AUTHOR=Zheng Yan-Qing , Pan Kai-Su , Latgé Jean-Paul , Andrianopoulos Alex , Luo Hong , Yan Ru-Fan , Wei Jin-Ying , Huang Chun-Yang , Cao Cun-Wei 

TITLE=Calcineurin A Is Essential in the Regulation of Asexual Development, Stress Responses and Pathogenesis in Talaromyces marneffei

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.03094

DOI=10.3389/fmicb.2019.03094

ISSN=1664-302X

ABSTRACT=<p><italic>Talaromyces marneffei</italic> is a common cause of infection in immunocompromised patients in Southeast Asia and Southern China. The pathogenicity of <italic>T. marneffei</italic> depends on the ability of the fungus to survive the cytotoxic processes of the host immune system and grow inside host macrophages. These mechanisms that allow <italic>T. marneffei</italic> to survive macrophage-induced death are poorly understood. In this study, we examined the role of a calcineurin homolog (<italic>cnaA</italic>) from <italic>T. marneffei</italic> during growth, morphogenesis and infection. Deletion of the <italic>cnaA</italic> gene in <italic>T. marneffei</italic> resulted in a strain with significant defects in conidiation, germination, morphogenesis, cell wall integrity, and resistance to various stressors. The Δ<italic>cnaA</italic> mutant showed a lower minimal inhibitory concentration (MIC) against caspofungin (16 μg/ml to 2 μg/ml) and micafungin (from 32 μg/ml to 4 μg/ml) compared with the wild-type. These results suggest that targeting calcineurin in combination with echinocandin treatment may be effective for life-threatening systemic <italic>T. marneffei</italic> infection. Importantly, the <italic>cnaA</italic> mutant was incapable of adapting to the macrophage environment <italic>in vitro</italic> and displayed virulence defects in a mouse model of invasive talaromycosis. For the first time, a role has been shown for <italic>cnaA</italic> in the morphology and pathogenicity of a dimorphic pathogenic filamentous fungus.</p>