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is one of the most common fungal pathogens, yet much remains unknown about how its virulence factors cooperate to promote pathogenicity. To investigate this, CRISPR-Cas9 technology was used to create a panel of 19 single, double, triple, and quadruple deletion mutant strains targeting four established virulence factors: (adhesin/invasin), (candidalysin toxin), (hypha formation regulator), and (protease). , the deletion of each gene had differing impacts across multiple characterization assays. The ∆/∆ mutant was unable to form hyphae under inducing conditions, leading to downstream impairment of epithelial invasion. The ∆/∆ mutant exhibited significantly reduced adhesion and invasion into epithelial cells, resulting in attenuated cellular damage. The ∆/∆ mutant displayed significantly reduced epithelial damage, cell signaling, and immune activation. The phenotype of the ∆/∆ mutant resembled that of wild type but was unable to degrade protein. In an immunocompromised murine model of oropharyngeal infection, hyphal growth and candidalysin production were the dominant drivers of elevated fungal burden, innate immune responses, and mortality. Following a 5-day infection with ∆/∆ and ∆/∆ single gene deletion strains, mice had survival rates of 100% and 80%, respectively, compared to 15% in wild-type infected mice. Notably, 100% survival was also observed following challenge with all ∆/∆ and ∆/∆ combination mutants. This study demonstrates that specific virulence attributes act in combination to promote mucosal infection, with hyphal growth and candidalysin production being a critical driver of oropharyngeal infection.IMPORTANCE has been classified by the WHO as a \"critical priority\" pathogen, highlighting the urgent need for a greater understanding of the mechanisms that enable it to cause disease. possesses numerous virulence attributes, but how they synergize during infection is not well understood. Here, using reverse genetics, we dissect the individual and combinatorial roles of four virulence factors (Als3p, candidalysin, hyphal growth, and Sap2p) and in an murine model of oropharyngeal candidiasis. Increasing the number of gene deletions correlated with reduced oral fungal burden, with hyphal growth and candidalysin together being critical for infection, inflammation, and mortality during oropharyngeal infection. These findings demonstrate that virulence attributes act cooperatively as a collective network to promote pathogenicity, a finding also observed in plant fungal pathogens. Our approach has identified specific fungal virulence factors that can be targeted for new treatment strategies against infections.

Candida albicans is a commensal yeast that is a common component of the gastrointestinal (GI) microbiome of humans. C. albicans has been shown to bloom in the GI tract of individuals with alcohol use disorder (AUD) and can promote and increase the severity of alcoholic liver disease. However, the effects of C. albicans blooms on the host in the context of AUD or AUD-related phenotypes, such as ethanol preference, have been unstudied. In this work, we report a reduction in ethanol consumption and preference in mice colonized with C. albicans. C. albicans-colonized mice exhibited elevated levels of serum prostaglandin E2 (PGE2), and the reduced ethanol preference was reversed by injection with antagonists of PGE2 receptors. Furthermore, injection of mice with a PGE2 derivative decreased their ethanol preference. These results show that PGE2 acting on its receptors prostaglandin E receptor 1 (EP1) and prostaglandin E receptor 2 (EP2) drives reduced ethanol preference in C. albicans-colonized mice. We also showed altered transcription of dopamine receptors in the dorsal striatum of C. albicans-colonized mice and more rapid acquisition of ethanol-conditioned taste aversion, suggesting alterations to reinforcement or aversion learning. Finally, C. albicans-colonized mice were more susceptible to ethanol-induced motor coordination impairment, showing significant alterations to the behavioral effects of ethanol. This study identifies a member of the fungal microbiome that alters ethanol preference and demonstrates a role for PGE2 signaling in these phenotypes.IMPORTANCECandida albicans is a commensal yeast that is found in the gut of most individuals. C. albicans has been shown to contribute to alcoholic liver disease. Outside of this, the impact of intestinal fungi on alcohol use disorder (AUD) had been unstudied. As AUD is a complex disorder characterized by high relapse rates and there are only three FDA-approved therapies for the maintenance of abstinence, it is important to study novel AUD contributors to find new therapeutic targets. Here, we show that an intestinal fungus, C. albicans, can alter mammalian ethanol consumption through an immune modulator, prostaglandin E2. The results highlight novel contributors to AUD-related phenotypes and further implicate the gut-brain axis in AUD. Future studies could lead to new therapeutic avenues for the treatment of AUD.

Human cytomegalovirus (HCMV) is a master of immune evasion and a potent modulator of the human immune system. The best-characterized mechanism employed by HCMV to suppress host immunity is the production of a viral interleukin-10 homolog (CMVIL-10). While CMVIL-10 is known to suppress immune responses and promote viral persistence, its capacity to promote increased susceptibility to co-infecting pathogens like Aspergillus fumigatus remains unknown. Therefore, we studied the impact of wild-type (WT) HCMV (strain TB40), a CMVIL-10-deficient HCMV mutant (ΔUL111A), and recombinant CMVIL-10 on the immune activity of monocyte-derived dendritic cells (moDCs) during co-infection with A. fumigatus. Using a combination of transcriptomic and phenotypic readouts, our data revealed a strong and time-dependent immuno-paralytic effect of HCMV by suppressing pathogen recognition pathways, cytokine production, DC maturation, and expression of genes that are essential for host defense and tissue repair. Although infection with ΔUL111A lacking CMVIL-10 led to stronger expression of type I interferons, IFN-γ-inducible chemokines, and proinflammatory cytokines than WT infection, interference with antifungal immune defense and fungal clearance during co-infection was largely similar between both strains. The limited effect of CMVIL-10 on antifungal immune defense persisted even after prolonged pre-exposure of DCs to the recombinant virokine. In summary, although CMVIL-10 contributes to shaping an anti-inflammatory environment, HCMV’s suppression of antifungal immunity appears to be multifactorial, with CMVIL-10 alone playing a rather subtle role in altering DC responses to A. fumigatus during viral-fungal co-infection.IMPORTANCEHuman cytomegalovirus (HCMV) is a highly prevalent herpesvirus that establishes lifelong latency and frequently reactivates in immunocompromised individuals, including hematopoietic stem cell transplant recipients. Reactivation not only causes direct disease but also increases the risk of secondary infections, such as invasive pulmonary aspergillosis caused by Aspergillus fumigatus. Specifically, studies estimated that about 6%–25% of critically ill HCMV-positive patients develop HCMV-associated pulmonary aspergillosis. However, the mechanisms by which HCMV creates a permissive environment for fungal superinfection remain poorly understood. HCMV encodes a viral homolog of interleukin-10 (CMVIL-10), which mimics host IL-10 and elicits potent immunomodulatory activity. Here, we show that CMVIL-10 dampens specific anti-viral responses, DC activation, and cytokine signaling. However, HCMV-mediated impairment of fungal control in co-infection settings occurred largely independent of CMVIL-10 expression. These findings suggest that HCMV undermines antifungal defenses through multifactorial mechanisms beyond CMVIL-10, highlighting the need for targeted strategies to restore immune function in high-risk patients.

Candida auris is an emerging fungal species, and several reports have recently identified C. auris in patients with vulvovaginal candidiasis (VVC), although few studies have investigated the relationship between C. auris and VVC or the associated host factors. Our study, using the VVC mouse model, confirmed persistent vaginal colonization by C. auris , especially clades I, III, and IV, along with reduced neutrophil infiltration and lower S100A8 secretion under interleukin-17A-deficient conditions. In addition, in vitro assays demonstrated enhanced C. auris adhesion to vaginal epithelial cells, especially microaerobic conditions imitating human vaginal microenvironments. Our findings suggest that C. auris exhibits strong vaginal tropism, and IL-17A plays a critical role in controlling C. auris -associated VVC.

Cryptococcosis is a fungal disease caused by multiple serotypes; particularly (serotypes A and D) and (serotypes B and C). To date, there is no clinically available vaccine to prevent cryptococcosis. Mice given an experimental pulmonary vaccination with a serotype A strain engineered to produce interferon-γ, denoted H99γ, are protected against a subsequent otherwise lethal experimental infection with serotype A. Thus, we determined the efficacy of immunization with strain H99γ to elicit broad-spectrum protection in BALB/c mice against multiple disparate serotypes. We observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99γ immunized mice challenged with serotypes A, B, or D compared to heat-killed H99γ (HKH99γ) immunized mice. Results indicated that prolonged protection against serotypes B or D in H99γ immunized mice was CD4 T cell dependent and associated with the induction of predominantly Th1-type cytokine responses. Interestingly, immunization with H99γ did not elicit greater protection against challenge with the serotype C tested either due to low overall virulence of this strain or enhanced capacity of this strain to evade host immunity. Altogether, these studies provide \"proof-of-concept\" for the development of a cryptococcal vaccine that provides cross-protection against multiple disparate serotypes of .

The fungal pathogen, Cryptococcus neoformans, causes devastating levels of morbidity and mortality. Infections with this fungus tend to be predominantly in immunocompromised individuals, such as those with HIV. Infections initiate with inhalation of cryptococcal cells and entry of the pathogen into the lungs. The bronchial epithelial cells of the upper airway and the alveolar epithelial cells of the lower airway are likely to be the first host cells that Cryptococcus engage with. Thus the interaction of cryptococci and the respiratory epithelia will be the focus of this review. C. neoformans has been shown to adhere to respiratory epithelial cells, although if the role of the capsule is in aiding or hindering this adhesion is debatable. The epithelia are also able to react to cryptococci with the release of cytokines and chemokines to start the immune response to this invading pathogen. The activity of surfactant components that line this mucosal barrier towards Cryptococcus and the metabolic and transcriptional reaction of cryptococci when encountering epithelial cells will also be discussed.

The rate of invasive fungal infections has risen drastically over the last decade and continues to carry devastatingly high mortality rates. Currently, there are no licensed vaccines and limited antifungal agents in clinical trials for fungal-mediated diseases. The limited effectiveness of FDA-approved antifungal medications against invasive fungal infections and the lack of mechanistic understanding of how these infections manifest pose a significant burden on healthcare systems worldwide. Therefore, understanding the molecular details of the host-fungal interactions has never been more urgent. Here, we examine the role of fungal melanin as a virulence factor through its immunomodulatory effects during respiratory infections. Although previous literature on fungal pathogenicity has touched briefly on fungal pigments, they are incomplete in discussing how melanin dysregulates essential functions of the innate immune system. To provide a contemporary perspective, literature on melanized fungal species commonly associated with infections via the respiratory tract has been reviewed to detail holistic mechanisms by which melanin subverts the immune system and manipulates the respiratory epithelium.

Cells of the innate immune system can be “trained” by inducers to have enhanced memory responses, a phenomenon known as trained immunity. We recently identified an anti-inflammatory training response that is induced by low virulence fungal species (i.e., Candida dubliniensis ) and is protective against acute lethal polymicrobial sepsis. Trained immunity inducers, including C. dubliniensis, can access the bone marrow and direct hematopoietic responses. Here, we demonstrate that protection is correlated with C. dubliniensis -induced bone marrow expansion, which directs a myeloid bias in the bone marrow and ultimately results in the expansion of protective myeloid-derived suppressor cells. Involvement of the C-type lectin receptor adaptor protein Card9 in the protective response suggests fungal recognition in the bone marrow drives this response. These findings offer new insights into how trained immunity inducers direct differential outcomes, which will inform the development of novel immunotherapeutics to exploit the full spectrum of trained immune responses.

Conidia serve as the primary infectious units of Aspergillus fumigatus , the causative agent of aspergillosis. This study identifies CrpA, a cysteine-rich protein found on the conidial surface, as a crucial regulator of immune modulation and fungal virulence. Loss of CrpA (Δ crpA ) alters host immune responses, resulting in reduced production of proinflammatory cytokines and increased IL-10 levels in both murine macrophages and infected lungs. ΔcrpA conidia also stimulate elevated levels of prostaglandins PGE2 and PGD2. This immunomodulatory effect is dependent on eicosanoid signaling as the virulence of Δ crpA is restored in prostaglandin-deficient zebrafish larvae. CrpA directly modulates macrophage production of PGE2 and cytokines. Solid-state NMR analysis shows that Δ crpA conidia expose lower levels of β−1,3-glucan and chitin, suggesting that CrpA influences both cell wall composition and host pattern recognition receptor engagement. Δ crpA strains are avirulent in immunocompetent mice, and patients with invasive pulmonary aspergillosis exhibit elevated CrpA-specific IgG. These results highlight CrpA as a key virulence factor in A. fumigatus and a promising target for antifungal therapy.

Aspergillus fumigatus is one the most ubiquitous airborne opportunistic human fungal pathogens. Understanding its interaction with host immune system, composed of cellular and humoral arm, is essential to explain the pathobiology of aspergillosis disease spectrum. While cellular immunity has been well studied, humoral immunity has been poorly acknowledge, although it plays a crucial role in bridging the fungus and immune cells. In this review, we have summarized available data on major players of humoral immunity against A. fumigatus and discussed how they may help to identify at-risk individuals, be used as diagnostic tools or promote alternative therapeutic strategies. Remaining challenges are highlighted and leads are given to guide future research to better grasp the complexity of humoral immune interaction with A. fumigatus.