkholderia mallei, and Francisella tularensis for proof-of-principle studies. Here, we show that Lactea Lf can significantly inhibit biofilm and decrease the overall growth in a dose dependent manner for all Burkholderia species tested. Of note, Lactea Lf was found to completely inhibit biofilm formation by virulent B. pseudomallei without observing complete growth inhibition. The growth of F. tularensis was also significantly inhibited when cultured in the presence of Lactea Lf and appeared more sensitive to treatment when compared to B. pseudomallei. Based on these results, a pneumonic infection model using the F. tularensis LVS strain was performed prophylactically administering Lactea Lf and continuing treatment post challenge. No protection was observed in this model which prompted biodistribution studies using fluorescent tagged Lactea Lf. These experiments revealed that therapeutic material was mainly confined to the NALT region following intranasal delivery and then quickly dispersed or inactivated suggesting that future formulation and delivery method could be addressed to increase in vivo treatment efficacy. Taken together, these data support that Lactea Lf is a potentially new candidate for further studies as a broad-spectrum antimicrobial medical countermeasure with efficacy against several high priority biodefense-related bacterial pathogens.
2023-04-03 | IL-12p40 is essential but not sufficient for Francisella tularensis LVS clearance in chronically infected mice.
IL-12p40 plays an important role in F. tularensis Live Vaccine Strain (LVS) clearance that is independent of its functions as a part of the heterodimeric cytokines IL-12p70 or IL-23. In contrast to WT, p35, or p19 knockout (KO) mice, p40 KO mice infected with LVS develop a chronic infection that does not resolve. Here, we further evaluated the role of IL-12p40 in F. tularensis clearance. Despite reduced IFN-γ production, primed splenocytes from p40 KO and p35 KO mice appeared functionally similar to those from WT mice during in vitro co-culture assays of intramacrophage bacterial growth control. Gene expression analysis revealed a subset of genes that were upregulated in re-stimulated WT and p35 KO splenocytes, but not p40 KO splenocytes, and thus are candidates for involvement in F. tularensis clearance. To directly evaluate a potential mechanism for p40 in F. tularensis clearance, we reconstituted protein levels in LVS-infected p40 KO mice using either intermittent injections of p40 homodimer (p80) or treatment with a p40-producing lentivirus construct. Although both delivery strategies yielded readily detectable levels of p40 in sera and spleens, neither treatment had a measurable impact on LVS clearance by p40 KO mice. Taken together, these studies demonstrate that clearance of F. tularensis infection depends on p40, but p40 monomers and/or dimers alone are not sufficient.
other
2026-09-26 | A Tularemia cluster in Manisa, Türkiye: clinical characteristics and investigation of a probable waterborne source
Abstract Background Tularemia is a re-emerging zoonotic disease caused by Francisella tularensis. In Türkiye, water-associated transmission is an important epidemiological pattern and oropharyngeal disease is common. This study aimed to describe the clinical characteristics of a tularemia cluster identified in Manisa, western Türkiye, and to evaluate the epidemiological and environmental findings supporting a probable waterborne source. Methods This retrospective, observational, two-center study included 13 adult patients with clinically compatible tularemia and a single positive microagglutination test (MAT) titer of ≥ 1:160 diagnosed between January and May 2025. Demographic, epidemiological, clinical, laboratory, radiological, cytopathological, treatment, and outcome data were retrospectively collected. Twelve patients from Alaşehir reported natural spring-water consumption within the same local area, whereas one patient resided in Demirci and had a separate exposure history. Following recognition of the cluster, an environmental investigation was conducted under the coordination of the Provincial Directorate of Health. Results Thirteen patients were included. The median age was 33 years (range, 21–73 years), and eight (61.5%) were female. Twelve patients (92.3%) resided in rural Alaşehir and reported natural spring-water consumption within the same local area; one patient resided in Demirci and was not epidemiologically linked to that exposure. The oropharyngeal form was the most common presentation (10/13, 76.9%), followed by the glandular form (3/13, 23.1%). Cervical lymphadenopathy was present in all patients, and imaging frequently demonstrated necrosis, liquefaction, abscess formation, or surrounding soft-tissue involvement. Before referral, most patients had received antimicrobial therapy that was ineffective against tularemia. Because this was a selected tertiary-care referral cohort with persistent symptoms and/or complicated lymphadenopathy, treatment was individualized according to disease duration and clinical response; drainage was required in selected patients. All patients achieved clinical recovery. A stored natural spring-water sample obtained from a household in Alaşehir was reported culture-positive for F. tularensis by the National Reference Laboratory. Molecular confirmation or typing linking the environmental finding to the human cases was not available. Conclusions This cluster highlights the importance of considering tularemia in patients with persistent cervical lymphadenopathy and tonsillopharyngitis unresponsive to beta-lactam antibiotics, particularly in rural settings with natural spring-water exposure. The shared exposure among the Alaşehir cases and the culture-positive environmental sample support a probable waterborne source; however, the absence of direct microbiological confirmation of the human cases and molecular linkage prevents definitive attribution of the transmission chain.
2026-07-28 | MAIT17 Cells and IL-17-Driven iBALT Formation Protect Against Pulmonary Tularemia 2267799
Abstract Introduction Here we demonstrate that respiratory infection with Francisella tularensis induces the formation of induced bronchus-associated lymphoid tissue (iBALT) as a protective mechanism against pulmonary tularemia-like disease in mice. While semi-invariant natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are abundant at the lung mucosa, their roles in infectious diseases remain poorly understood. Pulmonary tularemia, the most severe form of tularemia, arises from respiratory infection with F. tularensis. Using C57BL/6 mice infected with the live vaccine strain (LVS) of F. tularensis to model tularemia-like disease, we previously showed that NKT cells exacerbate disease, as NKT-deficient CD1d⁻/⁻ mice were protected. Notably, protected CD1d⁻/⁻ mice developed iBALT structures in the lungs, which were absent in C57BL/6 mice. Methods Molecular immunology methods. Results Respiratory LVS infection in CD1d⁻/⁻ mice induced a robust expansion of IL-17-producing MAIT17 cells and a decrease in regulatory T cells in the lungs compared to C57BL/6 mice. Single-cell RNA sequencing revealed a gene signature in MAIT cells linked to factors that drive iBALT formation. Supporting this notion, adoptive transfer of LVS-activated lung MAIT cells from infected CD1d⁻/⁻ mice conferred protection against tularemia-like disease in RAG2⁻/⁻ recipients, while splenic MAIT cells did not despite the fact that both populations homed to the lungs after transfer. Lung-derived MAIT cells were enriched in IL-17-producing MAIT17 cells, whereas splenic MAIT cells predominantly consisted of interferon-gamma-producing MAIT1 cells. Last, IL-17 was identified as critical for iBALT development during respiratory LVS infection in CD1d⁻/⁻ mice. Conclusion In summary, our findings establish MAIT cells as central mediators of IL-17-dependent protection against pulmonary tularemia-like disease and underscore the potential protective role of iBALT in disease resistance. Funding Source NIH AI137082, VA Merit BX001610, VA SRCS BX004595 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
2026-03-28 | Tularemia: Historical Perspectives and Current Challenges of a Re-Emerging Zoonosis.
Tularemia is a plague-like, potentially fatal zoonosis caused by the coccobacillus Francisella tularensis. It was discovered at the beginning of the last century in the United States and was soon recognized in Japan and in the former Soviet Union as the cause of clinical conditions that had been known for one and two centuries, respectively. More than 250 animal species are susceptible to infection, with rodents and lagomorphs serving as key reservoirs, and several vectors may transmit the disease, mainly ticks and mosquitoes. Humans are incidental hosts and are infected primarily by two F. tularensis subspecies, tularensis and holarctica: the former is more severe and is found almost exclusively in North America, whereas the latter is distributed throughout the Northern Hemisphere, mainly in Europe and Asia. Tularemia is highly infectious; therefore, diagnostic cultures should be handled in biosafety level 3 laboratories. Nevertheless, interhuman transmission is exceedingly rare. Although tularemia is relatively uncommon, it shows a re-emerging pattern at the global level, particularly in Europe. As with plague, mitigation may be more effectively achieved through a One Health approach. Neither approved vaccines nor therapeutic antibodies are currently available, whereas aminoglycoside, tetracycline, and quinolone antibiotics are effective. Owing to its high infectivity, its ease of transmission by inhalation, its clinical severity, with a prolonged and debilitating course, and its potential lethality, F. tularensis has long been considered a potential biological weapon, particularly if antibiotic-resistant strains were used. Although natural antibiotic resistance has not been described to date, research programs aimed at obtaining resistant strains have been conducted. It has been suggested that the disease was already present in the Middle East during the second millennium BC; should this hypothesis be confirmed by paleogenomic studies, plague and tularemia would have coexisted for more than three millennia, with plague masking the less severe tularemia. Many challenges related to tularemia are still unresolved.
2026-01-21 | Behind the COVID-19 Curtain: A Rare Case of Autochthonous Pneumonic Tularemia in Portugal.
The presence of Francisella tularensis has been well documented in Portugal; however, reports of human infection remain rare. We report the case of a 63-year-old woman presenting with pneumonia and SARS-CoV-2 infection. The relapsing course of infection, partial response to fluoroquinolone and macrolide antibiotics, and epidemiological background led to the suspicion of an underlying zoonotic disease. Serology later confirmed F. tularensis infection, and the patient improved under directed therapy. To the best of our knowledge, this is the first case of autochthonous pneumonic tularemia reported in Portugal.
2026-01-01 | MODERN ASPECTS OF TULAREMIA EPIDEMIOLOGY IN THE RUSSIAN FEDERATION
The analysis of the incidence of tularemia in the Russian Federation in 2024 was conducted, including age and gender characteristics, occupational and social structure of patients, clinical forms and severity of the disease. Based on this research, the modern clinical and epidemiological features of tularemia were identified and the relevance of this infection was confirmed.
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Drug Discovery Landscape
2 orphan drug designations for Tularemia.
2 orphan drug designations for Tularemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
1-(4-(N-glycylamido)phenyl)-3-trifluoromethyl-5-(phenanthren-2-yl)-pyrazole-hydrochloride | small molecules | EMA | — | Arno Therapeutics UK, Limited |
cethromycin | small molecules | FDA | — | Advanced Life Sciences, Inc. |
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