RARE DISEASE
Invasive candidiasis
Invasive candidiasis
Invasive candidiasis
Synonyms: Disseminated candidiasis, Systemic candidiasis
Synonyms: Disseminated candidiasis, Systemic candidiasis
Synonyms: Disseminated candidiasis, Systemic candidiasis
Drug discovery
13
drugs
With orphan designations
Overview
Invasive candidiasis is a life-threatening fungal infection caused by Candida species, primarily affecting immunocompromised individuals and hospitalized patients. It manifests as candidemia or deep-seated infections in sterile sites (e.g., abdomen, heart, brain). Diagnosis relies on blood cultures and non-cultural methods (e.g., β-D-glucan), while treatment involves systemic antifungals tailored to resistance patterns and host factors [1][2][11]. Mortality remains high despite advances in antifungal therapies.
Population
High-risk groups: ICU patients, those with central venous catheters, abdominal surgery recipients, immunocompromised individuals (e.g., hematologic malignancies, transplants), and neonates [1][5][12][17].
Emerging risk: Injection drug use contributors to rising candidemia cases in younger adults [12].
Burden
Incidence: ~25,000 annual U.S. cases (3–5 per 100,000 globally) [5][12].
Mortality: 25–55% in-hospital mortality (attributable mortality: 19–24%) [4][9][12].
Costs: U.S. direct medical costs exceed $1.2 billion annually; ICU stays increase by 3–13 days per case [4][12][17].
Resistance: Rising echinocandin resistance in C. glabrata (3%) and pan-resistant C. auris outbreaks [5][12].
Therapies
First-line: Echinocandins (caspofungin, micafungin) for critically ill patients or azole-resistant strains [2][8].
Alternatives: Fluconazole for stable patients with susceptible isolates; lipid-based amphotericin B for refractory cases [3][8].
Duration: Minimum 14 days post-negative blood cultures and symptom resolution; catheter removal strongly recommended [2][3].
Categories: rare infectious diseases
Research Papers
5,292 drug discovery papers about Invasive candidiasis, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
5,292 drug discovery papers about Invasive candidiasis, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Epigenetic repression of IL-1β by C1QBP restricts Dectin-1-mediated host defense against murine invasive candidiasis
Invasive candidiasis, predominantly caused by Candida albicans, threatens immunocompromised individuals with high mortality. Dendritic cell-derived interleukin-1β, orchestrated via Dectin-1-mediated β-glucan recognition, is central to antifungal defense. While the Dectin-1/Syk/CARD9 axis governing Il1b transcription is defined, the epigenetic regulatory mechanisms remain elusive. Here, we identify Complement C1q binding protein (C1QBP) as a critical negative regulator of Dectin-1-mediated interleukin-1β production. C1QBP sequesters phosphorylated protein kinase C δ in the cytoplasm, preventing its nuclear transport. Nuclear phosphorylated-PKCδ activates the RNF20/RNF40 ubiquitin ligase complex, which recruits the methyltransferase DOT1L to catalyze histone H3 lysine 79 trimethylation at the Il1b locus to promote its transcription. DC-specific C1QBP depletion enhances interleukin-1β secretion, amplifies protective T helper 17 cell responses, and improves host resistance to systemic C. albicans infection in mice. Collectively, our findings establish C1QBP as a key checkpoint in a PKCδ-dependent epigenetic pathway that constrains antifungal immunity, highlighting its therapeutic potential for invasive fungal diseases. Engagement of Dectin-1 on dendritic cells drives IL-1β production and is a critical component of the immune response to invasive candidiasis. Here the authors show epigenetic repression of IL-1β by a complement binding protein can restrain the dectin1 driven immune response in a murine model of invasive candidiasis.
2026-08-14 | First Reported Neonatal Invasive Candidozyma auris (Candida auris) Infection in Brazil: Successful Management, Evolving Amphotericin B Resistance, and Infection Containment.
To describe the first neonatal invasive Candida auris infection in Brazil and its successful clinical and infection control management. Retrospective description of the clinical course, microbiological findings, antifungal susceptibility evolution, and follow-up of an extremely preterm infant. A 25 + 4-week male neonate developed bloodstream and urinary C. auris infection during the first week of life. Progressive amphotericin B resistance in urine isolates required the addition of fluconazole. No secondary NICU cases occurred. Early diagnosis, serial susceptibility testing, and immediate containment measures enabled successful treatment and prevented nosocomial spread.
2026-08-11 | Mitochondrial characteristics of echinocandin tolerance and resistance in Candida glabrata and Candida krusei.
Candidiasis, especially candidemia, is one of the most common invasive fungal infections. With the increase of risk factors such as tumors, its high incidence and high mortality rate pose a significant challenge to public health. Echinocandins, as first-line drugs for candidemia, have their clinical efficacy severely weakened by the emergence of tolerant or resistant strains such as Candida glabrata and Candida krusei. The study evaluated the changes in mitochondrial phenotype (intracellular ATP levels, mitochondrial membrane potential, mitochondrial superoxide levels, and intracellular ROS levels), proteomic, metabolomic, and genomic in C. glabrata and C. krusei. By analyzing strains with different susceptibility profiles, the study found that echinocandin tolerant or resistant strains displayed significant upregulation of ATP levels and unique metabolic adaptations. Quantitative proteomics identified differentially expressed proteins associated with mitochondrial function and energy metabolism. Metabolomic analysis further revealed distinct profiles linking resistance to alterations in purine metabolism and oxidative phosphorylation. Additionally, genomic sequencing of the resistant strains highlighted mutations in key genes involved in ATP binding. These findings highlight the mitochondrial characteristics in echinocandin tolerance and resistance in C. glabrata and C. krusei, providing valuable insights into potential pathways for future therapeutic interventions targeting resistant Candida species.
2026-08-10 | Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance in Candida glabrata.
Candida glabrata is an opportunistic yeast that causes invasive infections in immunocompromised individuals. Echinocandin antifungals are first-line agents in the treatment of invasive candidiasis and act by inhibiting fungal cell wall synthesis by targeting β-1,3-glucan synthase. Echinocandin resistance is primarily associated with mutations in FKS1 or FKS2, which encode for the catalytic subunit (Fks1 or Fks2) of the targeted glucan synthase. The cell wall integrity (CWI) pathway, including Slt2 kinase, is known to mediate tolerance to antifungal drugs, but its role in resistance is not completely defined. Here, we observed that disruption of SLT2 abrogated echinocandin resistance due to FKS2, but not FKS1, mutation in C. glabrata. As expected, reintroduction of plasmid-borne SLT2 restored elevated MICs of fks2 mutants. RT-qPCR revealed that loss of SLT2 led to decreased FKS2 expression levels in wild-type and echinocandin-resistant strains following echinocandin exposure. In conclusion, the CWI pathway and Slt2 comprise a primary control mechanism for FKS2-mediated echinocandin resistance in C. glabrata.IMPORTANCEThe higher rates of acquired antifungal resistance exhibited by Candida glabrata merit further understanding of resistance mechanisms including fungal regulation of drug target genes and enzymes. Here, we focused on a fungal tolerance pathway, the cell wall integrity pathway, and its requirement in C. glabrata echinocandin antifungal resistance. Interestingly, we found that targeting the pathway through disruption of a key protein, Slt2, reversed echinocandin resistance within one subset of resistant strains (fks2 mutants) but not another (fks1 mutants). Gene expression studies demonstrated the requirement of SLT2 for full FKS2 gene expression following echinocandin treatment. Overall, we discovered that Slt2 is specifically required for Fks2-mediated echinocandin resistance through partial regulation of FKS2 expression. This study provides further insight into the regulation of drug target genes in C. glabrata and provides a possible therapeutic target for echinocandin-resistant infections caused by mutation of FKS2.
2026-08-09 | Mutations in MRR1 that confer fluconazole resistance in C. parapsilosis and C. albicans confer cross-resistance to manogepix.
Fluconazole resistance has been documented in Candida albicans and Candida parapsilosis, both leading causes of invasive candidiasis, driven in part by mutations in MRR1 which encodes a transcription factor that regulates drug efflux pump expression. A correlation has been observed between susceptibilities to fluconazole and manogepix, the active moiety of fosmanogepix, a promising new antifungal with activity against most Candida species. We aimed to determine whether MRR1-activating mutations driving fluconazole resistance in these species conferred cross-resistance to manogepix. C. albicans and C. parapsilosis clinical isolates and strains engineered to express wild-type or mutant MRR1 alleles, and their derivatives deleted for target drug transporters, were assessed for fluconazole and manogepix susceptibility. Introducing Mrr1 I283R and A854V substitutions into C. parapsilosis clinical isolate Cp13 increased fluconazole MIC from 0.25 to 32 mg/L and increased manogepix MIC from 0.008 to 0.25 mg/L, whereas correcting to MRR1 wild-type sequence in fluconazole-resistant clinical isolates reduced fluconazole MICs from 64, 128, and 64 mg/L to 1, 1, and 2 mg/L, respectively, and manogepix MICs from 0.125, 0.25, and 0.125 mg/L to 0.015 mg/L for all. This was dependent upon genes encoding Mdr1b and Cdr1b transporters. In C. albicans, introducing different MRR1-activating mutations into SC5314 increased fluconazole MICs from 0.5 mg/L to 4-16 mg/L and increased manogepix MICs from 0.015-0.03 mg/L to 0.06 mg/L. Activating mutations in clinical isolates increased fluconazole MICs from 1-2 mg/L to 32-64 mg/L and manogepix MICs by 2- to 4-fold. MRR1 deletion in resistant isolates restored susceptibility to both drugs. Our findings demonstrate that fluconazole and manogepix cross-resistance in C. parapsilosis conferred by MRR1-activating mutations is mediated by Cdr1b and Mdr1b transporters. MRR1-activating mutations conferred cross-resistance, to a lesser degree, in C. albicans, but independent of drug transporters known to be regulated by Mrr1.
proteins
2026-08-02 | The potential of bacteriocins in invasive fungal infections: Antifungal activities and intestinal protection.
Invasive fungal infections are life-threatening complications in immunocompromised and critically ill patients. Invasive candidiasis may arise from endogenous fungal reservoirs, particularly under conditions of intestinal barrier disruption. Although conventional antifungal agents remain the therapeutic foundation, their clinical use is increasingly challenged by the emergence of resistant fungal pathogens, such as Candida auris. Bacteriocins are ribosomally synthesized antimicrobial peptides produced by microorganisms. Beyond their well-established applications in the food industry, bacteriocins have attracted increasing attention in recent years for their antifungal properties. In this review, we provide an overview of bacteriocins with reported antifungal activity and summarize their underlying mechanisms. In addition, we discuss the potential protective effects of bacteriocins on the microbial, mechanical, chemical, and immune barriers of the intestine. Finally, we evaluate the potential clinical applications of these bacteriocins, along with future challenges and research directions related to invasive fungal infections.
2026-07-21 | Tissue-type plasminogen activator protects against kidney damage in invasive fungal infection.
Invasive Candida albicans infections (candidiasis) cause progressive organ damage through fungal tissue invasion and toxin-mediated injury, including in the kidney. Hyphal invasion induces apoptosis of renal tubular epithelial cells (RTEC), a key driver of kidney pathology, yet intrinsic renal protective mechanisms remain poorly defined. We identify fibrinolytic tissue-type plasminogen activator (tPA) as a critical mediator of renal tissue protection in candidiasis. tPA is induced by IL-17 and TNFα in renal endothelial cells and RTEC. tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and activates ERK1/2 signaling to suppress apoptosis in RTEC. Mice with RTEC-specific deletion of LRP1 exhibited exaggerated kidney damage during candidiasis. Administration of a nonenzymatic form of tPA recapitulated the protective effect of tPA by limiting RTEC apoptosis. These findings reveal the role of tPA/LRP1 axis in preserving renal integrity in candidiasis and suggest clinically approved tPA as a potential therapeutic strategy to mitigate candidiasis-associated tissue injury.
2026-06-30 | Evaluation of immunological and gene expression responses induced by Galectin-3 and whole-sonicated Candida krusei antigen in rats experimentally infected with Candida krusei.
Candida krusei is an emerging non-Candida albicans species increasingly associated with antifungal resistance and invasive systemic infections. Galectin-3 (GAL-3), a β-galactosidase-binding lectin, and the surfactant protein D gene are important components of innate antifungal immunity. The chemokine (C-X-C motif) ligand-1 gene plays a central role in neutrophil recruitment, whereas whole-sonicated C. krusei antigen may act as a broad fungal immunogen. To evaluate the immunological and pulmonary gene expression responses induced by GAL-3, whole-sonicated C. krusei antigen, and their combination in rats experimentally infected with C. krusei, via measurement of serum immunoglobulin G, interleukin-17, interleukin-23, and lung expression of Chemokine (C-X-C motif) ligand 1 (CXCL-1) and surfactant protein D genes. A total of 120 rats were randomly allocated into four experimental groups (n = 30). Animals received GAL-3, whole-sonicated C. krusei antigen, and their combination, while the control group was subdivided into infected and healthy controls. Immunized groups were administered subcutaneously according to the experimental schedule. Systemic C. krusei infection was induced intraperitoneally, and samples were collected at 15 and 30 days post-challenge. Serum Immunoglobulin G, Interleukin -17 (IL-17), and Interleukin -23 (IL-23) levels were measured using ELISA. Pulmonary CXCL-1 and surfactant protein D gene expression were quantified using SYBR Green reverse transcription quantitative polymerase chain reaction and analyzed using the 2⁻ΔΔCt method. Immunoglobulin G levels increased significantly in all treated groups compared with infected and healthy controls, with the highest levels at day 30. Whole-sonicated C. krusei antigen and mixed treatment groups showed significant increases in IL-17 and IL-23, indicating activation of Th17-mediated immune responses. Galectin-3 treatment produced upregulation of CXCL-1 and surfactant protein D genes, whereas the antigen-treated group showed moderate gene expression changes. The combined treatment group demonstrated reduced CXCL-1 induction but maintained a modest increase in surfactant protein D expression. Galectin-3 and whole-sonicated C. krusei antigen may enhance antifungal immune responses through partially distinct mechanisms. Galectin-3 modulates the CXCL-1 and surfactant protein D gene axis and activate innate immune pathways, whereas whole-sonicated antigen stimulates IL-23/IL-17-mediated responses and humoral immunity. These findings suggest that GAL-3 and fungal antigen immunization may represent support immunomodulatory approaches for controlling infections caused by non-C. albicans.
2026-05-10 | Candidalysin promotes fungal-specific Th17 CD4 T cell differentiation and protective systemic immunogenicity.
Commensal microbes can cause invasive infection but can also stimulate protective immune responses as exemplified by the gut pathobiont Candida albicans. This species primes systemic Th17 immunogenicity which protects against disseminated infection, and yet the fungal determinants driving protection remain uncertain. Here we show an essential role for the cytolytic toxin candidalysin for C. albicans colonization-induced systemic Th17 immunogenicity and protection against invasive infection. Mice intestinally colonized with candidalysin-deficient cells show reduced accumulation of CD4 T cells with defined fungal specificity, despite similar intestinal colonization levels to wildtype C. albicans cells. Fungal-specific RORγt+ CD4 T cells are particularly reduced together with their production of IL17A and IL17F cytokines, whereas expression of transcription factors and production of cytokines representative of other helper T cell lineages are unaffected. Protection against fungemia conferred by colonization with wildtype C. albicans is overturned in mice colonized with candidalysin-deficient cells as shown by increased fungal pathogen burden and reduced survival after intravenous infection. These results establish the necessity for candidalysin for priming Th17 fungal-specific adaptive immune cells and highlight paradoxical protective roles for this fungal virulence factor for promoting host defense against invasive systemic disease.
2026-05-02 | MCPIP1 modulates host antifungal immunity and exacerbates lethal Candida albicans infection.
Candida albicans (C. albicans) is the leading cause of systemic candidiasis in immunocompromised individuals and is associated with substantial mortality. As current antifungal therapies are limited by suboptimal efficacy and the emergence of resistance, improved understanding of host-pathogen interactions that govern antifungal immunity is essential for identifying new therapeutic strategies. Here, we identify MCPIP1 as a host factor that negatively regulates antifungal immune responses during lethal C. albicans infection. Integrative bioinformatic analyses of transcriptomic profiles from human peripheral blood mononuclear cells (PBMCs) exposed to C. albicans identified MCPIP1 as a macrophage-associated gene closely linked to infection-induced immune remodeling. Functional validation using in vivo and in vitro models demonstrated that MCPIP1 expression was markedly induced following systemic C. albicans infection and that MCPIP1 impaired host antifungal defenses. In a murine model of systemic candidiasis, administration of recombinant MCPIP1 exacerbated disease severity, leading to increased fungal burdens, aggravated kidney injury, and reduced host survival. Consistently, MCPIP1 suppressed macrophage-mediated phagocytosis and killing of C. albicans in vitro, indicating a direct role in regulating host-pathogen interactions at the cellular level. Mechanistically, MCPIP1 attenuated macrophage antifungal activity by suppressing p38 MAPK and ERK1/2 signaling pathways, whereas activation of these pathways restored antifungal immune function and mitigated MCPIP1-mediated immunosuppression. Together, these findings identify MCPIP1 as a key host regulator that shapes antifungal immunity during systemic C. albicans infection and highlight MCPIP1 as a potential immunomodulatory target for the treatment of invasive fungal disease.
vaccines
2026-07-15 | Evaluating the impact of immunization with the "pan-fungal" vaccine, NXT-2, on the gut mycobiome and microbiome in non-human primates (NHPs).
Fungal infections remain a significant public health concern with high mortality, morbidity, and increasing associated health costs. This burden is projected to rise due to expansion of at-risk populations, limited therapeutics, increasing drug resistance, and the emergence of new fungal pathogens. Even with these challenges, there are currently no approved vaccines. We previously developed a "pan-fungal" vaccine candidate, NXT-2, that confers protection against multiple invasive fungal infections such as pulmonary aspergillosis, pneumocystosis, and invasive candidiasis, as well as non-invasive vulvovaginal candidiasis. NXT-2 is a 90 amino acid consensus peptide designed from a conserved region of the fungal antigen (KEX1). We assessed the effect of NXT-2 immunization on gut microbial diversity, composition, and functional capacity in non-human primates. To do this, we monitored changes in the gut mycobiome and microbiome pre- and post-vaccination using ITS2 and metagenomic sequencing, respectively, in Japanese and rhesus macaque cohorts. NXT-2 elicited a robust antibody response without disrupting the gut microbial communities in both macaque species. The mycobiome exhibited stability with no significant changes in alpha and beta diversity, taxonomic composition, or functional guild distributions. The relative abundance of gut resident Candida and Aspergillus species remained stable and was not significantly altered following vaccination. The microbiome showed stability with preserved alpha and beta diversities, taxonomic composition, and functional capacity. Results from this study show the first cross-kingdom analysis demonstrating that antifungal vaccination can achieve protective immunity without perturbing gut microbial communities. This establishes a framework for microbiome-informed vaccine assessment beyond conventional immunogenicity and adverse effect monitoring.IMPORTANCEFungal infections cause millions of deaths annually, yet no vaccines are approved despite growing drug resistance and limited treatment options. NXT-2 is a pan-fungal vaccine that protects against multiple fungal infections such as pneumocystosis, candidiasis, and aspergillosis. Here, we demonstrate in NHPs that NXT-2 elicits robust protective antibody responses without altering gut bacterial or fungal communities. This is the first study to assess antifungal vaccination across both microbial kingdoms and establish that protective antifungal immunity can be achieved while preserving resident microbiota. This work provides a framework for incorporating microbiome assessment into vaccine development beyond conventional immunogenicity and adverse event monitoring.
2025-12-16 | Next-generation Candida albicans vaccine VXV-01 containing recombinant Als3p and Hyr1p antigens for invasive Candida infections.
Candida species, including Candida albicans and Candida auris, represent a growing public health concern due to their increasing prevalence and resistance to antifungal agents. C. albicans is known for causing both superficial and invasive infections, while C. auris is a newly emerged, multidrug-resistant pathogen responsible for severe hospital outbreaks with a high mortality rate of ~ 60% in bloodstream infections. Vaccine candidates targeting C. albicans hyphal cell wall proteins Als3p and Hyr1p have shown protective efficacy in mice. NDV-3A, an alum-formulated Als3p-based vaccine, protected against recurrent vulvovaginal candidiasis in women. We earlier showed that both Als3p and Hyr1p have orthologs in C. auris, and that the NDV-3A vaccine, alongside an anti-Hyr1p monoclonal antibody, protected mice from multidrug resistant C. auris candidemia. Here, we optimized VXV-01, an Als3p and Hyr1p dual antigen vaccine formulated with the clinical-stage adjuvant CAF01, demonstrating robust immunity and CD4 T cell-dependent protection against lethal C. albicans and C. auris. The VXV-01 vaccine did not antagonize antifungal drug therapy and showed higher overall mouse survival than mice receiving the vaccine or antifungal drug alone, albeit this difference did not reach statistical significance. This study highlights the potential of VXV-01 in providing durable protective immunity against hematogenously disseminated C. albicans and C. auris and mucosal C. albicans infections.
2025-10-28 | Active and Passive Immunization of Pan-Fungal Vaccine NXT-2 Reduces Morbidity and Mortality in an Immunosuppressed Murine Model of Candida auris Systemic Infection.
Candida auris has emerged as a significant public health threat causing life-threatening systemic infections. Of particular concern is the frequency of multidrug resistance, high transmissibility, and persistence in the environment; thus, there is a need for novel strategies to prevent and treat this infection. We previously generated a "pan-fungal" vaccine candidate, NXT-2, which induces protective immunity against several invasive fungal infections. In this study, we investigated the efficacy of NXT-2 immunization against systemic C. auris infection in an immunosuppressed murine model and investigated the possible mechanisms by which NXT-2 protection is mediated in vitro. Active immunization afforded significant improvement in survival and reduced morbidity in neutropenic mice challenged intravenously with C. auris compared to controls (48.4% vs. 13.8%). To assess humoral immunity in promoting protection, passive immunization with NXT-2-specific IgG to neutropenic mice prior to the challenge with C. auris resulted in significantly higher survival (42% vs. 0%) and low morbidity compared to controls. Sera from NXT-2-immunized animals inhibited biofilm formation and enhanced opsonophagocytic killing of multiple C. auris clades in vitro. These findings show that immunization with NXT-2 improves survival in C. auris infection and that NXT-2 antibodies promote antifungal activity in vitro and in vivo. These results extend the range of the pan-fungal NXT-2 vaccine to include protection against systemic C. auris-mediated infection and provide a rationale for the development of NXT-2 monoclonal antibodies for the treatment of C. auris infections.
2025-09-22 | Loss of CHT3 in Candida albicans wild-type strains increases surface-exposed chitin and affects host-pathogen interaction.
The chitinase Cht3 plays a major role in the chitinolytic activity of the pathogenic yeast Candida albicans and has also been proposed as a major antigen with potential for vaccine development against systemic candidiasis. The current study aims to enhance our knowledge on the role of Cht3 in cell surface organization and virulence of C. albicans. To this end, CHT3 deletion mutants generated in two wild-type genetic backgrounds (reference strain SC5314 and clinical isolate 124A) were phenotypically characterized. Absence of CHT3 did not affect growth rate but affected cell separation of dividing yeast cells at 37 °C. Further, cht3Δ mutants showed enhanced levels of surface-exposed chitin and slightly increased resistance to the cell wall perturbants Calcofluor white and Congo red and the β-1,3-glucan hydrolyzing enzyme Zymolyase, while the total level of chitin appeared unaltered. Deletion of one gene copy diminished CHT3 transcript levels by about 90% in both backgrounds. In strain 124A, showing two-fold higher CHT3 expression than SC5314, loss of CHT3 was compensated by upregulation of CHT2. Infection studies with cht3Δ mutants in strain 124A showed that CHT3 deletion led to attenuated virulence. Histological analysis of infected kidneys showed that CHT3 deletion did not affect the morphology of C. albicans cells during infection, but it appeared to delay activation of macrophages for efficient yeast killing. In conclusion, this study demonstrated that Cht3 activity is required for normal cell separation during yeast growth, cell surface organization, and full virulence of C. albicans in vivo. Its importance for virulence aligns with the earlier observed potential of Cht3 as vaccine candidate and warrants further studies to elucidate the mechanisms underlying its role in virulence and interaction with the host immune system.
2025-09-15 | Next-generation Candida albicans recombinant Als3p and Hyr1p dual antigen vaccine for invasive Candida infections.
Candida species, including Candida albicans and Candida auris, represent a growing public health concern due to their increasing prevalence and resistance to antifungal agents. C. albicans is known for causing both superficial and invasive infections, while C. auris is a newly emerged, multidrug-resistant pathogen responsible for severe hospital outbreaks with a high mortality rate of ~ 60% in bloodstream infections. Vaccine candidates targeting C. albicans hyphal cell wall proteins Als3p and Hyr1p have shown protective efficacy in mice. NDV-3A, an alum-formulated Als3p-based vaccine, protects against recurrent vulvovaginal candidiasis in women. We earlier showed that both Als3p and Hyr1p have orthologs in C. auris, and that the NDV-3A vaccine, alongside an anti-Hyr1p monoclonal antibody, protect mice from lethal C. auris candidemia. Here, we optimized Als3p and Hyr1p dual antigen vaccine formulations with the clinical-stage adjuvant CAF01, demonstrating robust immunity and CD4 T celldependent protection against lethal C. albicans and C. auris. The vaccine formulations also showed enhanced protective efficacy when combined with antifungal drugs. This study highlights the potential of the CAF01-formulated Als3p/Hyr1p dual antigen vaccine in providing durable protective immunity against systemic and mucosal C. albicans and cross-protection against systemic multidrug-resistant C. auris infections.
antibodies
2026-08-12 | Candidalysin at the epithelial-systemic interface: mechanistic evidence, critical-care relevance, and translational opportunities in invasive candidiasis
Invasive candidiasis remains a stubborn source of morbidity and mortality in critically ill and immunocompromised patients. One reason progress has been slow is that the route from epithelial colonization to bloodstream or deep-organ infection is still described with more confidence than the evidence often allows. Candidalysin, a 31-amino-acid amphipathic peptide released from the Ece1 precursor by Candida albicans hyphae, is well established as a driver of epithelial damage and mucosal immune activation. Its contribution to invasive disease is far less certain. Recent work has broadened the molecular framework for candidalysin biology. Host-binding studies have identified sulfated glycosaminoglycans and other candidate partners. Biophysical studies have refined models of peptide polymerization, membrane insertion, and host membrane repair. Infection models have linked candidalysin to intestinal epithelial barrier failure, catheter persistence, macrophage escape, neutrophil remodeling, commensal fitness, and protective Th17 immunity. These observations sit at different distances from human invasive candidiasis: some are biochemical or cell-based, some are supported by organotypic or animal models, and only a small subset currently has human diagnostic or clinical correlation. In this review, we separate these evidence layers and argue that candidalysin should be treated as a candidate biomarker or adjunctive target for selected toxin-producing Candida albicans infections, not as a general explanation for invasive candidiasis.
2026-05-18 | A Candida glabrata adhesin-like effector drives fitness and immunogenicity in the gut.
Candida glabrata is a leading cause of invasive candidiasis. The gut serves as its primary reservoir, yet factors governing colonization and pathogenic potential remain poorly defined. Here, we identify immunoglobulin A (IgA) as a key regulator of C. glabrata within the intestinal microbiome. We found that C. glabrata induces an IgA response in a strain-specific manner. Comparative transcriptional and proteomic analyses of IgA-inducing and non-inducing strains identified a putative adhesin, Awp11, whose expression correlated with IgA induction. Awp11 is directly targeted by IgA and is required for inducing C. glabrata-specific IgA and Th17 responses in vivo. Functionally, Awp11 promotes colonization of a complex intestinal microbiome, and intestinal IgA limits this advantage. In most strains, AWP11 transcription is dynamic and limited by IgA in the gut. This identifies Awp11 as a key determinant of strain-dependent immunogenicity and gut colonization that C. glabrata may dynamically regulate to balance colonization and immune evasion.
2026-03-09 | The pathogenicity and future treatment strategies of Candida albicans.
Candida albicans (C. albicans) is a major pathogenic fungus that severely impacts on human health. This review systematically elaborates on the key pathogenic processes of C. albicans, starting with its colonization, morphological transformation and biofilm formation under different carbon sources. The interaction between C. albicans and host immunity, including the role of PRRs, host genetics and immune polymorphisms, and trained immunity. Candidalysin regulating cAMP/PKA signaling pathway of C. albicans hyphae-biofilm transformation, the interaction between C. albicans and bacteria, as well as mucosal and invasive C. albicans infections, persister cells in anti-C. albicans therapy, emerging biology and pathogenicity aspects, epigenetic and chromatin regulation of host-drug adaptation, and strain-specific heterogeneity in pathogenicity, biofilm traits and drug susceptibility. Additionally, it summarizes novel therapeutic strategies, emphasizing probiotics and antimicrobial peptides (AMPs), and combination strategies with novel targeted therapy and traditional anti-fungal therapy to improve the survival of patients with Candida albicans infection. It systematically and comprehensively summarizes the pathogenicity of C. albicans and the possible therapeutic targets, providing new ideas for the development of novel antifungal drugs in the future.
2026-01-28 | Meteorin-like is associated with poor outcome in invasive candidiasis in mouse models and in humans.
Invasive candidiasis is a leading cause of nosocomial bloodstream infection associated with high mortality, and there is a pressing need to develop biomarker-guided antifungal therapy to improve clinical outcomes. Meteorin-like (METRNL) is a cytokine that can act as a high-affinity ligand for the stem cell factor receptor KIT; however, the functional role of METRNL in fungal infection remains unclear. Here, we found that METRNL acts as a disease-promoting immune checkpoint to facilitate invasive Candida albicans (C. albicans) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with C. albicans. Treatment with a METRNL blocking antibody protected mice from invasive C. albicans infection, whereas treatment with recombinant METRNL or overexpression of endogenous METRNL dampened fungal clearance and aggravated disease mortality but not in mice with macrophage-specific deletion of KIT. The METRNL-KIT axis decreased dectin-1 expression and impaired fungal phagocytosis and killing capacity in macrophages, which was dependent on signal transducer and activator of transcription 3 signaling, thereby negatively regulating host antifungal immunity. In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with patients with bacteremia or healthy volunteers. In both cohorts, a higher circulating METRNL concentration was associated with poor survival. Therefore, our study provides mechanistic and translational insights into how METRNL orchestrates macrophage-dependent antifungal immunity, implying that a potential theranostic approach involving blood-circulating METRNL-guided patient stratification and targeted therapy of blocking METRNL may help improve the management of human fungal disease through a precision medicine strategy.
2025-10-22 | Eosinophil CD48 interactions with Candida albicans Als6 is protective in vitro and in mouse systemic candidiasis.
Eosinophils are innate immune cells with central roles in allergy, parasitic diseases and multiple inflammatory conditions. Moreover, their role in host-pathogen interactions has been well characterized. However, the role of eosinophils during fungal infection is poorly defined. In this study, we delineate the importance of eosinophils during C. albicans systemic infections. C. albicans is promptly phagocytosed by human eosinophils, but growing hyphae escape this mechanism by releasing the fungal toxin candidalysin, which causes eosinophil membrane damage and cell death. Concomitantly, eosinophil mediators, notably major basic protein 1 (MBP-1), released during cytolysis, inhibits C. albicans growth and viability. Moreover, systemic candidiasis in genetic (Δdbl/GATA) or anti-IL-5-mediated depletion of eosinophils results in increased fungal burden and decreased survival. We here identified CD48 as a major receptor of eosinophils and possibly of other immune cells involved in the recognition of C. albicans via agglutinin-like sequence 6 (Als6). CD48 is important for protection in a model of systemic candidiasis as shown in CD48-/- mice and it binds clinical isolates of C. albicans. In conclusion, we have defined a protective role for eosinophils in vitro and in mouse C. albicans infections through CD48/Als6 host-pathogen interaction axis.
other
2025-12-06 | Extracellular vesicles from Candidozyma (Candida) auris inhibit proliferation of CD4 T cells by disrupting the IL-2 axis.
Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant pathogenic fungus that has rapidly spread across the world. Due to the high frequency of multidrug-resistant strains and mortality rate, C. auris is considered a critical health threat by the Centers for Disease Control and Prevention and the World Health Organization. Like other pathogens, C. auris employs virulence factors that are delivered by extracellular vesicles (EVs). We have shown that EVs from C. auris (CauEVs) activate murine phagocytes, boosting innate immune mechanisms. However, the effect of fungal EVs on lymphoid cells has not yet been addressed. Upon activation, CD4 T cells undergo clonal expansion and cytokine production that orchestrate immune responses to eradicate invading pathogens, a process of critical importance in controlling invasive candidiasis. Here, we show that the treatment with CauEVs inhibited the activation-induced CD4 T cells proliferation in a dose-dependent manner. Notably, we found that CauEVs acted at early events downstream to the T cell receptor signaling, inhibiting the MAPK phosphorylation. Interestingly, the inhibition of CD4 T cell proliferation by CauEVs was associated with an inhibition of the IL-2 signaling, followed by an increase on the IL-2 production that failed to restore proliferation. Taken together, our results suggest that CauEVs may contain an immunomodulatory factor(s) that affect the CD4 T cell activation and their fate from early to later events in a previously undescribed mechanism.
2025-11-19 | Characterization of dual DNA polymerase knockout strains of Candida albicans with live whole-cell vaccine competence.
Systemic candidiasis inflicts ~1.2 million deaths annually worldwide. Despite its severity, an approved antifungal vaccine remains an unmet human need. In a quest to design a live-whole cell vaccine, we characterized and demonstrated the vaccine potential of two dual DNA polymerase-defective strains of Candida albicans. While the deletion of POL32 in a hyper-virulent rad30ΔΔ strain attenuated the virulence, the deletion of RAD30 in an avirulent pol32ΔΔ did not revert to a hypervirulence phenotype. Both the dual polymerase-defective strains replicate transiently in the host and trigger immune responses to prevent reinfections in mice by employing a concerted involvement of innate, adaptive, and trained immunity. The cellular and molecular depletion in immunized mice suggested the role of B- and T-cells, neutrophils, and macrophages in antifungal immunity. Altogether, our results confirmed that Pol32 is a true virulence factor and intravenous vaccination with these attenuated strains could prevent systemic candidiasis in the preclinical models without evident safety concerns; thus, these candidate strains have enormous translational potential to fully develop as antifungal vaccines.
2025-06-11 | Mannan-targeting chimeric antigen receptor redirected antifungal activity of NK-92 cells against Candida albicans.
Chimeric antigen receptors (CARs) offer promising prospects for innovative cell-based therapies against invasive fungal infections such as invasive candidiasis. Here, we have developed 4 CARs targeting Candida albicans with distinct single-chain variable fragments (scFvs): scFv3-CAR, scFv5-CAR, scFv12-CAR, and scFvκ3-1-CAR. In T cells, scFv5-CAR induced IL-2 expression in response to C. albicans hyphae, while scFv3-CAR and scFv12-CAR did not mediate cell activation against C. albicans. Notably, scFvκ3-1-CAR mediated the strongest cell activation against C. albicans yeast, hyphae, and other clinically relevant Candida species. scFvκ3-1-CAR-NK-92 cells exhibited elevated IFN-γ and CD107a expression, reducing C. albicans viability. NOD scid gamma (NSG) mice treated with scFvκ3-1-CAR-NK-92 cells had reduced C. albicans burden in the kidneys 24 hours postinfection. We showed that scFvκ3-1-CAR targets C. albicans mannan but no other glycans in glycan microarray screening analyses. These findings reveal the scFvκ3-1-CAR potential as a therapeutic strategy for treating Candida spp. by modifying peripheral blood mononuclear cells.
2025-05-13 | Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
Central trained immunity, induced via reprogramming of hematopoietic stem and progenitor cells (HSPCs), mediates sustained heightened responsiveness of mature myeloid cells to secondary challenges. We have previously demonstrated that HSPCs use TLR2 and Dectin-1 to sense Candida albicans to induce the production of trained monocytes/macrophages to fight against secondary infection. Neutrophils play an important role in innate immunity and are critical for clearance of C. albicans. In this work, we used an in vitro model of mouse HSPC differentiation to investigate the functional phenotype of neutrophils derived from HSPCs exposed to various PAMPs and C. albicans cells. We found that neutrophils derived from HSPCs stimulated by a TLR2 agonist exhibit reduced inflammatory cytokine production (tolerized neutrophils) whereas neutrophils generated from a Dectin-1 agonist or C. albicans stimulated HSPCs produce higher amounts of cytokines (trained neutrophils). We further demonstrated that a transient exposure of HSPCs to live C. albicans cells is sufficient to induce a trained phenotype of the neutrophils they produce in a Dectin-1- and TLR2-dependent manner. These trained neutrophils exhibited higher phagocytosis and microbicidal capacity than control neutrophils. Additionally, their adoptive transfer was sufficient to reduce fungal burden during invasive candidiasis. Mechanistically, we demonstrated that trained neutrophils use mitochondrial ROS (mtROS) to enhance their ability to kill C. albicans cells, as they produce higher amounts of mtROS and scavenging mtROS with MitoTEMPO attenuated their yeast-killing ability to match that of control neutrophils. Altogether, these data suggest that infection-experienced HSPCs contribute to trained immunity by providing a source of trained neutrophils with enhanced antimicrobial activity which may confer prolonged protection from infection. The tailored manipulation of this mechanism might offer new therapeutic strategies for controlling fungal infections by harnessing neutrophils.
2025-04-16 | Mannan is a context-dependent shield that modifies virulence in Nakaseomyces glabratus.
Fungal-host interaction outcomes are influenced by how the host recognizes fungal cell wall components. Mannan is a major cell wall carbohydrate and can be a glycoshield that blocks the inner cell wall β-1,3-glucan from activating pro-inflammatory immune responses. Disturbing this glycoshield in Candida albicans results in enhanced antifungal host responses and reduced fungal virulence. However, deletions affecting mannan synthesis can lead to systemic hypervirulence for Nakaseomyces glabratus (formerly Candida glabrata) suggesting that proper mannan architecture dampens virulence for this organism. N. glabratus is the second leading cause of invasive and superficial candidiasis, but little is known about how the cell wall affects N. glabratus pathogenesis. In order to better understand the importance of these species-specific cell wall adaptations in infection, we set out to investigate how the mannan polymerase II complex gene, MNN10, contributes to N. glabratus cell wall architecture, immune recognition, and virulence in reference strains BG2 and CBS138. mnn10Δ cells had thinner inner and outer cell wall layers and elevated mannan, chitin, and β-1,3-glucan exposure compared to wild-type cells. Consistent with these observations, mnn10Δ cells activated the β-1,3-glucan receptor in oral epithelial cells (OECs), EphA2, and caused less OEC damage than wild-type. mnn10Δ replication was also restricted in macrophages compared to wild-type controls. Yet, during systemic infection in Galleria mellonella larvae, mnn10Δ cells induced rapid larval melanization and BG2 mnn10Δ cells killed larvae significantly faster than wild-type. Thus, our data suggest that mannan plays context-dependent roles in N. glabratus pathogenesis, acting as a glycoshield in superficial disease models and modulating virulence during systemic infection.
small molecules
2026-08-14 | Epigenetic repression of IL-1β by C1QBP restricts Dectin-1-mediated host defense against murine invasive candidiasis
Invasive candidiasis, predominantly caused by Candida albicans, threatens immunocompromised individuals with high mortality. Dendritic cell-derived interleukin-1β, orchestrated via Dectin-1-mediated β-glucan recognition, is central to antifungal defense. While the Dectin-1/Syk/CARD9 axis governing Il1b transcription is defined, the epigenetic regulatory mechanisms remain elusive. Here, we identify Complement C1q binding protein (C1QBP) as a critical negative regulator of Dectin-1-mediated interleukin-1β production. C1QBP sequesters phosphorylated protein kinase C δ in the cytoplasm, preventing its nuclear transport. Nuclear phosphorylated-PKCδ activates the RNF20/RNF40 ubiquitin ligase complex, which recruits the methyltransferase DOT1L to catalyze histone H3 lysine 79 trimethylation at the Il1b locus to promote its transcription. DC-specific C1QBP depletion enhances interleukin-1β secretion, amplifies protective T helper 17 cell responses, and improves host resistance to systemic C. albicans infection in mice. Collectively, our findings establish C1QBP as a key checkpoint in a PKCδ-dependent epigenetic pathway that constrains antifungal immunity, highlighting its therapeutic potential for invasive fungal diseases. Engagement of Dectin-1 on dendritic cells drives IL-1β production and is a critical component of the immune response to invasive candidiasis. Here the authors show epigenetic repression of IL-1β by a complement binding protein can restrain the dectin1 driven immune response in a murine model of invasive candidiasis.
2026-08-14 | First Reported Neonatal Invasive Candidozyma auris (Candida auris) Infection in Brazil: Successful Management, Evolving Amphotericin B Resistance, and Infection Containment.
To describe the first neonatal invasive Candida auris infection in Brazil and its successful clinical and infection control management. Retrospective description of the clinical course, microbiological findings, antifungal susceptibility evolution, and follow-up of an extremely preterm infant. A 25 + 4-week male neonate developed bloodstream and urinary C. auris infection during the first week of life. Progressive amphotericin B resistance in urine isolates required the addition of fluconazole. No secondary NICU cases occurred. Early diagnosis, serial susceptibility testing, and immediate containment measures enabled successful treatment and prevented nosocomial spread.
2026-08-11 | Mitochondrial characteristics of echinocandin tolerance and resistance in Candida glabrata and Candida krusei.
Candidiasis, especially candidemia, is one of the most common invasive fungal infections. With the increase of risk factors such as tumors, its high incidence and high mortality rate pose a significant challenge to public health. Echinocandins, as first-line drugs for candidemia, have their clinical efficacy severely weakened by the emergence of tolerant or resistant strains such as Candida glabrata and Candida krusei. The study evaluated the changes in mitochondrial phenotype (intracellular ATP levels, mitochondrial membrane potential, mitochondrial superoxide levels, and intracellular ROS levels), proteomic, metabolomic, and genomic in C. glabrata and C. krusei. By analyzing strains with different susceptibility profiles, the study found that echinocandin tolerant or resistant strains displayed significant upregulation of ATP levels and unique metabolic adaptations. Quantitative proteomics identified differentially expressed proteins associated with mitochondrial function and energy metabolism. Metabolomic analysis further revealed distinct profiles linking resistance to alterations in purine metabolism and oxidative phosphorylation. Additionally, genomic sequencing of the resistant strains highlighted mutations in key genes involved in ATP binding. These findings highlight the mitochondrial characteristics in echinocandin tolerance and resistance in C. glabrata and C. krusei, providing valuable insights into potential pathways for future therapeutic interventions targeting resistant Candida species.
2026-08-10 | Slt2 kinase of the cell wall integrity pathway is required for Fks2-specific echinocandin resistance in Candida glabrata.
Candida glabrata is an opportunistic yeast that causes invasive infections in immunocompromised individuals. Echinocandin antifungals are first-line agents in the treatment of invasive candidiasis and act by inhibiting fungal cell wall synthesis by targeting β-1,3-glucan synthase. Echinocandin resistance is primarily associated with mutations in FKS1 or FKS2, which encode for the catalytic subunit (Fks1 or Fks2) of the targeted glucan synthase. The cell wall integrity (CWI) pathway, including Slt2 kinase, is known to mediate tolerance to antifungal drugs, but its role in resistance is not completely defined. Here, we observed that disruption of SLT2 abrogated echinocandin resistance due to FKS2, but not FKS1, mutation in C. glabrata. As expected, reintroduction of plasmid-borne SLT2 restored elevated MICs of fks2 mutants. RT-qPCR revealed that loss of SLT2 led to decreased FKS2 expression levels in wild-type and echinocandin-resistant strains following echinocandin exposure. In conclusion, the CWI pathway and Slt2 comprise a primary control mechanism for FKS2-mediated echinocandin resistance in C. glabrata.IMPORTANCEThe higher rates of acquired antifungal resistance exhibited by Candida glabrata merit further understanding of resistance mechanisms including fungal regulation of drug target genes and enzymes. Here, we focused on a fungal tolerance pathway, the cell wall integrity pathway, and its requirement in C. glabrata echinocandin antifungal resistance. Interestingly, we found that targeting the pathway through disruption of a key protein, Slt2, reversed echinocandin resistance within one subset of resistant strains (fks2 mutants) but not another (fks1 mutants). Gene expression studies demonstrated the requirement of SLT2 for full FKS2 gene expression following echinocandin treatment. Overall, we discovered that Slt2 is specifically required for Fks2-mediated echinocandin resistance through partial regulation of FKS2 expression. This study provides further insight into the regulation of drug target genes in C. glabrata and provides a possible therapeutic target for echinocandin-resistant infections caused by mutation of FKS2.
2026-08-09 | Mutations in MRR1 that confer fluconazole resistance in C. parapsilosis and C. albicans confer cross-resistance to manogepix.
Fluconazole resistance has been documented in Candida albicans and Candida parapsilosis, both leading causes of invasive candidiasis, driven in part by mutations in MRR1 which encodes a transcription factor that regulates drug efflux pump expression. A correlation has been observed between susceptibilities to fluconazole and manogepix, the active moiety of fosmanogepix, a promising new antifungal with activity against most Candida species. We aimed to determine whether MRR1-activating mutations driving fluconazole resistance in these species conferred cross-resistance to manogepix. C. albicans and C. parapsilosis clinical isolates and strains engineered to express wild-type or mutant MRR1 alleles, and their derivatives deleted for target drug transporters, were assessed for fluconazole and manogepix susceptibility. Introducing Mrr1 I283R and A854V substitutions into C. parapsilosis clinical isolate Cp13 increased fluconazole MIC from 0.25 to 32 mg/L and increased manogepix MIC from 0.008 to 0.25 mg/L, whereas correcting to MRR1 wild-type sequence in fluconazole-resistant clinical isolates reduced fluconazole MICs from 64, 128, and 64 mg/L to 1, 1, and 2 mg/L, respectively, and manogepix MICs from 0.125, 0.25, and 0.125 mg/L to 0.015 mg/L for all. This was dependent upon genes encoding Mdr1b and Cdr1b transporters. In C. albicans, introducing different MRR1-activating mutations into SC5314 increased fluconazole MICs from 0.5 mg/L to 4-16 mg/L and increased manogepix MICs from 0.015-0.03 mg/L to 0.06 mg/L. Activating mutations in clinical isolates increased fluconazole MICs from 1-2 mg/L to 32-64 mg/L and manogepix MICs by 2- to 4-fold. MRR1 deletion in resistant isolates restored susceptibility to both drugs. Our findings demonstrate that fluconazole and manogepix cross-resistance in C. parapsilosis conferred by MRR1-activating mutations is mediated by Cdr1b and Mdr1b transporters. MRR1-activating mutations conferred cross-resistance, to a lesser degree, in C. albicans, but independent of drug transporters known to be regulated by Mrr1.
proteins
2026-08-02 | The potential of bacteriocins in invasive fungal infections: Antifungal activities and intestinal protection.
Invasive fungal infections are life-threatening complications in immunocompromised and critically ill patients. Invasive candidiasis may arise from endogenous fungal reservoirs, particularly under conditions of intestinal barrier disruption. Although conventional antifungal agents remain the therapeutic foundation, their clinical use is increasingly challenged by the emergence of resistant fungal pathogens, such as Candida auris. Bacteriocins are ribosomally synthesized antimicrobial peptides produced by microorganisms. Beyond their well-established applications in the food industry, bacteriocins have attracted increasing attention in recent years for their antifungal properties. In this review, we provide an overview of bacteriocins with reported antifungal activity and summarize their underlying mechanisms. In addition, we discuss the potential protective effects of bacteriocins on the microbial, mechanical, chemical, and immune barriers of the intestine. Finally, we evaluate the potential clinical applications of these bacteriocins, along with future challenges and research directions related to invasive fungal infections.
2026-07-21 | Tissue-type plasminogen activator protects against kidney damage in invasive fungal infection.
Invasive Candida albicans infections (candidiasis) cause progressive organ damage through fungal tissue invasion and toxin-mediated injury, including in the kidney. Hyphal invasion induces apoptosis of renal tubular epithelial cells (RTEC), a key driver of kidney pathology, yet intrinsic renal protective mechanisms remain poorly defined. We identify fibrinolytic tissue-type plasminogen activator (tPA) as a critical mediator of renal tissue protection in candidiasis. tPA is induced by IL-17 and TNFα in renal endothelial cells and RTEC. tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and activates ERK1/2 signaling to suppress apoptosis in RTEC. Mice with RTEC-specific deletion of LRP1 exhibited exaggerated kidney damage during candidiasis. Administration of a nonenzymatic form of tPA recapitulated the protective effect of tPA by limiting RTEC apoptosis. These findings reveal the role of tPA/LRP1 axis in preserving renal integrity in candidiasis and suggest clinically approved tPA as a potential therapeutic strategy to mitigate candidiasis-associated tissue injury.
2026-06-30 | Evaluation of immunological and gene expression responses induced by Galectin-3 and whole-sonicated Candida krusei antigen in rats experimentally infected with Candida krusei.
Candida krusei is an emerging non-Candida albicans species increasingly associated with antifungal resistance and invasive systemic infections. Galectin-3 (GAL-3), a β-galactosidase-binding lectin, and the surfactant protein D gene are important components of innate antifungal immunity. The chemokine (C-X-C motif) ligand-1 gene plays a central role in neutrophil recruitment, whereas whole-sonicated C. krusei antigen may act as a broad fungal immunogen. To evaluate the immunological and pulmonary gene expression responses induced by GAL-3, whole-sonicated C. krusei antigen, and their combination in rats experimentally infected with C. krusei, via measurement of serum immunoglobulin G, interleukin-17, interleukin-23, and lung expression of Chemokine (C-X-C motif) ligand 1 (CXCL-1) and surfactant protein D genes. A total of 120 rats were randomly allocated into four experimental groups (n = 30). Animals received GAL-3, whole-sonicated C. krusei antigen, and their combination, while the control group was subdivided into infected and healthy controls. Immunized groups were administered subcutaneously according to the experimental schedule. Systemic C. krusei infection was induced intraperitoneally, and samples were collected at 15 and 30 days post-challenge. Serum Immunoglobulin G, Interleukin -17 (IL-17), and Interleukin -23 (IL-23) levels were measured using ELISA. Pulmonary CXCL-1 and surfactant protein D gene expression were quantified using SYBR Green reverse transcription quantitative polymerase chain reaction and analyzed using the 2⁻ΔΔCt method. Immunoglobulin G levels increased significantly in all treated groups compared with infected and healthy controls, with the highest levels at day 30. Whole-sonicated C. krusei antigen and mixed treatment groups showed significant increases in IL-17 and IL-23, indicating activation of Th17-mediated immune responses. Galectin-3 treatment produced upregulation of CXCL-1 and surfactant protein D genes, whereas the antigen-treated group showed moderate gene expression changes. The combined treatment group demonstrated reduced CXCL-1 induction but maintained a modest increase in surfactant protein D expression. Galectin-3 and whole-sonicated C. krusei antigen may enhance antifungal immune responses through partially distinct mechanisms. Galectin-3 modulates the CXCL-1 and surfactant protein D gene axis and activate innate immune pathways, whereas whole-sonicated antigen stimulates IL-23/IL-17-mediated responses and humoral immunity. These findings suggest that GAL-3 and fungal antigen immunization may represent support immunomodulatory approaches for controlling infections caused by non-C. albicans.
2026-05-10 | Candidalysin promotes fungal-specific Th17 CD4 T cell differentiation and protective systemic immunogenicity.
Commensal microbes can cause invasive infection but can also stimulate protective immune responses as exemplified by the gut pathobiont Candida albicans. This species primes systemic Th17 immunogenicity which protects against disseminated infection, and yet the fungal determinants driving protection remain uncertain. Here we show an essential role for the cytolytic toxin candidalysin for C. albicans colonization-induced systemic Th17 immunogenicity and protection against invasive infection. Mice intestinally colonized with candidalysin-deficient cells show reduced accumulation of CD4 T cells with defined fungal specificity, despite similar intestinal colonization levels to wildtype C. albicans cells. Fungal-specific RORγt+ CD4 T cells are particularly reduced together with their production of IL17A and IL17F cytokines, whereas expression of transcription factors and production of cytokines representative of other helper T cell lineages are unaffected. Protection against fungemia conferred by colonization with wildtype C. albicans is overturned in mice colonized with candidalysin-deficient cells as shown by increased fungal pathogen burden and reduced survival after intravenous infection. These results establish the necessity for candidalysin for priming Th17 fungal-specific adaptive immune cells and highlight paradoxical protective roles for this fungal virulence factor for promoting host defense against invasive systemic disease.
2026-05-02 | MCPIP1 modulates host antifungal immunity and exacerbates lethal Candida albicans infection.
Candida albicans (C. albicans) is the leading cause of systemic candidiasis in immunocompromised individuals and is associated with substantial mortality. As current antifungal therapies are limited by suboptimal efficacy and the emergence of resistance, improved understanding of host-pathogen interactions that govern antifungal immunity is essential for identifying new therapeutic strategies. Here, we identify MCPIP1 as a host factor that negatively regulates antifungal immune responses during lethal C. albicans infection. Integrative bioinformatic analyses of transcriptomic profiles from human peripheral blood mononuclear cells (PBMCs) exposed to C. albicans identified MCPIP1 as a macrophage-associated gene closely linked to infection-induced immune remodeling. Functional validation using in vivo and in vitro models demonstrated that MCPIP1 expression was markedly induced following systemic C. albicans infection and that MCPIP1 impaired host antifungal defenses. In a murine model of systemic candidiasis, administration of recombinant MCPIP1 exacerbated disease severity, leading to increased fungal burdens, aggravated kidney injury, and reduced host survival. Consistently, MCPIP1 suppressed macrophage-mediated phagocytosis and killing of C. albicans in vitro, indicating a direct role in regulating host-pathogen interactions at the cellular level. Mechanistically, MCPIP1 attenuated macrophage antifungal activity by suppressing p38 MAPK and ERK1/2 signaling pathways, whereas activation of these pathways restored antifungal immune function and mitigated MCPIP1-mediated immunosuppression. Together, these findings identify MCPIP1 as a key host regulator that shapes antifungal immunity during systemic C. albicans infection and highlight MCPIP1 as a potential immunomodulatory target for the treatment of invasive fungal disease.
vaccines
2026-07-15 | Evaluating the impact of immunization with the "pan-fungal" vaccine, NXT-2, on the gut mycobiome and microbiome in non-human primates (NHPs).
Fungal infections remain a significant public health concern with high mortality, morbidity, and increasing associated health costs. This burden is projected to rise due to expansion of at-risk populations, limited therapeutics, increasing drug resistance, and the emergence of new fungal pathogens. Even with these challenges, there are currently no approved vaccines. We previously developed a "pan-fungal" vaccine candidate, NXT-2, that confers protection against multiple invasive fungal infections such as pulmonary aspergillosis, pneumocystosis, and invasive candidiasis, as well as non-invasive vulvovaginal candidiasis. NXT-2 is a 90 amino acid consensus peptide designed from a conserved region of the fungal antigen (KEX1). We assessed the effect of NXT-2 immunization on gut microbial diversity, composition, and functional capacity in non-human primates. To do this, we monitored changes in the gut mycobiome and microbiome pre- and post-vaccination using ITS2 and metagenomic sequencing, respectively, in Japanese and rhesus macaque cohorts. NXT-2 elicited a robust antibody response without disrupting the gut microbial communities in both macaque species. The mycobiome exhibited stability with no significant changes in alpha and beta diversity, taxonomic composition, or functional guild distributions. The relative abundance of gut resident Candida and Aspergillus species remained stable and was not significantly altered following vaccination. The microbiome showed stability with preserved alpha and beta diversities, taxonomic composition, and functional capacity. Results from this study show the first cross-kingdom analysis demonstrating that antifungal vaccination can achieve protective immunity without perturbing gut microbial communities. This establishes a framework for microbiome-informed vaccine assessment beyond conventional immunogenicity and adverse effect monitoring.IMPORTANCEFungal infections cause millions of deaths annually, yet no vaccines are approved despite growing drug resistance and limited treatment options. NXT-2 is a pan-fungal vaccine that protects against multiple fungal infections such as pneumocystosis, candidiasis, and aspergillosis. Here, we demonstrate in NHPs that NXT-2 elicits robust protective antibody responses without altering gut bacterial or fungal communities. This is the first study to assess antifungal vaccination across both microbial kingdoms and establish that protective antifungal immunity can be achieved while preserving resident microbiota. This work provides a framework for incorporating microbiome assessment into vaccine development beyond conventional immunogenicity and adverse event monitoring.
2025-12-16 | Next-generation Candida albicans vaccine VXV-01 containing recombinant Als3p and Hyr1p antigens for invasive Candida infections.
Candida species, including Candida albicans and Candida auris, represent a growing public health concern due to their increasing prevalence and resistance to antifungal agents. C. albicans is known for causing both superficial and invasive infections, while C. auris is a newly emerged, multidrug-resistant pathogen responsible for severe hospital outbreaks with a high mortality rate of ~ 60% in bloodstream infections. Vaccine candidates targeting C. albicans hyphal cell wall proteins Als3p and Hyr1p have shown protective efficacy in mice. NDV-3A, an alum-formulated Als3p-based vaccine, protected against recurrent vulvovaginal candidiasis in women. We earlier showed that both Als3p and Hyr1p have orthologs in C. auris, and that the NDV-3A vaccine, alongside an anti-Hyr1p monoclonal antibody, protected mice from multidrug resistant C. auris candidemia. Here, we optimized VXV-01, an Als3p and Hyr1p dual antigen vaccine formulated with the clinical-stage adjuvant CAF01, demonstrating robust immunity and CD4 T cell-dependent protection against lethal C. albicans and C. auris. The VXV-01 vaccine did not antagonize antifungal drug therapy and showed higher overall mouse survival than mice receiving the vaccine or antifungal drug alone, albeit this difference did not reach statistical significance. This study highlights the potential of VXV-01 in providing durable protective immunity against hematogenously disseminated C. albicans and C. auris and mucosal C. albicans infections.
2025-10-28 | Active and Passive Immunization of Pan-Fungal Vaccine NXT-2 Reduces Morbidity and Mortality in an Immunosuppressed Murine Model of Candida auris Systemic Infection.
Candida auris has emerged as a significant public health threat causing life-threatening systemic infections. Of particular concern is the frequency of multidrug resistance, high transmissibility, and persistence in the environment; thus, there is a need for novel strategies to prevent and treat this infection. We previously generated a "pan-fungal" vaccine candidate, NXT-2, which induces protective immunity against several invasive fungal infections. In this study, we investigated the efficacy of NXT-2 immunization against systemic C. auris infection in an immunosuppressed murine model and investigated the possible mechanisms by which NXT-2 protection is mediated in vitro. Active immunization afforded significant improvement in survival and reduced morbidity in neutropenic mice challenged intravenously with C. auris compared to controls (48.4% vs. 13.8%). To assess humoral immunity in promoting protection, passive immunization with NXT-2-specific IgG to neutropenic mice prior to the challenge with C. auris resulted in significantly higher survival (42% vs. 0%) and low morbidity compared to controls. Sera from NXT-2-immunized animals inhibited biofilm formation and enhanced opsonophagocytic killing of multiple C. auris clades in vitro. These findings show that immunization with NXT-2 improves survival in C. auris infection and that NXT-2 antibodies promote antifungal activity in vitro and in vivo. These results extend the range of the pan-fungal NXT-2 vaccine to include protection against systemic C. auris-mediated infection and provide a rationale for the development of NXT-2 monoclonal antibodies for the treatment of C. auris infections.
2025-09-22 | Loss of CHT3 in Candida albicans wild-type strains increases surface-exposed chitin and affects host-pathogen interaction.
The chitinase Cht3 plays a major role in the chitinolytic activity of the pathogenic yeast Candida albicans and has also been proposed as a major antigen with potential for vaccine development against systemic candidiasis. The current study aims to enhance our knowledge on the role of Cht3 in cell surface organization and virulence of C. albicans. To this end, CHT3 deletion mutants generated in two wild-type genetic backgrounds (reference strain SC5314 and clinical isolate 124A) were phenotypically characterized. Absence of CHT3 did not affect growth rate but affected cell separation of dividing yeast cells at 37 °C. Further, cht3Δ mutants showed enhanced levels of surface-exposed chitin and slightly increased resistance to the cell wall perturbants Calcofluor white and Congo red and the β-1,3-glucan hydrolyzing enzyme Zymolyase, while the total level of chitin appeared unaltered. Deletion of one gene copy diminished CHT3 transcript levels by about 90% in both backgrounds. In strain 124A, showing two-fold higher CHT3 expression than SC5314, loss of CHT3 was compensated by upregulation of CHT2. Infection studies with cht3Δ mutants in strain 124A showed that CHT3 deletion led to attenuated virulence. Histological analysis of infected kidneys showed that CHT3 deletion did not affect the morphology of C. albicans cells during infection, but it appeared to delay activation of macrophages for efficient yeast killing. In conclusion, this study demonstrated that Cht3 activity is required for normal cell separation during yeast growth, cell surface organization, and full virulence of C. albicans in vivo. Its importance for virulence aligns with the earlier observed potential of Cht3 as vaccine candidate and warrants further studies to elucidate the mechanisms underlying its role in virulence and interaction with the host immune system.
2025-09-15 | Next-generation Candida albicans recombinant Als3p and Hyr1p dual antigen vaccine for invasive Candida infections.
Candida species, including Candida albicans and Candida auris, represent a growing public health concern due to their increasing prevalence and resistance to antifungal agents. C. albicans is known for causing both superficial and invasive infections, while C. auris is a newly emerged, multidrug-resistant pathogen responsible for severe hospital outbreaks with a high mortality rate of ~ 60% in bloodstream infections. Vaccine candidates targeting C. albicans hyphal cell wall proteins Als3p and Hyr1p have shown protective efficacy in mice. NDV-3A, an alum-formulated Als3p-based vaccine, protects against recurrent vulvovaginal candidiasis in women. We earlier showed that both Als3p and Hyr1p have orthologs in C. auris, and that the NDV-3A vaccine, alongside an anti-Hyr1p monoclonal antibody, protect mice from lethal C. auris candidemia. Here, we optimized Als3p and Hyr1p dual antigen vaccine formulations with the clinical-stage adjuvant CAF01, demonstrating robust immunity and CD4 T celldependent protection against lethal C. albicans and C. auris. The vaccine formulations also showed enhanced protective efficacy when combined with antifungal drugs. This study highlights the potential of the CAF01-formulated Als3p/Hyr1p dual antigen vaccine in providing durable protective immunity against systemic and mucosal C. albicans and cross-protection against systemic multidrug-resistant C. auris infections.
antibodies
2026-08-12 | Candidalysin at the epithelial-systemic interface: mechanistic evidence, critical-care relevance, and translational opportunities in invasive candidiasis
Invasive candidiasis remains a stubborn source of morbidity and mortality in critically ill and immunocompromised patients. One reason progress has been slow is that the route from epithelial colonization to bloodstream or deep-organ infection is still described with more confidence than the evidence often allows. Candidalysin, a 31-amino-acid amphipathic peptide released from the Ece1 precursor by Candida albicans hyphae, is well established as a driver of epithelial damage and mucosal immune activation. Its contribution to invasive disease is far less certain. Recent work has broadened the molecular framework for candidalysin biology. Host-binding studies have identified sulfated glycosaminoglycans and other candidate partners. Biophysical studies have refined models of peptide polymerization, membrane insertion, and host membrane repair. Infection models have linked candidalysin to intestinal epithelial barrier failure, catheter persistence, macrophage escape, neutrophil remodeling, commensal fitness, and protective Th17 immunity. These observations sit at different distances from human invasive candidiasis: some are biochemical or cell-based, some are supported by organotypic or animal models, and only a small subset currently has human diagnostic or clinical correlation. In this review, we separate these evidence layers and argue that candidalysin should be treated as a candidate biomarker or adjunctive target for selected toxin-producing Candida albicans infections, not as a general explanation for invasive candidiasis.
2026-05-18 | A Candida glabrata adhesin-like effector drives fitness and immunogenicity in the gut.
Candida glabrata is a leading cause of invasive candidiasis. The gut serves as its primary reservoir, yet factors governing colonization and pathogenic potential remain poorly defined. Here, we identify immunoglobulin A (IgA) as a key regulator of C. glabrata within the intestinal microbiome. We found that C. glabrata induces an IgA response in a strain-specific manner. Comparative transcriptional and proteomic analyses of IgA-inducing and non-inducing strains identified a putative adhesin, Awp11, whose expression correlated with IgA induction. Awp11 is directly targeted by IgA and is required for inducing C. glabrata-specific IgA and Th17 responses in vivo. Functionally, Awp11 promotes colonization of a complex intestinal microbiome, and intestinal IgA limits this advantage. In most strains, AWP11 transcription is dynamic and limited by IgA in the gut. This identifies Awp11 as a key determinant of strain-dependent immunogenicity and gut colonization that C. glabrata may dynamically regulate to balance colonization and immune evasion.
2026-03-09 | The pathogenicity and future treatment strategies of Candida albicans.
Candida albicans (C. albicans) is a major pathogenic fungus that severely impacts on human health. This review systematically elaborates on the key pathogenic processes of C. albicans, starting with its colonization, morphological transformation and biofilm formation under different carbon sources. The interaction between C. albicans and host immunity, including the role of PRRs, host genetics and immune polymorphisms, and trained immunity. Candidalysin regulating cAMP/PKA signaling pathway of C. albicans hyphae-biofilm transformation, the interaction between C. albicans and bacteria, as well as mucosal and invasive C. albicans infections, persister cells in anti-C. albicans therapy, emerging biology and pathogenicity aspects, epigenetic and chromatin regulation of host-drug adaptation, and strain-specific heterogeneity in pathogenicity, biofilm traits and drug susceptibility. Additionally, it summarizes novel therapeutic strategies, emphasizing probiotics and antimicrobial peptides (AMPs), and combination strategies with novel targeted therapy and traditional anti-fungal therapy to improve the survival of patients with Candida albicans infection. It systematically and comprehensively summarizes the pathogenicity of C. albicans and the possible therapeutic targets, providing new ideas for the development of novel antifungal drugs in the future.
2026-01-28 | Meteorin-like is associated with poor outcome in invasive candidiasis in mouse models and in humans.
Invasive candidiasis is a leading cause of nosocomial bloodstream infection associated with high mortality, and there is a pressing need to develop biomarker-guided antifungal therapy to improve clinical outcomes. Meteorin-like (METRNL) is a cytokine that can act as a high-affinity ligand for the stem cell factor receptor KIT; however, the functional role of METRNL in fungal infection remains unclear. Here, we found that METRNL acts as a disease-promoting immune checkpoint to facilitate invasive Candida albicans (C. albicans) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with C. albicans. Treatment with a METRNL blocking antibody protected mice from invasive C. albicans infection, whereas treatment with recombinant METRNL or overexpression of endogenous METRNL dampened fungal clearance and aggravated disease mortality but not in mice with macrophage-specific deletion of KIT. The METRNL-KIT axis decreased dectin-1 expression and impaired fungal phagocytosis and killing capacity in macrophages, which was dependent on signal transducer and activator of transcription 3 signaling, thereby negatively regulating host antifungal immunity. In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with patients with bacteremia or healthy volunteers. In both cohorts, a higher circulating METRNL concentration was associated with poor survival. Therefore, our study provides mechanistic and translational insights into how METRNL orchestrates macrophage-dependent antifungal immunity, implying that a potential theranostic approach involving blood-circulating METRNL-guided patient stratification and targeted therapy of blocking METRNL may help improve the management of human fungal disease through a precision medicine strategy.
2025-10-22 | Eosinophil CD48 interactions with Candida albicans Als6 is protective in vitro and in mouse systemic candidiasis.
Eosinophils are innate immune cells with central roles in allergy, parasitic diseases and multiple inflammatory conditions. Moreover, their role in host-pathogen interactions has been well characterized. However, the role of eosinophils during fungal infection is poorly defined. In this study, we delineate the importance of eosinophils during C. albicans systemic infections. C. albicans is promptly phagocytosed by human eosinophils, but growing hyphae escape this mechanism by releasing the fungal toxin candidalysin, which causes eosinophil membrane damage and cell death. Concomitantly, eosinophil mediators, notably major basic protein 1 (MBP-1), released during cytolysis, inhibits C. albicans growth and viability. Moreover, systemic candidiasis in genetic (Δdbl/GATA) or anti-IL-5-mediated depletion of eosinophils results in increased fungal burden and decreased survival. We here identified CD48 as a major receptor of eosinophils and possibly of other immune cells involved in the recognition of C. albicans via agglutinin-like sequence 6 (Als6). CD48 is important for protection in a model of systemic candidiasis as shown in CD48-/- mice and it binds clinical isolates of C. albicans. In conclusion, we have defined a protective role for eosinophils in vitro and in mouse C. albicans infections through CD48/Als6 host-pathogen interaction axis.
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2025-12-06 | Extracellular vesicles from Candidozyma (Candida) auris inhibit proliferation of CD4 T cells by disrupting the IL-2 axis.
Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant pathogenic fungus that has rapidly spread across the world. Due to the high frequency of multidrug-resistant strains and mortality rate, C. auris is considered a critical health threat by the Centers for Disease Control and Prevention and the World Health Organization. Like other pathogens, C. auris employs virulence factors that are delivered by extracellular vesicles (EVs). We have shown that EVs from C. auris (CauEVs) activate murine phagocytes, boosting innate immune mechanisms. However, the effect of fungal EVs on lymphoid cells has not yet been addressed. Upon activation, CD4 T cells undergo clonal expansion and cytokine production that orchestrate immune responses to eradicate invading pathogens, a process of critical importance in controlling invasive candidiasis. Here, we show that the treatment with CauEVs inhibited the activation-induced CD4 T cells proliferation in a dose-dependent manner. Notably, we found that CauEVs acted at early events downstream to the T cell receptor signaling, inhibiting the MAPK phosphorylation. Interestingly, the inhibition of CD4 T cell proliferation by CauEVs was associated with an inhibition of the IL-2 signaling, followed by an increase on the IL-2 production that failed to restore proliferation. Taken together, our results suggest that CauEVs may contain an immunomodulatory factor(s) that affect the CD4 T cell activation and their fate from early to later events in a previously undescribed mechanism.
2025-11-19 | Characterization of dual DNA polymerase knockout strains of Candida albicans with live whole-cell vaccine competence.
Systemic candidiasis inflicts ~1.2 million deaths annually worldwide. Despite its severity, an approved antifungal vaccine remains an unmet human need. In a quest to design a live-whole cell vaccine, we characterized and demonstrated the vaccine potential of two dual DNA polymerase-defective strains of Candida albicans. While the deletion of POL32 in a hyper-virulent rad30ΔΔ strain attenuated the virulence, the deletion of RAD30 in an avirulent pol32ΔΔ did not revert to a hypervirulence phenotype. Both the dual polymerase-defective strains replicate transiently in the host and trigger immune responses to prevent reinfections in mice by employing a concerted involvement of innate, adaptive, and trained immunity. The cellular and molecular depletion in immunized mice suggested the role of B- and T-cells, neutrophils, and macrophages in antifungal immunity. Altogether, our results confirmed that Pol32 is a true virulence factor and intravenous vaccination with these attenuated strains could prevent systemic candidiasis in the preclinical models without evident safety concerns; thus, these candidate strains have enormous translational potential to fully develop as antifungal vaccines.
2025-06-11 | Mannan-targeting chimeric antigen receptor redirected antifungal activity of NK-92 cells against Candida albicans.
Chimeric antigen receptors (CARs) offer promising prospects for innovative cell-based therapies against invasive fungal infections such as invasive candidiasis. Here, we have developed 4 CARs targeting Candida albicans with distinct single-chain variable fragments (scFvs): scFv3-CAR, scFv5-CAR, scFv12-CAR, and scFvκ3-1-CAR. In T cells, scFv5-CAR induced IL-2 expression in response to C. albicans hyphae, while scFv3-CAR and scFv12-CAR did not mediate cell activation against C. albicans. Notably, scFvκ3-1-CAR mediated the strongest cell activation against C. albicans yeast, hyphae, and other clinically relevant Candida species. scFvκ3-1-CAR-NK-92 cells exhibited elevated IFN-γ and CD107a expression, reducing C. albicans viability. NOD scid gamma (NSG) mice treated with scFvκ3-1-CAR-NK-92 cells had reduced C. albicans burden in the kidneys 24 hours postinfection. We showed that scFvκ3-1-CAR targets C. albicans mannan but no other glycans in glycan microarray screening analyses. These findings reveal the scFvκ3-1-CAR potential as a therapeutic strategy for treating Candida spp. by modifying peripheral blood mononuclear cells.
2025-05-13 | Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
Central trained immunity, induced via reprogramming of hematopoietic stem and progenitor cells (HSPCs), mediates sustained heightened responsiveness of mature myeloid cells to secondary challenges. We have previously demonstrated that HSPCs use TLR2 and Dectin-1 to sense Candida albicans to induce the production of trained monocytes/macrophages to fight against secondary infection. Neutrophils play an important role in innate immunity and are critical for clearance of C. albicans. In this work, we used an in vitro model of mouse HSPC differentiation to investigate the functional phenotype of neutrophils derived from HSPCs exposed to various PAMPs and C. albicans cells. We found that neutrophils derived from HSPCs stimulated by a TLR2 agonist exhibit reduced inflammatory cytokine production (tolerized neutrophils) whereas neutrophils generated from a Dectin-1 agonist or C. albicans stimulated HSPCs produce higher amounts of cytokines (trained neutrophils). We further demonstrated that a transient exposure of HSPCs to live C. albicans cells is sufficient to induce a trained phenotype of the neutrophils they produce in a Dectin-1- and TLR2-dependent manner. These trained neutrophils exhibited higher phagocytosis and microbicidal capacity than control neutrophils. Additionally, their adoptive transfer was sufficient to reduce fungal burden during invasive candidiasis. Mechanistically, we demonstrated that trained neutrophils use mitochondrial ROS (mtROS) to enhance their ability to kill C. albicans cells, as they produce higher amounts of mtROS and scavenging mtROS with MitoTEMPO attenuated their yeast-killing ability to match that of control neutrophils. Altogether, these data suggest that infection-experienced HSPCs contribute to trained immunity by providing a source of trained neutrophils with enhanced antimicrobial activity which may confer prolonged protection from infection. The tailored manipulation of this mechanism might offer new therapeutic strategies for controlling fungal infections by harnessing neutrophils.
2025-04-16 | Mannan is a context-dependent shield that modifies virulence in Nakaseomyces glabratus.
Fungal-host interaction outcomes are influenced by how the host recognizes fungal cell wall components. Mannan is a major cell wall carbohydrate and can be a glycoshield that blocks the inner cell wall β-1,3-glucan from activating pro-inflammatory immune responses. Disturbing this glycoshield in Candida albicans results in enhanced antifungal host responses and reduced fungal virulence. However, deletions affecting mannan synthesis can lead to systemic hypervirulence for Nakaseomyces glabratus (formerly Candida glabrata) suggesting that proper mannan architecture dampens virulence for this organism. N. glabratus is the second leading cause of invasive and superficial candidiasis, but little is known about how the cell wall affects N. glabratus pathogenesis. In order to better understand the importance of these species-specific cell wall adaptations in infection, we set out to investigate how the mannan polymerase II complex gene, MNN10, contributes to N. glabratus cell wall architecture, immune recognition, and virulence in reference strains BG2 and CBS138. mnn10Δ cells had thinner inner and outer cell wall layers and elevated mannan, chitin, and β-1,3-glucan exposure compared to wild-type cells. Consistent with these observations, mnn10Δ cells activated the β-1,3-glucan receptor in oral epithelial cells (OECs), EphA2, and caused less OEC damage than wild-type. mnn10Δ replication was also restricted in macrophages compared to wild-type controls. Yet, during systemic infection in Galleria mellonella larvae, mnn10Δ cells induced rapid larval melanization and BG2 mnn10Δ cells killed larvae significantly faster than wild-type. Thus, our data suggest that mannan plays context-dependent roles in N. glabratus pathogenesis, acting as a glycoshield in superficial disease models and modulating virulence during systemic infection.
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Drug Discovery Landscape
13 orphan drug designations for Invasive candidiasis, including 3 approved therapies.
13 orphan drug designations for Invasive candidiasis, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
triterpenoid antifungal | small molecules | FDA | 2026-03-15 | — | SCYNEXIS, Inc. |
Fosmanogepix | small molecules | EMA | 2022-07-18 | — | Basilea Pharmaceutica Deutschland GmbH |
Ibrexafungerp | small molecules | EMA | 2021-11-12 | — | GlaxoSmithKline Trading Services Limited |
Miltefosine | small molecules | FDA | 2021-11-01 | — | Profounda, lnc. |
Rezafungin acetate [Rezzayo] | small molecules | EMA | 2021-01-06 | 2023-12-22 | Mundipharma GmbH |
fosmanogepix | small molecules | FDA | 2016-10-19 | — | Basilea Pharmaceutica Ltd, Allschwil |
ibrexafungerp | small molecules | FDA | 2016-05-10 | — | GlaxoSmithKline LLC |
rezafungin [Rezzayo] | small molecules | FDA | 2016-02-08 | 2023-03-22 | Mundipharma GmbH |
isavuconazonium sulfate | small molecules | FDA | 2014-10-20 | — | Astellas Pharma Global Development, Inc. |
recombinant human monoclonal antibody to hsp90 | antibodies | FDA | 2002-09-16 | — | Novartis Pharmaceuticals Corp. |
Liposomal nystatin | small molecules | FDA | 2000-06-13 | — | The University of Texas |
Amphotericin B lipid complex | other | FDA | 1996-06-27 | — | The Liposome Company, Inc. |
Amphotericin B lipid complex [Abelcet] | small molecules | FDA | 1991-12-05 | 1996-10-18 | Liposome Company, Inc. |
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