Intrinsic and extrinsic factors affecting the evolution of virulence in the HIV-associated opportunistic human fungal pathogen Cryptococcus neoformans
Yuanyuan Wang,
Yiwu Yu,
Jihong Liu,
Linghua Li,
Xiaoqing Chen,
Sichu Xiong,
Yuying Pan,
Qinyu Tang,
Munika Moses,
Ping Zhan,
Guojian Liao,
Min Chen,
Liping Zhu,
Muyuan Li,
Tao Zhou,
Jingjun Zhao,
Changbin Chen
Affiliations
Yuanyuan Wang
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Yiwu Yu
Department of Dermatology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Jihong Liu
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Linghua Li
Institute of Infectious Disease, Guangzhou No.8 People’s Hospital, Guangzhou, China
Xiaoqing Chen
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Sichu Xiong
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Yuying Pan
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Qinyu Tang
Department of Dermatology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Munika Moses
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
Ping Zhan
Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Guojian Liao
College of Pharmaceutical Sciences, Southwest University, Chongqing, China
Min Chen
Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Second Military Medical University, Shanghai, China
Liping Zhu
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Muyuan Li
College of Pharmaceutical Sciences, Southwest University, Chongqing, China
Tao Zhou
College of Pharmaceutical Sciences, Southwest University, Chongqing, China
Jingjun Zhao
Department of Dermatology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Changbin Chen
Joint Laboratory for Biomedical Research and Pharmaceutical Innovation, Unit of Pathogenic Fungal Infection & Host Immunity, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
The fungus Cryptococcus neoformans is considered the leading cause of mortality in immunocompromised patients. While extensive research has unveiled the molecular epidemiology of C. neoformans, the influence of genetic and environmental factors on genotype–phenotype correlations remains poorly understood. Specifically, it remains unclear whether the genetic and environmental variability observed across isolates from diverse sources has significant implications for the pathogen’s virulence. In this study, we analyzed 105 Chinese C. neoformans isolates, including 54 from HIV-infected patients, 44 from HIV-uninfected individuals and seven from a natural environment. Multilocus sequence typing (MLST) revealed that sequence type (ST) 5 predominates across all clinical isolates; however, genotypic diversity was notably higher in isolates from HIV-uninfected individuals and the natural environment, whereas HIV-infected isolates exhibited restricted genetic variation. Furthermore, isolates from HIV-uninfected individuals exhibited significantly enhanced virulence traits, including elevated capsule production, increased melanin production, improved survival in human cerebrospinal fluid (CSF), reduced phagocytic uptake, and higher mortality in both Galleria mellonella and murine models of cryptococcosis. Importantly, these pathogenic phenotypes were correlated with CD4+ T cell counts, highlighting the critical role of host immunity in shaping C. neoformans virulence. Whole-genome sequencing and genome-wide association studies (GWAS) further revealed that variations in genes involved in carbohydrate metabolism, such as CDA3 and GPD1, may drive host-specific virulence evolution. Our results support a genotype–phenotype correlation, demonstrating that both genetic and environmental factors shape the virulence of C. neoformans, with significant implications for understanding host–pathogen interactions and guiding therapeutic strategies.
