Redistribution of a glucuronoxylomannan epitope towards the capsule surface coincides with Titanisation in the human fungal pathogen<i>Cryptococcus neoformans</i>

Probert, Matt; Zhou, Xin; Goodall, Margaret; Sa, Jae-Hoon; Bielska, Ewa; Ballou, Elizabeth R.; May, Robin C.

doi:10.1101/431650

Cited by 1 publication

(1 citation statement)

References 52 publications

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“…Occurrences of fungal invasive diseases are always caused by invading fungi and also involved with aspects of hosts closely [1][2][3]. Studies have shown the raised body temperature, limited nutrients of glucose and metal ions, phagocytosis by phagocytes and cellular immunities are powerful weapons for fungal elimination in hosts [4][5][6][7][8][9][10], while fungal evolved strategies in return, such as temperature resistance, polysaccharide capsule and melanin production, morphology switching, and virulence gene expressions [11][12][13][14][15][16]. Nonetheless, the mechanisms of fungal central nervous system (CNS) invasion have not been determined, which is also a mystery in cryptococcosis, a life-threatening fungal invasive disease, initialized by human pathogen Cryptococcus neoformans [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Comparative miRNA Transcriptomics of Mouse and Macaque Reveals MYOC is An Inhibitor for C. neoformans Invasion into Brain

Li¹,

Han²,

et al. 2022

Preprint

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Cryptococcal meningitis is a major risk for immune compromised patients mainly caused by the human opportunistic pathogen Cryptococcus neoformans, yet mechanisms of the brain or CNS dissemination remain to elucidate, which is the deadest process for the disease. Meanwhile, illustrations of clinically relevant responses in cryptococcosis were limited, as the low availabilities of clinical samples. In this study, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton was a centric pathway regulated in both two organisms. Notably, myocilin, a novel modulator encoded by MYOC, was identified during cryptococcal pneumonia. An enhanced fungal burden was achieved in the brains of MYOC transgenic mice. Importantly, C. neoformans dissemination to the brain was inhibited by cytoskeleton inhibitor, which ruined “Trojan Horse” by dampening migration and phagocytosis of macrophages, but toxic to hosts. Taking together, this study provides new pathways and modulators during C. neoformans infections and reveals fundamental roles of cytoskeleton and MYOC in blocking fungal CNS dissemination that facilitate the development of novel drug targets for therapies of meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.Author summaryFungal CNS dissemination is vital and lethal, which is the most important step for both fungal pathogenesis and host defense. Many milestones have been made to illustrate processes of invasion, such as the “Trojan Horse” derived by macrophages. However, blocking this “road” is still on the way. In our work, to mimic real responses in humans, macaque and mouse were included, miRNA-Seq and mRNA-Seq were combined, and we identified the core-pathway (cytoskeleton) during C. neoformans pathogenesis, which plays important roles in migration and phagocytosis for macrophages, key factors for macrophage “Trojan horse”, and cytoskeleton was also ruined in HIV/AIDS patients. Fungal brain dissemination was weakened by cytoskeleton inhibitor in mice. Meanwhile, we identified a novel modulator for macrophage “Trojan Horse”, MYOC, involved with C. neoformans brain dissemination. Consistently, we assume macrophages are the key executor cells for fungal CNS dissemination, and we propose the processes can be shut down by cytoskeleton or MYOC inhibitors. Our research would not only help to understand the high prevalence of cryptococcal meningitis in HIV/AIDS but also provides putative ways to block fungal cells invading the brain.

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