Cryptococcus neoformans - Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics
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- Department of Dermatology and Venereology, Changzheng Hospital, Second Military Medical University, Shanghai, China, Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Changzheng Hospital, Second Military Medical University, Shanghai, China, Department of Dermatology, Shaanxi Provincial People’s Hospital, Xi’an, China, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA
- Department of Dermatology and Venereology, Changzheng Hospital, Second Military Medical University, Shanghai, China, Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Changzheng Hospital, Second Military Medical University, Shanghai, China
- MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
- Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Pós-Graduaçao em Doença Infecciosas e Parasitárias, Rio de Janeiro, Brazil
- Institute of Immunology and Immunotherapy, Institute of Biomedical Research College of Medical and Dental Science, Birmingham, United Kingdom
- Department of Dermatology and Venereology, Taiyuan Central Hospital of Shanxi Medical University, Shanxi, China
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA
Cryptococcus neoformans causes deadly mycosis in immunocompromised individuals. Macrophages are key cells fighting against microbes. Extracellular vesicles (EVs) are cell-to-cell communication mediators. The roles of EVs from infected host cells in the interaction with Cryptococcus remain uninvestigated. Here, EVs from viable C. neoformans-infected macrophages reduced fungal burdens but led to shorter survival of infected mice. In vitro, EVs induced naive macrophages to an inflammatory phenotype. Transcriptome analysis showed that EVs from viable C. neoformans-infected macrophages activated immune-related pathways, including p53 in naive human and murine macrophages. Conserved analysis demonstrated that basic cell biological processes, including cell cycle and division, were activated by infection-derived EVs from both murine and human infected macrophages. Combined proteomics, lipidomics, and metabolomics of EVs from infected macrophages showed regulation of pathways such as extracellular matrix (ECM) receptors and phosphatidylcholine. This form of intermacrophage communication could serve to prepare cells at more distant sites of infection to resist C. neoformans infection. Cryptococcus neoformans causes cryptococcal meningitis, which is frequent in patients with HIV/AIDS, especially in less-developed countries. The incidence of cryptococcal meningitis is close to 1 million each year globally. Macrophages are key cells that protect the body against microbes, including C. neoformans. Extracellular vesicles are a group of membrane structures that are released from cells such as macrophages that modulate cell activities via the transfer of materials such as proteins, lipids, and RNAs. In this study, we found that Cryptococcus neoformans-infected macrophages produce extracellular vesicles that enhance the inflammatory response in Cryptococcus-infected mice. These Cryptococcus neoformans-infected macrophage vesicles also showed higher fungicidal biological effects on inactivated macrophages. Using omics technology, unique protein and lipid signatures were identified in these extracellular vesicles. Transcriptome analysis showed that these vesicles activated immune-related pathways like p53 in naive macrophages. The understanding of this intermacrophage communication could provide potential targets for the design of therapeutic agents to fight this deadly mycosis.
- Research Organization:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Health Department; National Natural Science Foundation of China (NSFC); Shanghai Science and Technology Committee; Chinese Academy of Engineering; Shanghai Municipal Commission of Health and Family Planning; Shanghai Sailing Program; National Institutes of Health (NIH)
- Grant/Contract Number:
- grid.436923.9; AI052733; AI15207; HL059842; AC05-76RL01830; 2018ZX10101003; 31770161; 82072257; 17DZ2272900; 14495800500; 2019-XY-33; 2017ZZ01024-001; 19YF1448000
- OSTI ID:
- 2203473
- Alternate ID(s):
- OSTI ID: 1781105
- Report Number(s):
- PNNL-SA-160420; e00279-21
- Journal Information:
- mBio (Online), Journal Name: mBio (Online) Vol. 12 Journal Issue: 2; ISSN 2150-7511
- Publisher:
- American Society for MicrobiologyCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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