ERG3-Encoding Sterol C5,6-DESATURASE in Candida albicans Is Required for Virulence in an Enterically Infected Invasive Candidiasis Mouse Model.

Yoshifumi Imamura,Takahiro Takazono,Makoto Sumiyoshi,Katsunori Yanagihara,Koichi Izumikawa,Hiroshi Mukae,Shigeru Kohno,Taiga Miyazaki,Tatsuro Hirayama,Nobuyuki Ashizawa,Kazuko Yamamoto

doi:10.3390/pathogens10010023

Yoshifumi Imamura, Takahiro Takazono + Show 9 more

Open Access

https://doi.org/10.3390/pathogens10010023

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Abstract

Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.

Highlights

Candidemia is cited as the fourth leading cause of bloodstream infections [1]
We assessed the virulence of the C. albicans erg3 null mutant CAE3DU3
The loss of sterol C5,6-desaturase activity is associated with reduced virulence in mouse models of disseminated candidiasis developed by intravenous injection of Candida cells [8,9]

Summary

Introduction

Candidemia is cited as the fourth leading cause of bloodstream infections [1]. Candida albicans is the most frequently isolated species that is associated with candidemia [2].Several species of Candida are ubiquitous commensal yeasts and are normal components of human skin and gut microbiota, with estimates of C. albicans carriage in healthy individuals ranging from 30–60% [3]. Candidemia is cited as the fourth leading cause of bloodstream infections [1]. Candida albicans is the most frequently isolated species that is associated with candidemia [2]. Several species of Candida are ubiquitous commensal yeasts and are normal components of human skin and gut microbiota, with estimates of C. albicans carriage in healthy individuals ranging from 30–60% [3]. When the intestinal mucosal barrier is damaged (for example, by anticancer chemotherapy), the inhabiting C. albicans can further damage the intestinal mucosal barrier, which allows direct invasion of C. albicans into the bloodstream and abdominal cavity. Impairment of the host immune response allows the overgrowth of C. albicans and dissemination into the bloodstream and adjacent organs, leading to the establishment of infections in various organs [5]

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