Reciprocal modulation of ammonia and melanin production has implications for cryptococcal virulence

被引:18
作者
Baker, Rosanna P. [1 ]
Casadevall, Arturo [1 ]
机构
[1] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
MOLECULAR CHARACTERIZATION; HELICOBACTER-PYLORI; NEOFORMANS; UREASE; CAPSULE; MECHANISMS; EXPRESSION; INFECTION; DIAGNOSIS; LACCASE;
D O I
10.1038/s41467-023-36552-7
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cryptococcus neoformans has numerous described virulence mechanisms including urease secretion and melanization. Here, Baker and Casadevall, describe the reciprocal relationship between these two factors and their contribution to infection. The fungus Cryptococcus neoformans is the causative agent of cryptococcosis, a disease that is uniformly lethal unless treated with antifungal drugs, yet current regimens are hindered by host toxicity and pathogen resistance. An attractive alternative approach to combat this deadly disease is the direct targeting of pathogen-derived virulence mechanisms. C. neoformans expresses multiple virulence factors that have been studied previously as isolated entities. Among these, are urease, which increases phagosomal pH and promotes brain invasion, and melanization, which protects against immune cells and antifungal treatments. Here we report a reciprocal interdependency between these two virulence factors. Cells hydrolyzing urea release ammonia gas which acts at a distance to raise pH and increase melanization rates for nearby cells, which in turn reduces secretion of urease-carrying extracellular vesicles. This reciprocal relationship manifests as an emergent property that may explain why targeting isolated virulence mechanisms for drug development has been difficult and argues for a more holistic approach that considers the virulence composite.
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页数:11
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