The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4+ T-cell counts. Previously, we deleted three chitin deacetylase genes from Cryptococcus neoformans to create a chitosan-deficient, avirulent strain, designated as cda1∆2∆3∆, which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8+ T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4+ T cells. Moreover, CD4+ T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4+ T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4+ T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-γ (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4+ T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8+ T cells are dispensable, IFNγ and CD4+ T cells have overlapping roles in generating protective immunity prior to cda1∆2∆3∆ vaccination. However, once vaccinated, protection becomes less dependent on CD4+ T cells, suggesting a strategy for vaccinating HIV+ persons prior to loss of CD4+ T cells.
OBJECTIVE: The fungus Cryptococcus neoformans is responsible for >100,000 deaths annually, mostly in persons with impaired CD4+ T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans, designated as cda1∆2∆3∆. When used as a vaccine, cda1∆2∆3∆ protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8+ T cells were dispensible, protection was lost in mice genetically deficient in CD4+ T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4+ T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4+ T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4+ T-cell dysfunction.

UNASSIGNED: Otomycosis is common in environments with hot, humid weather, and it may be challenging to manage.
UNASSIGNED: To profile common clinical presentations, the pathogenic fungi, the treatment modalities with responses, and explore clinical factors associated with having positive fungal culture in Otomycosis.
UNASSIGNED: Retrospective review of patients with Otomycosis. Demographic and clinical parameters, otoscopic findings and mycological study results were recorded. The treatment modalities used and treatment response were summarized. Comparative statistical analyses of associated factors to positive fungal culture were performed with Chi square test, and Student\'s t-test, using SPSS version 22.0.
UNASSIGNED: Total of 71 patients with M: F=1:1.8, mean age 38.5±19.8 years. Average duration of symptoms was 5.4 ±4.6 weeks; common presenting complaint was itchy ear (33.8%). Majority of patients (85.9%) had unilateral ear involvement, 50.0% applied ototopic medications before presentation, 8.5% had multiple co-morbidities. 20 patients had positive fungal culture results; common fungal isolate was Aspergillus niger 9 (45.0%).Clinical factors associated with positive culture of fungus were age, non-previous use of ototopic drugs, and presence of co-morbidity. The most common treatment was local ear debridement and use of topical antifungal creams. Majority (91.5%) of the patients responded with resolution of fungal infection. Complications rate was 8.4%.
UNASSIGNED: Otomycosis commonly present with itchy ears, the pathogenic fungi commonly being Aspergillus species. The factors associated with positive fungal culture were age, non-usage of ototopic agents and presence of co-morbidity. Treatment modality used was local debridement and topical antifungal agents, which produced favourable response in most patients.

Cryptococcus neoformans is an environmentally acquired fungal pathogen that causes over 140,000 deaths per year. Cryptococcal infection occurs when infectious particles are deposited into the lung, where they encounter host phagocytic cells. C. neoformans may be engulfed by these phagocytes, an important step of infection that leads to outcomes ranging from termination of infection to cryptococcal dissemination. To study this critical process, we screened approximately 4,700 cryptococcal gene deletion mutants for altered uptake, using primary mouse and human phagocytic cells. Among the hits of these two screens, we identified 93 mutants with perturbed uptake in both systems, as well as others with differences in uptake by only one cell type. We further screened the hits for changes in thickness of the capsule, a protective polysaccharide layer around the cell which is an important cryptococcal virulence factor. The combination of our three screens yielded 45 mutants, including one lacking the phosphatidylinositol-4-phosphate phosphatase Sac1. In this work, we implicate Sac1 in both host cell uptake and capsule production. We found that sac1 mutants exhibit lipid trafficking defects, reductions in secretory system function, and changes in capsule size and composition. Many of these changes occur specifically in tissue culture media, highlighting the role of Sac1 phosphatase activity in responding to the stress of host-like conditions. Overall, these findings show how genome-scale screening can identify cellular factors that contribute to our understanding of cryptococcal biology and demonstrate the role of Sac1 in determining fungal virulence.IMPORTANCECryptococcus neoformans is a fungal pathogen with significant impact on global health. Cryptococcal cells inhaled from the environment are deposited into the lungs, where they first contact the human immune system. The interaction between C. neoformans and host cells is critical because this step of infection can determine whether the fungal cells die or proliferate within the human host. Despite the importance of this stage of infection, we have limited knowledge of cryptococcal factors that influence its outcome. In this study, we identify cryptococcal genes that affect uptake by both human and mouse cells. We also identify mutants with altered capsule, a protective coating that surrounds the cells to shield them from the host immune system. Finally, we characterize the role of one gene, SAC1, in these processes. Overall, this study contributes to our understanding of how C. neoformans interacts with and protects itself from host cells.

The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment of a novel genetic technique to repress gene expression in Trichophyton rubrum, the primary causal fungus of dermatophytosis, we demonstrated that fungal Cdc42 and Rac GTPases are promising antifungal drug targets. Chemical inhibitors of these GTPases impair hyphal formation, which is crucial for growth and virulence in T. rubrum. Conditional repression of Cdc24, a guanine nucleotide exchange factor for Cdc42 and Rac, led to hyphal growth defects, abnormal cell morphology, and cell death. EHop-016 inhibited the promotion of the guanine nucleotide exchange reaction in Cdc42 and Rac by Cdc24 as well as germination and growth on the nail fragments of T. rubrum and improved animal survival in an invertebrate infection model of T. rubrum. Our results provide a novel antifungal therapeutic target and a potential lead compound.

This review is intended to familiarize readers with an emerging group of fungal infections that mostly manifest in immunocompetent individuals. This group was initially considered endemic to the tropics, but increasing worldwide prevalence has been reported. The organisms have been divided into dominant non-invasive forms and dominant invasive forms for ease of understanding. The non-invasive organisms include the group Entomophthoromycota, under which two genera Basidiobolus and Conidiobolus, have been identified as human pathogens. They present with plaques in the extremities and rhinofacial region, respectively. The invasive organisms are dematiaceous fungi (phaeohypomycosis), which includes Cladophialophora and Exophiala among others. They cause invasion of deep tissues, with the central nervous system being the most common target. The mycology, epidemiology, diagnosis, and treatment options have been summarized in brief. The clinical presentation, imaging manifestations, differentiation from other common infections and malignancies that show similar features have been detailed.

Evading host innate immune defenses is a critical feature of Chlamydia trachomatis infections, and the mechanisms used by C. trachomatis to subvert these pathways are incompletely understood. We screened a library of chimeric C. trachomatis mutants for genetic factors important for interference with cell-autonomous immune defenses. Mutant strains with predicted truncations of the inclusion membrane protein CT135 were susceptible to interferon gamma-activated immunity in human cells. CT135 functions to prevent host-driven recruitment of ubiquitin and p62/SQSTM to the inclusion membrane. In a nonhuman primate model of C. trachomatis infection, a CT135-deficient strain was rapidly cleared, highlighting the importance of this virulence factor for C. trachomatis pathogenesis. Analysis of CT135 phenotypes in primary macaque cells revealed that cell-autonomous immune defenses against C. trachomatis are conserved between humans and nonhuman primates and connects mechanistic findings with in vivo infection outcomes.

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Wood decomposition through fungal activity is essential to the natural carbon cycle. There are three primary patterns of wood decay: white rot, brown rot, and soft rot. However, geological records of wood decay mainly originate from fossil woods, which exclusively describe white rot before the Cenozoic. Fossilized charcoal is another excellent medium for preserving pre-charring decay structures. In this study, we collected numerous charcoals from the upper Permian and observed multiple microstructures indicative of wood decay. The distinctive characteristics closely resemble the symptoms of contemporary wood-rotting types, including the removal of the middle lamella and channel-like lysis seen in white rot, shot-like holes and wavy cell walls in brown rot, and cavities within the secondary walls in soft rot. This study documents the early occurrences of multiple wood-rotting types during the Late Paleozoic and provides insights into the range of fungal metabolic strategies employed during this period.

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