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Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host–pathogen interactions of the pathogenic mucoralean fungus M ucor circinelloides
Author(s) -
Lee Soo Chan,
Li Alicia,
Calo Silvia,
Inoue Makoto,
Tonthat Nam K.,
Bain Judith M.,
Louw Johanna,
Shinohara Mari L.,
Erwig Lars P.,
Schumacher Maria A.,
Ko Dennis C.,
Heitman Joseph
Publication year - 2015
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13071
Subject(s) - biology , calcineurin , virulence , microbiology and biotechnology , pathogen , cryptococcus neoformans , innate immune system , dimorphic fungus , pathogenic fungus , antifungal drug , protein subunit , immune system , yeast , gene , genetics , candida albicans , transplantation , medicine , surgery
Summary Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK 506 and C yclosporine A . In the pathogenic mucoralean fungus M ucor circinelloides , calcineurin mutation or inhibition confers a yeast‐locked phenotype indicating that calcineurin governs the dimorphic transition. Genetic analysis in this study reveals that two calcineurin A catalytic subunits (out of three) are functionally diverged. Homology modeling illustrates modes of resistance resulting from amino substitutions in the interface between each calcineurin subunit and the inhibitory drugs. In addition, we show how the dimorphic transition orchestrated by calcineurin programs different outcomes during host–pathogen interactions. For example, when macrophages phagocytose M ucor yeast, subsequent phagosomal maturation occurs, indicating host cells respond appropriately to control the pathogen. On the other hand, upon phagocytosis of spores, macrophages fail to form mature phagosomes. Cytokine production from immune cells differs following exposure to yeast versus spores (which germinate into hyphae). Thus, the morphogenic transition can be targeted as an efficient treatment option against M ucor infection. In addition, genetic analysis (including gene disruption and mutational studies) further strengthens the understanding of calcineurin and provides a foundation to develop antifungal agents targeting calcineurin to deploy against M ucor and other pathogenic fungi.