RARE DISEASE
Rocky Mountain spotted fever
Rocky Mountain spotted fever
Rocky Mountain spotted fever
Drug discovery
0
drugs
With orphan designations
Overview
Rocky Mountain spotted fever (RMSF) is a tick-borne illness caused by Rickettsia rickettsii, characterized by fever, headache, rash, and potential progression to severe vascular injury, organ failure, or death. Early diagnosis is challenging due to nonspecific initial symptoms, but prompt treatment with doxycycline—initiated empirically upon clinical suspicion—significantly reduces mortality (5–10% in the U.S., higher in endemic regions) [1][13][17].
Population
Most common in southeastern/south-central U.S. (e.g., North Carolina, Tennessee) and parts of Mexico/South America [1][13][17].
Higher incidence in males, individuals >40 years, and American Indian populations [1][4][5].
High-risk groups: children (5–9 years) and older adults (60–69 years) [5][7][17].
Burden
Incidence: ~6,000 U.S. cases/year, rising since 2000 due to diagnostic/surveillance changes [1][7][19].
Complications: 0.5–7% fatality (treated), with residual neurological deficits, amputations, or organ damage in severe cases [1][12][13].
Economic impact: Hospitalization, ICU needs, and long-term care for survivors drive healthcare costs [4][13][17].
Therapies
First-line: Doxycycline (100 mg BID adults; 2.2 mg/kg BID children <45 kg) for ≥5–7 days or 3 days post-fever resolution [3][6][11].
Timing: Mortality drops with early initiation (<5 days of symptoms); delays correlate with fatal outcomes [4][6][13].
Alternatives: Chloramphenicol (less effective, limited availability); no role for non-tetracyclines [1][3][8].
Categories: rare infectious diseases
Research Papers
217 drug discovery papers about Rocky Mountain spotted fever, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
217 drug discovery papers about Rocky Mountain spotted fever, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2023-07-31 | Identification of an autotransporter peptidase of Rickettsia rickettsii responsible for maturation of surface exposed autotransporters
Members of the spotted fever group rickettsia express four large, surface-exposed autotransporters, at least one of which is a known virulence determinant. Autotransporter translocation to the bacterial outer surface, also known as type V secretion, involves formation of a β-barrel autotransporter domain in the periplasm that inserts into the outer membrane to form a pore through which the N-terminal passenger domain is passed and exposed on the outer surface. Two major surface antigens of Rickettsia rickettsii , are known to be surface exposed and the passenger domain cleaved from the autotransporter domain. A highly passaged strain of R . rickettsii , Iowa, fails to cleave these autotransporters and is avirulent. We have identified a putative peptidase, truncated in the Iowa strain, that when reconstituted into Iowa restores appropriate processing of the autotransporters as well as restoring a modest degree of virulence.
2018-07-31 | Th1 epitope peptides induce protective immunity against Rickettsia rickettsii infection in C3H/HeN mice.
Rickettsia rickettsii is the causative pathogen of Rocky Mountain spotted fever (RMSF). Adr2, YbgF and OmpB are protective antigens of R. rickettsii. In this study, 90 candidate peptides were selected from these antigens based on their high-affinity binding capacity for the MHC class II molecule H2 I-A or H2 I-E using bioinformatic methods. Six peptides were determined using ELISPOT assay to be immunodominant based on the IFN-γ recall responses of CD4+ T cells from mice immunized with R. rickettsii. Six nucleotide sequences encoding the immunodominant peptides were linked in series and inserted into a plasmid for expression in Escherichia coli cells, resulting in a new, recombinant polypeptide termed GWP. After immunization and challenge, the rickettsial load or histopathological lesions in the organs of mice immunized with GWP or pooled peptides was significantly lower than that in organs of mice immunized with PBS or the individual peptide OmpB399. An in vitro neutralization test revealed that sera from mice immunized with GWP, OmpB399, or pooled peptides reduced R. rickettsii adherence to, and invasion of, vascular endothelial cells. Furthermore, significantly higher levels of IgG, IgG1, or IgG2a were detected in sera from mice immunized with GWP or pooled peptides, and significantly higher levels of IFN-γ or TNF-α secreted by CD4+ T cells from R. rickettsii-infected mice were detected after immunization with GWP. Altogether, our results indicated that polypeptides, especially GWP, could induce a Th1-type immune response against R. rickettsii infection, which might contribute to the rational design of peptide-based vaccines for RMSF.
2017-03-01 | The Rickettsia conorii Adr1 Interacts with the C-Terminus of Human Vitronectin in a Salt-Sensitive Manner
Spotted fever group (SFG) Rickettsia species are inoculated into the mammalian bloodstream by hematophagous arthropods. Once in the bloodstream and during dissemination, the survival of these pathogens is dependent upon the ability of these bacteria to evade serum-borne host defenses until a proper cellular host is reached. Rickettsia conorii expresses an outer membrane protein, Adr1, which binds the complement inhibitory protein vitronectin to promote resistance to the anti-bacterial effects of the terminal complement complex. Adr1 is predicted to consist of 8 transmembrane beta sheets that form a membrane-spanning barrel with 4 peptide loops exposed to the extracellular environment. We previously demonstrated that Adr1 derivatives containing either loop 3 or 4 are sufficient to bind Vn and mediate resistance to serum killing when expressed at the outer-membrane of E. coli. By expressing R. conorii Adr1 on the surface of non-pathogenic E. coli, we demonstrate that the interaction between Adr1 and vitronectin is salt-sensitive and cannot be interrupted by addition of heparin. Additionally, we utilized vitroenctin-derived peptides to map the minimal Adr1/vitronectin interaction to the C-terminal region of vitronectin. Furthermore, we demonstrate that specific charged amino acid residues located within loops 3 and 4 of Adr1 are critical for mediating resistance to complement-mediated killing. Interestingly, Adr1 mutants that were no longer sufficient to mediate resistance to serum killing still retained the ability to bind to Vn, suggesting that Adr1-Vn interactions responsible for resistance to serum killing are more complex than originally hypothesized. In summary, elucidation of the mechanisms governing Adr1-Vn binding will be useful to specifically target this protein-protein interaction for therapeutic intervention.
2016-08-08 | Intravenous Immunoglobulin Therapy for Cerebral Vasculitis Associated with Rocky Mountain Spotted Fever
Rocky Mountain spotted fever is a tick-borne illness that is prevalent in the south and the central United States, primarily during the summer months. Patients with delayed diagnosis can experience increased mortality and morbidity, particularly poor neurological outcome. We present a case of a 7-year-old girl with Rocky Mountain spotted fever who was admitted with severe neurological changes and septic shock on day 8 of illness. She was initially diagnosed with Kawasaki disease and treated with intravenous immunoglobulin. Her treatment also included doxycycline, vancomycin, and ceftriaxone due to concerns regarding Rocky Mountain spotted fever and bacterial sepsis. During hospitalization, the patient required mechanical ventilation for respiratory distress, inotropic support, and fluid resuscitation for hypotension. Titers for Rocky Mountain spotted fever were ultimately positive, with magnetic resonance imaging of the brain demonstrating numerous punctate foci of restricted diffusion within the supratentorium, including the corpus callosum and basal ganglia. Although the patient presented late in the disease course, she ultimately had a good neurological outcome. We theorized that administration of intravenous immunoglobulin prevented ongoing neurological injuries from the cerebral vasculitis, which are associated with Rocky Mountain spotted fever.
2016-08-03 | Ongoing Cerebral Vasculitis During Treatment of Rocky Mountain Spotted Fever.
Rocky Mountain spotted fever is a tickborne infection that produces a systemic small-vessel vasculitis; its prognosis is excellent if appropriate treatment is initiated early. Because the advent of effective antirickettsial therapies predates the widespread use of brain magnetic resonance imaging, there are limited data on the effect of untreated Rocky Mountain spotted fever infection on neuroimaging studies. We describe a 7-year-old girl with delayed treatment of Rocky Mountain spotted fever who suffered severe neurological impairment. Serial brain magnetic resonance images revealed a progressive "starry sky appearance," which is proposed to result from the same small vessel vasculitis that causes the characteristic skin rash of this infection. Neurological injury can continue to occur despite specific antirickettsial therapy in Rocky Mountain spotted fever. This child's clinical features raise questions about the optimal management of this infection, particularly the utility of immune modulating therapies in cases of delayed treatment and neurological involvement.
small molecules
2026-05-18 | Rocky Mountain spotted fever
1 Rocky Mountain spotted fever (RMSF) is a severe tick-borne infection The disease is caused by Rickettsia rickettsii and is transmitted by multiple tick species including the American dog tick, Rocky Mountain wood tick, and brown dog tick. 1 Rickettsia rickettsii is considered endemic in certain regions of Canada, 2 but human cases of RMSF are rare.
2026-04-17 | Secondary Hemophagocytic Lymphohistiocytosis in a Rocky Mountain Spotted Fever Patient.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages, leading to cytokine storm and multiorgan dysfunction. Due to its nonspecific clinical presentation and high mortality, early recognition and multidisciplinary management are essential. We report the case of a 28-year-old woman admitted with fever, myalgias, arthralgias, and generalized exanthema. Initial laboratory evaluation revealed pancytopenia. Polymerase chain reaction (PCR) testing was positive for Rickettsia, and bone marrow examination demonstrated findings consistent with HLH. Despite appropriate management, the patient developed septic shock and died due to multiple complications, including multiorgan failure.
2026-01-05 | Epidemiologic Characterization and Risk Factors of Rocky Mountain Spotted Fever in Children in Northeastern Mexico: A Retrospective Cross-sectional Study (2018-2024).
Rocky Mountain spotted fever (RMSF) is a vector-borne disease with nonspecific symptoms, including fever, headache, myalgia, and exanthema, which complicates timely diagnosis and treatment. Despite its significant morbidity and mortality, epidemiological data and risk factor analyses remain scarce in Mexico. A retrospective cross-sectional study was conducted from 2018-2024 in three hospitals in northeastern Mexico. We analyzed 90 pediatric patients with confirmed rickettsiosis via polymerase chain reaction (PCR) or immunofluorescence assay (IFA). Demographic, clinical, and laboratory data were evaluated to identify independent risk factors associated with disease severity and outcomes. Statistical analyses included logistic regression, Mann-Whitney U tests, and Pearson χ2 tests (p ≤0.05). School-aged children comprised 46.6% of cases, with a predominance of females (54.4%). Key epidemiological exposures included tick bites (17.8%) and pet cohabitation (54.5%). Delayed doxycycline treatment (>5 d after symptom onset) was associated with increased mortality. Significant predictors of poor outcomes were neurological impairment (OR: 3.7, CI: 1.9-7.3), shock upon admission (OR: 4.5, CI: 2.2-9.1), and thrombocytopenia (p < 0.001). The overall mortality rate was 36.7%. Our findings underscore the significant clinical impact of rickettsioses in northeastern Mexico and the need to improve diagnostic capabilities, raising public awareness, and implementing effective vector control programs. Early recognition and timely doxycycline treatment are crucial to improving patient outcomes. Strengthening public health strategies through preventive measures and clinician education could reduce the morbidity and mortality associated with these infections.
2026-01-01 | NNDSS - Table II. Spotted Fever Rickettsiosis to Syphilis
NNDSS - Table II. Spotted Fever Rickettsiosis to Syphilis - 2017. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding year), and selected low frequency diseases are displayed. The Table includes total number of cases reported in the United States, by region and by states, in accordance with the current method of displaying MMWR data. Data on United States exclude counts from US territories. Note: These are provisional cases of selected national notifiable diseases, from the National Notifiable Diseases Surveillance System (NNDSS). NNDSS data reported by the 50 states, New York City, the District of Columbia, and the U.S. territories are collated and published weekly as numbered tables printed in the back of the Morbidity and Mortality Weekly Report (MMWR). Cases reported by state health departments to CDC for weekly publication are provisional because of ongoing revision of information and delayed reporting. Case counts in this table are presented as they were published in the MMWR issues. Therefore, numbers listed in later MMWR weeks may reflect changes made to these counts as additional information becomes available. Footnotes: C.N.M.I.: Commonwealth of Northern Mariana Islands. U: Unavailable. —: No reported cases. N: Not reportable. NN: Not Nationally Notifiable. NP: Nationally notifiable but not published. Cum: Cumulative year-to-date counts. Med: Median. Max: Maximum. *Three low incidence conditions, rubella, rubella congenital, and tetanus, are in Table II to facilitate case count verification with reporting jurisdictions. † Case counts for reporting year 2017 are provisional and subject to change. For further information on interpretation of these data, see http://wwwn.cdc.gov/nndss/document/ ProvisionalNationaNotifiableDiseasesSurveillanceData20100927.pdf. Data for tuberculosis are displayed in Table IV, which appears quarterly. § Illnesses with similar clinical presentation that result from Spotted Fever Group Rickettsia infections are reported as Spotted Fever Rickettsioses. Rocky Mountain Spotted Fever (RMSF), caused by Rickettsia rickettsii, is the most common and well-known Spotted Fever. Read less
2026-01-01 | Scoping Review on Rocky Mountain Spotted Fever
A scoping review was prioritized to identify and characterize the global literature on Rocky Mountain Spotted Fever.
vaccines
2026-03-25 | Effects of exposure to Rickettsia bellii on reservoir competence of guinea pigs for Rickettsia rickettsii.
Amblyomma sculptum is the main vector implicated in the transmission of Rickettsia rickettsii in southeastern Brazil, where capybaras are known to be the main amplifying hosts of this pathogen. Interestingly, many areas inhabited by large populations of capybaras and A. sculptum remain free of R. rickettsii, suggesting that other drivers may be involved in the pathogen perpetuation. A. sculptum frequently occurs in sympatry with Amblyomma dubitatum ticks, sharing the same hosts with them. Considering that A. dubitatum ticks are frequently infected with Rickettsia bellii, a possible interference of R. bellii in the reservoir competence of capybaras for R. rickettsii could explain the heterogeneous distribution of R. rickettsii in A. sculptum populations in southeastern Brazil. The present study aimed to evaluate the effect of primary exposure to R. bellii-infected A. dubitatum on the reservoir competence for R. rickettsii using guinea pigs as experimental models. Three guinea pigs were infested with R. bellii-infected A. dubitatum (Group GB), four guinea pigs with uninfected A. dubitatum (Group GD), and three guinea pigs were not exposed to A. dubitatum (Group GC). After infestation with A. dubitatum, all guinea pigs were exposed to one single R. rickettsii-infected A. sculptum female and then were infested with uninfected A. sculptum larvae. After ecdysis, nymphs were tested for detection of spotted fever group rickettsiae. Five out of six guinea pigs from GD and GC groups died, while one out of three guinea pigs in the GB group had a fatal outcome. R. rickettsii infection rate among ticks fed on animals from GB group was 21% (17/80), significantly lower than the rate of 54% (60/111) recorded in ticks fed on animals from GD and GC groups. Prior exposure of guinea pigs to R. bellii-infected A. dubitatum ticks reduced their reservoir competence for R. rickettsii.
2025-10-29 | Rickettsia rickettsii inactivated whole cell antigen vaccine protects against Rocky Mountain spotted fever independent of the adjuvant used.
Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii is the most fatal tick-borne disease in people and dogs in the Americas. This pathogen is transmitted by several hard ticks: Dermacentor species, Rhipicephalus sanguineus, and Amblyomma americanum. RMSF can quickly progress to a life-threatening illness with fatalities ranging from 30% to 80%. Doxycycline is the only treatment option, and currently, no methods are available to prevent RMSF. We previously reported that vaccination with R. rickettsii whole cell antigen vaccine (WCAV) with Montanide gel adjuvant offers protection against virulent R. rickettsii infection in dogs. Here, we compared three adjuvants to optimize the safety and immunogenicity of WCAV: Alhydrogel, Montanide, and Quil A. Independent of adjuvants, all vaccinees were protected, whereas unvaccinated dogs developed the clinical disease. Vaccination reduced the pathogen to undetectable levels in blood and various tissues. An R. rickettsii-specific IgG response was observed following primary vaccination in all vaccinated groups, which augmented after booster. The vaccine with Quil A had the highest IgG response with a significant rise in CD4+ and CD8+ T cell numbers, while Montanide and Alhydrogel resulted in a balanced IgG response. IgG2 was the primary antibody detected in unvaccinated infection controls. Several systemic proinflammatory cytokines varied after infection in both vaccinees and controls. Plasma concentration of intercellular adhesion molecule 1 was higher in unvaccinated compared to vaccinees in the first 9 days after infection. This study demonstrates that the WCAV efficacy is independent of the adjuvant, although Quil A induced a higher IgG response and expansion of CD4 and CD8 T cells.
2025-03-26 | In silico construction of a multi-epitope vaccine (RGME-VAC/ATS-1) against the Rickettsia genus using immunoinformatics.
Rickettsia is a genus of Gram-negative bacteria that causes various diseases, including epidemic typhus, Rocky Mountain spotted fever, and Mediterranean spotted fever. Ticks transmit these diseases and commonly found in developing regions with poor sanitation. As a result, it is difficult to estimate the number of these diseases cases, making it challenging to create prevention and diagnostic mechanisms. Thus, this study aimed to develop an in silico multi-epitope vaccine against Rickettsia. Eight proteins were previously identified as potential vaccine candidates through reverse vaccinology and were screened for epitopes that bind to MHC class I and II molecules. The epitopes were then analysed for antigenicity, allergenicity, and toxicity. The selected epitopes were linked with AAY and GPGPG sequences peptide and a known adjuvant, the B-chain of Escherichia coli heat-labile enterotoxin, to form a chimeric multi-epitope protein. The protein's three-dimensional structure was predicted, and molecular docking analysis was performed against the toll-like receptor 4 (TLR4). Finally, the immune response to the protein was simulated using C-ImmSim tool. A total of 26 immunogenic epitopes, formed the multi-epitope vaccine RGME-VAC/ATS-1. The vaccine showed excellent immunogenic parameters and was predicted to do not be toxic or allergenic to the host. It also showed good potential stimulation of immune cells, with a propensity to generate memory cells and elicit IFN-γ secretion. The in silico validations suggest that our study successfully designed an innovative multi-epitope vaccine against Rickettsia, addressing the challenges posed by the elusive nature of diseases caused by this genus. We provide a promising potential for further experimental exploration and the development of targeted prevention and diagnostic strategies for these diseases.
2025-02-05 | A wolf at the door: the ecology, epidemiology, and emergence of community- and urban-level Rocky Mountain spotted fever in the Americas.
RMSF, a tickborne infection caused by Rickettsia rickettsii, produces severe and fatal disease in humans and dogs. Since the beginning of the 21st century, cases have risen dramatically, most notably in Mexico and Brazil, where outbreaks occur in urban centers including cities with populations of > 1,000,000 persons. Reported case fatality rates can exceed 50%. Factors consistent with high case fatality include lack of awareness of disease ecology, limited capacity for diagnosis, and delay in appropriate antimicrobial treatment. The emergence of urban hyperendemic foci has been leveraged by 2 distinct but similar anthropogenic events that create disproportionately high numbers of vertebrate amplifiers of R rickettsii, as well as the tick species that transmit this pathogen in proximity with dense human populations. This often occurs in neighborhoods with a highly marginalized at-risk population that includes persons in poverty and particularly children, and health management systems that are under-resourced. We discuss strategies to reduce host dog populations, particularly in Mexico, and capybaras in Brazil. We review challenges to the control of tick populations in these settings. Robust systems are required to enhance awareness of RMSF among medical practitioners and people at risk of RMSF. Public health campaigns should incorporate innovative behavioral science (eg, diverse learning models, motivational interviews, and gamification) to increase prevention and understanding within communities. While anti-Rickettsia or anti-tick vaccines will be necessary to resolve this One Health crisis, impactful implementation will require data-driven and multiple-target innovations to address challenges with hosts, ticks, medical systems, and public welfare. The companion Currents in One Health by Foley, Backus, and López-Pérez, JAVMA, March 2025, addresses helpful information for the practicing veterinarian.
2025-01-07 | Core-genome guided novel therapeutic targets identification and chimeric vaccine designing against Rickettsia rickettsii.
Rocky Mountain Spotted Fever, caused by the gram-negative intracellular bacteria Rickettsia rickettsii, is a serious tick-borne infection with a fatality rate of 20-30%, if not treated. Since it is the most serious rickettsial disease in North America, modified prevention and treatment strategies are of critical importance. In order to find new therapeutic targets and create multiepitope vaccines, this study integrated subtractive proteomics with reverse vaccinology. The core genome of R. rickettsii was investigated, resulting in the identification of seven essential, human non-homologous proteins as potential drug targets, as well as four antigenic, non-allergenic proteins suitable for vaccine development. Using conserved antigenic peptides, two chimeric vaccine constructs were developed and assessed using molecular docking, molecular dynamics simulations, principal component analysis, MM-GBSA binding free energy, and dynamic cross-correlation matrix studies. The high immunogenic potential was indicated by the vaccine designs' robust and consistent interactions with human immunological receptors. Their capacity to trigger strong humoral and cellular immunological responses was further demonstrated by in silico immune simulations. The persistent interactions of vaccine V1 and V2 with human immunological receptor demonstrated that these might have high immunogenic potential. Moreover, the identified drug targets were annotated for essential biological processes, which shed light on their therapeutic potential. The vaccine constructs were cloned and expressed in suitable systems. This study displays a comprehensive strategy for managing Rocky Mountain Spotted Fever via rational vaccine development. Further experimental research is needed to confirm the immunogenicity of the vaccines and the druggability of identified targets, establishing the path toward effective RMSF management.
antibodies
2024-05-20 | Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae.
Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species invade host cells, including MΦ, remain poorly defined. In this study, we describe a mechanism of host invasion by Rickettsia species, involving rickettsial phosphatidylserine (PS), as a ligand, and the CD300f receptor on MΦ. Using bone marrow-derived macrophages (BMDMΦ) from wild-type (WT) and CD300f-/- mice, we demonstrated that engulfment of both pathogenic R. typhi (the etiologic agent of murine typhus) and R. rickettsii (the etiologic agent of Rocky Mountain spotted fever) species as well as the non-pathogenic R. montanensis was significantly reduced in CD300f-/- BMDMΦ as compared to that of WT BMDMΦ. Furthermore, our mechanistic analysis suggests bacterial PS as the potential source for the CD300f-mediated rickettsiae engulfment by MΦ. In vivo infection studies using WT and CD300f-/- C57BL/6J mice showed that CD300f-/- animals were protected against R. typhi- or R. rickettsii-induced fatal rickettsiosis, which correlated with levels of bacterial burden detected in the spleens of mice. Adoptive transfer studies further revealed that CD300f-expressing MΦ are important mediators to control rickettsiosis in vivo. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment of rickettsiae within the host.
2019-08-14 | Rickettsia conorii O antigen is the target of bactericidal Weil-Felix antibodies.
Rickettsial diseases have long been diagnosed with serum antibodies cross-reactive against Proteus vulgaris (Weil-Felix reaction). Although Weil-Felix antibodies are associated with the development of immunity, their rickettsial target and contribution to disease pathogenesis are not established. Here, we developed a transposon for insertional mutagenesis of Rickettsia conorii, isolating variants defective for replication in cultured cells and in spotted fever pathogenesis. Mutations in the polysaccharide synthesis operon (pso) abolish lipopolysaccharide O-antigen synthesis and Weil-Felix serology and alter outer-membrane protein assembly. Unlike wild-type R. conorii, pso mutants cannot elicit bactericidal antibodies that bind O antigen. The pso operon is conserved among rickettsial pathogens, suggesting that bactericidal antibodies targeting O antigen may generate universal immunity that could be exploited to develop vaccines against rickettsial diseases.
2004-05-20 | Effect of Antibody on the Rickettsia-Host Cell Interaction
A recent study demonstrated that polyclonal antibodies to Rickettsia conorii and monoclonal antibodies to outer membrane proteins A (OmpA) and B (OmpB) provided effective, Fc-dependent, passive immunity, even in severe combined immunodeficient mice with an established infection. In order to determine the mechanism of protection, mouse endothelial and macrophage-like cell lines were infected with R. conorii that had been exposed to polyclonal antibodies, monoclonal antibodies to OmpA or OmpB, Fab fragments of the polyclonal antibodies, or normal serum or that were left untreated. At 0 h, Fc-dependent antibody enhancement of R. conorii adherence to endothelial and macrophage-like cell lines was inhibited by the presence of normal serum, suggesting Fc receptor-mediated adherence of opsonized rickettsiae. At 3 h, the opsonized rickettsiae had been internalized. After 72 h, inhibited survival of rickettsiae exposed to polyclonal antibodies or monoclonal antibodies to OmpA or OmpB was evident compared with growth of untreated and normal serum-treated and polyclonal Fab antibody-treated R. conorii. Polyclonal antibodies and an anti-OmpB monoclonal antibody inhibited the escape of R. conorii from the phagosome, resulting in intraphagolysosomal rickettsial death. At 48 h of infection, rickettsicidal activity of macrophages by opsonized rickettsiae was inhibited by NG-monomethyl-L-arginine, superoxide dismutase, mannitol, or supplemental L-tryptophan, and endothelial rickettsicidal activity against opsonized rickettsiae was inhibited by NG-monomethyl-L-arginine, superoxide dismutase, catalase, or supplemental L-tryptophan. Thus, Fc-dependent antibodies protected against R. conorii infection of endothelium and macrophages by opsonization that inhibited phagosomal escape and resulted in phagolysosomal killing mediated by nitric oxide, reactive oxygen intermediates, and L-tryptophan starvation.
2001-10-04 | Quantitative analyses of variations in the injury of endothelial cells elicited by 11 isolates of Rickettsia rickettsii.
Eleven isolates of spotted fever group rickettsiae from the blood of patients or ixodid ticks from North and South America were characterized. All isolates were identified as Rickettsia rickettsii using restriction fragment length polymorphism analysis of a 532-bp rOmpA gene fragment obtained by PCR. The ability of the R. rickettsii isolates to elicit cytopathic effects and parameters of oxidative injury were examined in cultured human EA.hy 926 endothelial cells. Cytopathic effects were determined by direct observation of infected cultures, by measuring the release of cytoplasmic lactate dehydrogenase (LDH), and by determination of intracellular pools of peroxide and reduced glutathione. Four biotypes of R. rickettsii were defined. Group I included two highly cytopathic isolates from Montana, Bitterroot and Sheila Smith, and three isolates from Maryland, North Carolina, and Brazil. These isolates rapidly damaged cells, released large amounts of cytoplasmic LDH, caused accumulation of intracellular peroxide, and depleted intracellular pools of reduced glutathione. Group II contained three isolates, two from Montana, Hlp#2 and Lost Horse Canyon, and an isolate from Colombia, which were similar to group I but caused either lower responses in LDH release or smaller changes in intracellular peroxide levels. The group III isolates, Sawtooth from Montana and 84JG from North Carolina, caused lower cellular injury by all measures. Group IV isolate Price T from Montana was the least cytopathic and caused minimal alterations of all parameters measured. Understanding the molecular basis for the varied cellular injury caused by different isolates of R. rickettsii may contribute to improved treatment of Rocky Mountain spotted fever and to the rapid identification of those isolates which are more likely to cause fulminant disease.
1985-07-11 | Characterization of monoclonal antibodies protecting mice against Rickettsia rickettsii.
Hybridomas producing monoclonal antibodies to Rickettsia rickettsii were prepared from mice to investigate the function of rickettsial antigens. Of the 31 reactive hybridoma lines thus far tested for immunoglobulin subclasses, 11 belonged to the IgG2A subclass, 9 to the IgG2B subclass, and 7 to the IgG3 subclass; four did not react with any of the isotyping sera. Five of the antibodies recognized epitopes present on molecules that were presumed to be polysaccharide and heterogeneous in molecular weight. Twenty monoclonal antibodies reacted with a 170,000-dalton antigen, and six precipitated both the 133,000- and 32,000-dalton polypeptides. Only those antibodies to the 170,000- and 133,000-dalton antigens protected mice from challenge with R. rickettsii. Antibodies to these same antigens were detected in sera from patients convalescing from Rocky Mountain spotted fever. All monoclonal antibodies reacted with antigens apparently located on the rickettsial surface. The protective activity of these antibodies was not correlated with their reactivity in complement fixation, enzyme-linked immunosorbent assay, and immunofluorescence tests.
other
2024-09-30 | Development of inducible promoter and CRISPRi plasmids functional in Rickettsia rickettsii.
Rickettsia rickettsii is an obligate intracellular, tick-borne bacterium that causes Rocky Mountain spotted fever. The demanding nature of cultivating these bacteria within host cells and the labor involved in obtaining clonal isolates have severely limited progress regarding the development of compatible genetic tools to study this pathogen. Conditional expression of genes that might be toxic or have an otherwise undesirable effect is the next logical goal to expand upon the constitutive expression plasmids generated thus far. We describe the construction of an inducible promoter system based on the tet-On system, leveraging design elements from the anhydrotetracycline-inducible promoter system used for Borrelia burgdorferi and one of the few characterized rickettsial promoters for the outer membrane gene, rompB (sca5). The functionality of this promoter is demonstrated via fluorescence of induced mScarlet production and was then used to construct a generalized inducible expression vector for R. rickettsii. The development of a functional inducible promoter was then applied to the construction of a CRISPR interference plasmid as a means to reduce or essentially silence the transcription of targeted genes. We demonstrate the viability of a simplified, single vector CRISPRi system to disrupt gene expression in R. rickettsii targeting the type IV secreted effector rarP2 and autotransporter peptidase rapL as examples. This work expands upon the genetic toolbox available for R. rickettsii. We describe both an inducible promoter and CRISPRi system compatible with Rickettsia, which may provide key instruments for the development of further tools. The development of an inducible promoter system allows for the overexpression of genes, which might be toxic when expressed constitutively. The CRISPRi system enables the ability to knock down genes with specificity, and critically, genes that may be essential and could not otherwise be knocked out. These developments may provide the foundation for unlocking genetic tools for other pathogens of the order Rickettsiales, such as the Anaplasma, Orientia, and Ehrlichia for which there are currently no inducible promoters or CRISPRi platforms.
2024-06-12 | Development of inducible promoter and CRISPRi plasmids functional inRickettsia rickettsii
ABSTRACT Rickettsia rickettsii is an obligate intracellular, tick-borne bacterium that causes Rocky Mountain spotted fever. The demanding nature of cultivating these bacteria within host cells and the labor involved in obtaining clonal isolates has severely limited progress regarding the development of compatible genetic tools to study this pathogen. Conditional expression of genes which might be toxic or have an otherwise undesirable effect is the next logical goal to expand upon the constitutive expression plasmids generated thus far. We describe the construction of an inducible promoter system based on the tet-On system, leveraging design elements from the anhydrotetracycline inducible promoter system used for Borrelia burgdorferi and one of the few characterized rickettsial promoters for the outer membrane gene, rompB ( sca5 ). The functionality of this promoter is demonstrated via fluorescence of induced mScarlet production and was then used to construct a generalized inducible expression vector for R. rickettsii . The development of a functional inducible promoter was then applied to the construction of a CRISPR interference plasmid as a means to reduce or essentially silence the transcription of targeted genes. We demonstrate the viability of a simplified, single vector CRISPRi system to disrupt gene expression in R. rickettsii targeting the type IV secreted effector rarP2 and autotransporter peptidase rapL as examples. IMPORTANCE This work expands upon the genetic toolbox available for R. rickettsii . This is the first report of both an inducible promoter and CRISPRi system compatible with Rickettsia , which may provide key instruments for the development of further tools. The development of an inducible promoter system allows for the overexpression of genes which might be toxic when expressed constitutively. The CRISPRi system enables the ability to knockdown genes with specificity, and critically, genes which may be essential and could not otherwise be knocked out. These developments may provide the foundation for unlocking genetic tools for other pathogens of the order Rickettsiales, such as the Anaplasma , Orientia , and Ehrlichia for which there are currently no inducible promoters or CRISPRi platforms.
proteins
2023-07-31 | Identification of an autotransporter peptidase of Rickettsia rickettsii responsible for maturation of surface exposed autotransporters
Members of the spotted fever group rickettsia express four large, surface-exposed autotransporters, at least one of which is a known virulence determinant. Autotransporter translocation to the bacterial outer surface, also known as type V secretion, involves formation of a β-barrel autotransporter domain in the periplasm that inserts into the outer membrane to form a pore through which the N-terminal passenger domain is passed and exposed on the outer surface. Two major surface antigens of Rickettsia rickettsii , are known to be surface exposed and the passenger domain cleaved from the autotransporter domain. A highly passaged strain of R . rickettsii , Iowa, fails to cleave these autotransporters and is avirulent. We have identified a putative peptidase, truncated in the Iowa strain, that when reconstituted into Iowa restores appropriate processing of the autotransporters as well as restoring a modest degree of virulence.
2018-07-31 | Th1 epitope peptides induce protective immunity against Rickettsia rickettsii infection in C3H/HeN mice.
Rickettsia rickettsii is the causative pathogen of Rocky Mountain spotted fever (RMSF). Adr2, YbgF and OmpB are protective antigens of R. rickettsii. In this study, 90 candidate peptides were selected from these antigens based on their high-affinity binding capacity for the MHC class II molecule H2 I-A or H2 I-E using bioinformatic methods. Six peptides were determined using ELISPOT assay to be immunodominant based on the IFN-γ recall responses of CD4+ T cells from mice immunized with R. rickettsii. Six nucleotide sequences encoding the immunodominant peptides were linked in series and inserted into a plasmid for expression in Escherichia coli cells, resulting in a new, recombinant polypeptide termed GWP. After immunization and challenge, the rickettsial load or histopathological lesions in the organs of mice immunized with GWP or pooled peptides was significantly lower than that in organs of mice immunized with PBS or the individual peptide OmpB399. An in vitro neutralization test revealed that sera from mice immunized with GWP, OmpB399, or pooled peptides reduced R. rickettsii adherence to, and invasion of, vascular endothelial cells. Furthermore, significantly higher levels of IgG, IgG1, or IgG2a were detected in sera from mice immunized with GWP or pooled peptides, and significantly higher levels of IFN-γ or TNF-α secreted by CD4+ T cells from R. rickettsii-infected mice were detected after immunization with GWP. Altogether, our results indicated that polypeptides, especially GWP, could induce a Th1-type immune response against R. rickettsii infection, which might contribute to the rational design of peptide-based vaccines for RMSF.
2017-03-01 | The Rickettsia conorii Adr1 Interacts with the C-Terminus of Human Vitronectin in a Salt-Sensitive Manner
Spotted fever group (SFG) Rickettsia species are inoculated into the mammalian bloodstream by hematophagous arthropods. Once in the bloodstream and during dissemination, the survival of these pathogens is dependent upon the ability of these bacteria to evade serum-borne host defenses until a proper cellular host is reached. Rickettsia conorii expresses an outer membrane protein, Adr1, which binds the complement inhibitory protein vitronectin to promote resistance to the anti-bacterial effects of the terminal complement complex. Adr1 is predicted to consist of 8 transmembrane beta sheets that form a membrane-spanning barrel with 4 peptide loops exposed to the extracellular environment. We previously demonstrated that Adr1 derivatives containing either loop 3 or 4 are sufficient to bind Vn and mediate resistance to serum killing when expressed at the outer-membrane of E. coli. By expressing R. conorii Adr1 on the surface of non-pathogenic E. coli, we demonstrate that the interaction between Adr1 and vitronectin is salt-sensitive and cannot be interrupted by addition of heparin. Additionally, we utilized vitroenctin-derived peptides to map the minimal Adr1/vitronectin interaction to the C-terminal region of vitronectin. Furthermore, we demonstrate that specific charged amino acid residues located within loops 3 and 4 of Adr1 are critical for mediating resistance to complement-mediated killing. Interestingly, Adr1 mutants that were no longer sufficient to mediate resistance to serum killing still retained the ability to bind to Vn, suggesting that Adr1-Vn interactions responsible for resistance to serum killing are more complex than originally hypothesized. In summary, elucidation of the mechanisms governing Adr1-Vn binding will be useful to specifically target this protein-protein interaction for therapeutic intervention.
2016-08-08 | Intravenous Immunoglobulin Therapy for Cerebral Vasculitis Associated with Rocky Mountain Spotted Fever
Rocky Mountain spotted fever is a tick-borne illness that is prevalent in the south and the central United States, primarily during the summer months. Patients with delayed diagnosis can experience increased mortality and morbidity, particularly poor neurological outcome. We present a case of a 7-year-old girl with Rocky Mountain spotted fever who was admitted with severe neurological changes and septic shock on day 8 of illness. She was initially diagnosed with Kawasaki disease and treated with intravenous immunoglobulin. Her treatment also included doxycycline, vancomycin, and ceftriaxone due to concerns regarding Rocky Mountain spotted fever and bacterial sepsis. During hospitalization, the patient required mechanical ventilation for respiratory distress, inotropic support, and fluid resuscitation for hypotension. Titers for Rocky Mountain spotted fever were ultimately positive, with magnetic resonance imaging of the brain demonstrating numerous punctate foci of restricted diffusion within the supratentorium, including the corpus callosum and basal ganglia. Although the patient presented late in the disease course, she ultimately had a good neurological outcome. We theorized that administration of intravenous immunoglobulin prevented ongoing neurological injuries from the cerebral vasculitis, which are associated with Rocky Mountain spotted fever.
2016-08-03 | Ongoing Cerebral Vasculitis During Treatment of Rocky Mountain Spotted Fever.
Rocky Mountain spotted fever is a tickborne infection that produces a systemic small-vessel vasculitis; its prognosis is excellent if appropriate treatment is initiated early. Because the advent of effective antirickettsial therapies predates the widespread use of brain magnetic resonance imaging, there are limited data on the effect of untreated Rocky Mountain spotted fever infection on neuroimaging studies. We describe a 7-year-old girl with delayed treatment of Rocky Mountain spotted fever who suffered severe neurological impairment. Serial brain magnetic resonance images revealed a progressive "starry sky appearance," which is proposed to result from the same small vessel vasculitis that causes the characteristic skin rash of this infection. Neurological injury can continue to occur despite specific antirickettsial therapy in Rocky Mountain spotted fever. This child's clinical features raise questions about the optimal management of this infection, particularly the utility of immune modulating therapies in cases of delayed treatment and neurological involvement.
small molecules
2026-05-18 | Rocky Mountain spotted fever
1 Rocky Mountain spotted fever (RMSF) is a severe tick-borne infection The disease is caused by Rickettsia rickettsii and is transmitted by multiple tick species including the American dog tick, Rocky Mountain wood tick, and brown dog tick. 1 Rickettsia rickettsii is considered endemic in certain regions of Canada, 2 but human cases of RMSF are rare.
2026-04-17 | Secondary Hemophagocytic Lymphohistiocytosis in a Rocky Mountain Spotted Fever Patient.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages, leading to cytokine storm and multiorgan dysfunction. Due to its nonspecific clinical presentation and high mortality, early recognition and multidisciplinary management are essential. We report the case of a 28-year-old woman admitted with fever, myalgias, arthralgias, and generalized exanthema. Initial laboratory evaluation revealed pancytopenia. Polymerase chain reaction (PCR) testing was positive for Rickettsia, and bone marrow examination demonstrated findings consistent with HLH. Despite appropriate management, the patient developed septic shock and died due to multiple complications, including multiorgan failure.
2026-01-05 | Epidemiologic Characterization and Risk Factors of Rocky Mountain Spotted Fever in Children in Northeastern Mexico: A Retrospective Cross-sectional Study (2018-2024).
Rocky Mountain spotted fever (RMSF) is a vector-borne disease with nonspecific symptoms, including fever, headache, myalgia, and exanthema, which complicates timely diagnosis and treatment. Despite its significant morbidity and mortality, epidemiological data and risk factor analyses remain scarce in Mexico. A retrospective cross-sectional study was conducted from 2018-2024 in three hospitals in northeastern Mexico. We analyzed 90 pediatric patients with confirmed rickettsiosis via polymerase chain reaction (PCR) or immunofluorescence assay (IFA). Demographic, clinical, and laboratory data were evaluated to identify independent risk factors associated with disease severity and outcomes. Statistical analyses included logistic regression, Mann-Whitney U tests, and Pearson χ2 tests (p ≤0.05). School-aged children comprised 46.6% of cases, with a predominance of females (54.4%). Key epidemiological exposures included tick bites (17.8%) and pet cohabitation (54.5%). Delayed doxycycline treatment (>5 d after symptom onset) was associated with increased mortality. Significant predictors of poor outcomes were neurological impairment (OR: 3.7, CI: 1.9-7.3), shock upon admission (OR: 4.5, CI: 2.2-9.1), and thrombocytopenia (p < 0.001). The overall mortality rate was 36.7%. Our findings underscore the significant clinical impact of rickettsioses in northeastern Mexico and the need to improve diagnostic capabilities, raising public awareness, and implementing effective vector control programs. Early recognition and timely doxycycline treatment are crucial to improving patient outcomes. Strengthening public health strategies through preventive measures and clinician education could reduce the morbidity and mortality associated with these infections.
2026-01-01 | NNDSS - Table II. Spotted Fever Rickettsiosis to Syphilis
NNDSS - Table II. Spotted Fever Rickettsiosis to Syphilis - 2017. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding year), and selected low frequency diseases are displayed. The Table includes total number of cases reported in the United States, by region and by states, in accordance with the current method of displaying MMWR data. Data on United States exclude counts from US territories. Note: These are provisional cases of selected national notifiable diseases, from the National Notifiable Diseases Surveillance System (NNDSS). NNDSS data reported by the 50 states, New York City, the District of Columbia, and the U.S. territories are collated and published weekly as numbered tables printed in the back of the Morbidity and Mortality Weekly Report (MMWR). Cases reported by state health departments to CDC for weekly publication are provisional because of ongoing revision of information and delayed reporting. Case counts in this table are presented as they were published in the MMWR issues. Therefore, numbers listed in later MMWR weeks may reflect changes made to these counts as additional information becomes available. Footnotes: C.N.M.I.: Commonwealth of Northern Mariana Islands. U: Unavailable. —: No reported cases. N: Not reportable. NN: Not Nationally Notifiable. NP: Nationally notifiable but not published. Cum: Cumulative year-to-date counts. Med: Median. Max: Maximum. *Three low incidence conditions, rubella, rubella congenital, and tetanus, are in Table II to facilitate case count verification with reporting jurisdictions. † Case counts for reporting year 2017 are provisional and subject to change. For further information on interpretation of these data, see http://wwwn.cdc.gov/nndss/document/ ProvisionalNationaNotifiableDiseasesSurveillanceData20100927.pdf. Data for tuberculosis are displayed in Table IV, which appears quarterly. § Illnesses with similar clinical presentation that result from Spotted Fever Group Rickettsia infections are reported as Spotted Fever Rickettsioses. Rocky Mountain Spotted Fever (RMSF), caused by Rickettsia rickettsii, is the most common and well-known Spotted Fever. Read less
2026-01-01 | Scoping Review on Rocky Mountain Spotted Fever
A scoping review was prioritized to identify and characterize the global literature on Rocky Mountain Spotted Fever.
vaccines
2026-03-25 | Effects of exposure to Rickettsia bellii on reservoir competence of guinea pigs for Rickettsia rickettsii.
Amblyomma sculptum is the main vector implicated in the transmission of Rickettsia rickettsii in southeastern Brazil, where capybaras are known to be the main amplifying hosts of this pathogen. Interestingly, many areas inhabited by large populations of capybaras and A. sculptum remain free of R. rickettsii, suggesting that other drivers may be involved in the pathogen perpetuation. A. sculptum frequently occurs in sympatry with Amblyomma dubitatum ticks, sharing the same hosts with them. Considering that A. dubitatum ticks are frequently infected with Rickettsia bellii, a possible interference of R. bellii in the reservoir competence of capybaras for R. rickettsii could explain the heterogeneous distribution of R. rickettsii in A. sculptum populations in southeastern Brazil. The present study aimed to evaluate the effect of primary exposure to R. bellii-infected A. dubitatum on the reservoir competence for R. rickettsii using guinea pigs as experimental models. Three guinea pigs were infested with R. bellii-infected A. dubitatum (Group GB), four guinea pigs with uninfected A. dubitatum (Group GD), and three guinea pigs were not exposed to A. dubitatum (Group GC). After infestation with A. dubitatum, all guinea pigs were exposed to one single R. rickettsii-infected A. sculptum female and then were infested with uninfected A. sculptum larvae. After ecdysis, nymphs were tested for detection of spotted fever group rickettsiae. Five out of six guinea pigs from GD and GC groups died, while one out of three guinea pigs in the GB group had a fatal outcome. R. rickettsii infection rate among ticks fed on animals from GB group was 21% (17/80), significantly lower than the rate of 54% (60/111) recorded in ticks fed on animals from GD and GC groups. Prior exposure of guinea pigs to R. bellii-infected A. dubitatum ticks reduced their reservoir competence for R. rickettsii.
2025-10-29 | Rickettsia rickettsii inactivated whole cell antigen vaccine protects against Rocky Mountain spotted fever independent of the adjuvant used.
Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii is the most fatal tick-borne disease in people and dogs in the Americas. This pathogen is transmitted by several hard ticks: Dermacentor species, Rhipicephalus sanguineus, and Amblyomma americanum. RMSF can quickly progress to a life-threatening illness with fatalities ranging from 30% to 80%. Doxycycline is the only treatment option, and currently, no methods are available to prevent RMSF. We previously reported that vaccination with R. rickettsii whole cell antigen vaccine (WCAV) with Montanide gel adjuvant offers protection against virulent R. rickettsii infection in dogs. Here, we compared three adjuvants to optimize the safety and immunogenicity of WCAV: Alhydrogel, Montanide, and Quil A. Independent of adjuvants, all vaccinees were protected, whereas unvaccinated dogs developed the clinical disease. Vaccination reduced the pathogen to undetectable levels in blood and various tissues. An R. rickettsii-specific IgG response was observed following primary vaccination in all vaccinated groups, which augmented after booster. The vaccine with Quil A had the highest IgG response with a significant rise in CD4+ and CD8+ T cell numbers, while Montanide and Alhydrogel resulted in a balanced IgG response. IgG2 was the primary antibody detected in unvaccinated infection controls. Several systemic proinflammatory cytokines varied after infection in both vaccinees and controls. Plasma concentration of intercellular adhesion molecule 1 was higher in unvaccinated compared to vaccinees in the first 9 days after infection. This study demonstrates that the WCAV efficacy is independent of the adjuvant, although Quil A induced a higher IgG response and expansion of CD4 and CD8 T cells.
2025-03-26 | In silico construction of a multi-epitope vaccine (RGME-VAC/ATS-1) against the Rickettsia genus using immunoinformatics.
Rickettsia is a genus of Gram-negative bacteria that causes various diseases, including epidemic typhus, Rocky Mountain spotted fever, and Mediterranean spotted fever. Ticks transmit these diseases and commonly found in developing regions with poor sanitation. As a result, it is difficult to estimate the number of these diseases cases, making it challenging to create prevention and diagnostic mechanisms. Thus, this study aimed to develop an in silico multi-epitope vaccine against Rickettsia. Eight proteins were previously identified as potential vaccine candidates through reverse vaccinology and were screened for epitopes that bind to MHC class I and II molecules. The epitopes were then analysed for antigenicity, allergenicity, and toxicity. The selected epitopes were linked with AAY and GPGPG sequences peptide and a known adjuvant, the B-chain of Escherichia coli heat-labile enterotoxin, to form a chimeric multi-epitope protein. The protein's three-dimensional structure was predicted, and molecular docking analysis was performed against the toll-like receptor 4 (TLR4). Finally, the immune response to the protein was simulated using C-ImmSim tool. A total of 26 immunogenic epitopes, formed the multi-epitope vaccine RGME-VAC/ATS-1. The vaccine showed excellent immunogenic parameters and was predicted to do not be toxic or allergenic to the host. It also showed good potential stimulation of immune cells, with a propensity to generate memory cells and elicit IFN-γ secretion. The in silico validations suggest that our study successfully designed an innovative multi-epitope vaccine against Rickettsia, addressing the challenges posed by the elusive nature of diseases caused by this genus. We provide a promising potential for further experimental exploration and the development of targeted prevention and diagnostic strategies for these diseases.
2025-02-05 | A wolf at the door: the ecology, epidemiology, and emergence of community- and urban-level Rocky Mountain spotted fever in the Americas.
RMSF, a tickborne infection caused by Rickettsia rickettsii, produces severe and fatal disease in humans and dogs. Since the beginning of the 21st century, cases have risen dramatically, most notably in Mexico and Brazil, where outbreaks occur in urban centers including cities with populations of > 1,000,000 persons. Reported case fatality rates can exceed 50%. Factors consistent with high case fatality include lack of awareness of disease ecology, limited capacity for diagnosis, and delay in appropriate antimicrobial treatment. The emergence of urban hyperendemic foci has been leveraged by 2 distinct but similar anthropogenic events that create disproportionately high numbers of vertebrate amplifiers of R rickettsii, as well as the tick species that transmit this pathogen in proximity with dense human populations. This often occurs in neighborhoods with a highly marginalized at-risk population that includes persons in poverty and particularly children, and health management systems that are under-resourced. We discuss strategies to reduce host dog populations, particularly in Mexico, and capybaras in Brazil. We review challenges to the control of tick populations in these settings. Robust systems are required to enhance awareness of RMSF among medical practitioners and people at risk of RMSF. Public health campaigns should incorporate innovative behavioral science (eg, diverse learning models, motivational interviews, and gamification) to increase prevention and understanding within communities. While anti-Rickettsia or anti-tick vaccines will be necessary to resolve this One Health crisis, impactful implementation will require data-driven and multiple-target innovations to address challenges with hosts, ticks, medical systems, and public welfare. The companion Currents in One Health by Foley, Backus, and López-Pérez, JAVMA, March 2025, addresses helpful information for the practicing veterinarian.
2025-01-07 | Core-genome guided novel therapeutic targets identification and chimeric vaccine designing against Rickettsia rickettsii.
Rocky Mountain Spotted Fever, caused by the gram-negative intracellular bacteria Rickettsia rickettsii, is a serious tick-borne infection with a fatality rate of 20-30%, if not treated. Since it is the most serious rickettsial disease in North America, modified prevention and treatment strategies are of critical importance. In order to find new therapeutic targets and create multiepitope vaccines, this study integrated subtractive proteomics with reverse vaccinology. The core genome of R. rickettsii was investigated, resulting in the identification of seven essential, human non-homologous proteins as potential drug targets, as well as four antigenic, non-allergenic proteins suitable for vaccine development. Using conserved antigenic peptides, two chimeric vaccine constructs were developed and assessed using molecular docking, molecular dynamics simulations, principal component analysis, MM-GBSA binding free energy, and dynamic cross-correlation matrix studies. The high immunogenic potential was indicated by the vaccine designs' robust and consistent interactions with human immunological receptors. Their capacity to trigger strong humoral and cellular immunological responses was further demonstrated by in silico immune simulations. The persistent interactions of vaccine V1 and V2 with human immunological receptor demonstrated that these might have high immunogenic potential. Moreover, the identified drug targets were annotated for essential biological processes, which shed light on their therapeutic potential. The vaccine constructs were cloned and expressed in suitable systems. This study displays a comprehensive strategy for managing Rocky Mountain Spotted Fever via rational vaccine development. Further experimental research is needed to confirm the immunogenicity of the vaccines and the druggability of identified targets, establishing the path toward effective RMSF management.
antibodies
2024-05-20 | Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae.
Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species invade host cells, including MΦ, remain poorly defined. In this study, we describe a mechanism of host invasion by Rickettsia species, involving rickettsial phosphatidylserine (PS), as a ligand, and the CD300f receptor on MΦ. Using bone marrow-derived macrophages (BMDMΦ) from wild-type (WT) and CD300f-/- mice, we demonstrated that engulfment of both pathogenic R. typhi (the etiologic agent of murine typhus) and R. rickettsii (the etiologic agent of Rocky Mountain spotted fever) species as well as the non-pathogenic R. montanensis was significantly reduced in CD300f-/- BMDMΦ as compared to that of WT BMDMΦ. Furthermore, our mechanistic analysis suggests bacterial PS as the potential source for the CD300f-mediated rickettsiae engulfment by MΦ. In vivo infection studies using WT and CD300f-/- C57BL/6J mice showed that CD300f-/- animals were protected against R. typhi- or R. rickettsii-induced fatal rickettsiosis, which correlated with levels of bacterial burden detected in the spleens of mice. Adoptive transfer studies further revealed that CD300f-expressing MΦ are important mediators to control rickettsiosis in vivo. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment of rickettsiae within the host.
2019-08-14 | Rickettsia conorii O antigen is the target of bactericidal Weil-Felix antibodies.
Rickettsial diseases have long been diagnosed with serum antibodies cross-reactive against Proteus vulgaris (Weil-Felix reaction). Although Weil-Felix antibodies are associated with the development of immunity, their rickettsial target and contribution to disease pathogenesis are not established. Here, we developed a transposon for insertional mutagenesis of Rickettsia conorii, isolating variants defective for replication in cultured cells and in spotted fever pathogenesis. Mutations in the polysaccharide synthesis operon (pso) abolish lipopolysaccharide O-antigen synthesis and Weil-Felix serology and alter outer-membrane protein assembly. Unlike wild-type R. conorii, pso mutants cannot elicit bactericidal antibodies that bind O antigen. The pso operon is conserved among rickettsial pathogens, suggesting that bactericidal antibodies targeting O antigen may generate universal immunity that could be exploited to develop vaccines against rickettsial diseases.
2004-05-20 | Effect of Antibody on the Rickettsia-Host Cell Interaction
A recent study demonstrated that polyclonal antibodies to Rickettsia conorii and monoclonal antibodies to outer membrane proteins A (OmpA) and B (OmpB) provided effective, Fc-dependent, passive immunity, even in severe combined immunodeficient mice with an established infection. In order to determine the mechanism of protection, mouse endothelial and macrophage-like cell lines were infected with R. conorii that had been exposed to polyclonal antibodies, monoclonal antibodies to OmpA or OmpB, Fab fragments of the polyclonal antibodies, or normal serum or that were left untreated. At 0 h, Fc-dependent antibody enhancement of R. conorii adherence to endothelial and macrophage-like cell lines was inhibited by the presence of normal serum, suggesting Fc receptor-mediated adherence of opsonized rickettsiae. At 3 h, the opsonized rickettsiae had been internalized. After 72 h, inhibited survival of rickettsiae exposed to polyclonal antibodies or monoclonal antibodies to OmpA or OmpB was evident compared with growth of untreated and normal serum-treated and polyclonal Fab antibody-treated R. conorii. Polyclonal antibodies and an anti-OmpB monoclonal antibody inhibited the escape of R. conorii from the phagosome, resulting in intraphagolysosomal rickettsial death. At 48 h of infection, rickettsicidal activity of macrophages by opsonized rickettsiae was inhibited by NG-monomethyl-L-arginine, superoxide dismutase, mannitol, or supplemental L-tryptophan, and endothelial rickettsicidal activity against opsonized rickettsiae was inhibited by NG-monomethyl-L-arginine, superoxide dismutase, catalase, or supplemental L-tryptophan. Thus, Fc-dependent antibodies protected against R. conorii infection of endothelium and macrophages by opsonization that inhibited phagosomal escape and resulted in phagolysosomal killing mediated by nitric oxide, reactive oxygen intermediates, and L-tryptophan starvation.
2001-10-04 | Quantitative analyses of variations in the injury of endothelial cells elicited by 11 isolates of Rickettsia rickettsii.
Eleven isolates of spotted fever group rickettsiae from the blood of patients or ixodid ticks from North and South America were characterized. All isolates were identified as Rickettsia rickettsii using restriction fragment length polymorphism analysis of a 532-bp rOmpA gene fragment obtained by PCR. The ability of the R. rickettsii isolates to elicit cytopathic effects and parameters of oxidative injury were examined in cultured human EA.hy 926 endothelial cells. Cytopathic effects were determined by direct observation of infected cultures, by measuring the release of cytoplasmic lactate dehydrogenase (LDH), and by determination of intracellular pools of peroxide and reduced glutathione. Four biotypes of R. rickettsii were defined. Group I included two highly cytopathic isolates from Montana, Bitterroot and Sheila Smith, and three isolates from Maryland, North Carolina, and Brazil. These isolates rapidly damaged cells, released large amounts of cytoplasmic LDH, caused accumulation of intracellular peroxide, and depleted intracellular pools of reduced glutathione. Group II contained three isolates, two from Montana, Hlp#2 and Lost Horse Canyon, and an isolate from Colombia, which were similar to group I but caused either lower responses in LDH release or smaller changes in intracellular peroxide levels. The group III isolates, Sawtooth from Montana and 84JG from North Carolina, caused lower cellular injury by all measures. Group IV isolate Price T from Montana was the least cytopathic and caused minimal alterations of all parameters measured. Understanding the molecular basis for the varied cellular injury caused by different isolates of R. rickettsii may contribute to improved treatment of Rocky Mountain spotted fever and to the rapid identification of those isolates which are more likely to cause fulminant disease.
1985-07-11 | Characterization of monoclonal antibodies protecting mice against Rickettsia rickettsii.
Hybridomas producing monoclonal antibodies to Rickettsia rickettsii were prepared from mice to investigate the function of rickettsial antigens. Of the 31 reactive hybridoma lines thus far tested for immunoglobulin subclasses, 11 belonged to the IgG2A subclass, 9 to the IgG2B subclass, and 7 to the IgG3 subclass; four did not react with any of the isotyping sera. Five of the antibodies recognized epitopes present on molecules that were presumed to be polysaccharide and heterogeneous in molecular weight. Twenty monoclonal antibodies reacted with a 170,000-dalton antigen, and six precipitated both the 133,000- and 32,000-dalton polypeptides. Only those antibodies to the 170,000- and 133,000-dalton antigens protected mice from challenge with R. rickettsii. Antibodies to these same antigens were detected in sera from patients convalescing from Rocky Mountain spotted fever. All monoclonal antibodies reacted with antigens apparently located on the rickettsial surface. The protective activity of these antibodies was not correlated with their reactivity in complement fixation, enzyme-linked immunosorbent assay, and immunofluorescence tests.
other
2024-09-30 | Development of inducible promoter and CRISPRi plasmids functional in Rickettsia rickettsii.
Rickettsia rickettsii is an obligate intracellular, tick-borne bacterium that causes Rocky Mountain spotted fever. The demanding nature of cultivating these bacteria within host cells and the labor involved in obtaining clonal isolates have severely limited progress regarding the development of compatible genetic tools to study this pathogen. Conditional expression of genes that might be toxic or have an otherwise undesirable effect is the next logical goal to expand upon the constitutive expression plasmids generated thus far. We describe the construction of an inducible promoter system based on the tet-On system, leveraging design elements from the anhydrotetracycline-inducible promoter system used for Borrelia burgdorferi and one of the few characterized rickettsial promoters for the outer membrane gene, rompB (sca5). The functionality of this promoter is demonstrated via fluorescence of induced mScarlet production and was then used to construct a generalized inducible expression vector for R. rickettsii. The development of a functional inducible promoter was then applied to the construction of a CRISPR interference plasmid as a means to reduce or essentially silence the transcription of targeted genes. We demonstrate the viability of a simplified, single vector CRISPRi system to disrupt gene expression in R. rickettsii targeting the type IV secreted effector rarP2 and autotransporter peptidase rapL as examples. This work expands upon the genetic toolbox available for R. rickettsii. We describe both an inducible promoter and CRISPRi system compatible with Rickettsia, which may provide key instruments for the development of further tools. The development of an inducible promoter system allows for the overexpression of genes, which might be toxic when expressed constitutively. The CRISPRi system enables the ability to knock down genes with specificity, and critically, genes that may be essential and could not otherwise be knocked out. These developments may provide the foundation for unlocking genetic tools for other pathogens of the order Rickettsiales, such as the Anaplasma, Orientia, and Ehrlichia for which there are currently no inducible promoters or CRISPRi platforms.
2024-06-12 | Development of inducible promoter and CRISPRi plasmids functional inRickettsia rickettsii
ABSTRACT Rickettsia rickettsii is an obligate intracellular, tick-borne bacterium that causes Rocky Mountain spotted fever. The demanding nature of cultivating these bacteria within host cells and the labor involved in obtaining clonal isolates has severely limited progress regarding the development of compatible genetic tools to study this pathogen. Conditional expression of genes which might be toxic or have an otherwise undesirable effect is the next logical goal to expand upon the constitutive expression plasmids generated thus far. We describe the construction of an inducible promoter system based on the tet-On system, leveraging design elements from the anhydrotetracycline inducible promoter system used for Borrelia burgdorferi and one of the few characterized rickettsial promoters for the outer membrane gene, rompB ( sca5 ). The functionality of this promoter is demonstrated via fluorescence of induced mScarlet production and was then used to construct a generalized inducible expression vector for R. rickettsii . The development of a functional inducible promoter was then applied to the construction of a CRISPR interference plasmid as a means to reduce or essentially silence the transcription of targeted genes. We demonstrate the viability of a simplified, single vector CRISPRi system to disrupt gene expression in R. rickettsii targeting the type IV secreted effector rarP2 and autotransporter peptidase rapL as examples. IMPORTANCE This work expands upon the genetic toolbox available for R. rickettsii . This is the first report of both an inducible promoter and CRISPRi system compatible with Rickettsia , which may provide key instruments for the development of further tools. The development of an inducible promoter system allows for the overexpression of genes which might be toxic when expressed constitutively. The CRISPRi system enables the ability to knockdown genes with specificity, and critically, genes which may be essential and could not otherwise be knocked out. These developments may provide the foundation for unlocking genetic tools for other pathogens of the order Rickettsiales, such as the Anaplasma , Orientia , and Ehrlichia for which there are currently no inducible promoters or CRISPRi platforms.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.