Competition of Candida glabrata against Lactobacillus is Hog1 dependent.

Reinhard Beyer,Birgit Willinger,Pavel Kovarik,Ilse D Jacobsen,Christa Gregori,Joseph Strauss,Zeljkica Jandric,Christoph Schüller,Christoph Zutz

doi:10.1111/cmi.12943

Abstract

Candida glabrata is a common human fungal commensal and opportunistic pathogen. This fungus shows remarkable resilience as it can form recalcitrant biofilms on indwelling catheters, has intrinsic resistance against azole antifungals, and is causing vulvovaginal candidiasis. As a nosocomial pathogen, it can cause life‐threatening bloodstream infections in immune‐compromised patients. Here, we investigate the potential role of the high osmolarity glycerol response (HOG) MAP kinase pathway for C. glabrata virulence. The C. glabrata MAP kinase CgHog1 becomes activated by a variety of environmental stress conditions such as osmotic stress, low pH, and carboxylic acids and subsequently accumulates in the nucleus. We found that CgHog1 allows C. glabrata to persist within murine macrophages, but it is not required for systemic infection in a mouse model. C. glabrata and Lactobacilli co‐colonise mucosal surfaces. Lactic acid at a concentration produced by vaginal Lactobacillus spp. causes CgHog1 phosphorylation and accumulation in the nucleus. In addition, CgHog1 enables C. glabrata to tolerate different Lactobacillus spp. and their metabolites when grown in co‐culture. Using a phenotypic diverse set of clinical C. glabrata isolates, we find that the HOG pathway is likely the main quantitative determinant of lactic acid stress resistance. Taken together, our data indicate that CgHog1 has an important role in the confrontation of C. glabrata with the common vaginal flora.

Highlights

Superficial and systemic infections with Candida species afflict millions of people worldwide
We found that C. glabrata CgHog1 protects against the secreted metabolites of Lactobacillus spp. and allows it to compete with co‐colonising Lactobacillus spp
The effect of the low pH was subtracted by preparing a separate control sample adjusted to pH 4 using HCl when evaluating the effect of nitrite, sorbic acid, Phenyl acetic acid (PAA), and lactic acid, which were all performed at pH 4

Summary

| INTRODUCTION

Superficial and systemic infections with Candida species afflict millions of people worldwide. Several Candida species are intimately connected to humans as they are a part of the human microbiome and appear both as commensals (e.g., in the gut) and pathogens (Huffnagle et al, 2013) They can cause life‐threatening bloodstream infections especially in immune‐compromised patients, such as preterm neonates and patients undergoing prolonged treatment in an intensive care unit (Sardi et al, 2013). The high osmolarity glycerol (HOG) pathway is activated in response to osmotic stress caused by high extracellular salt or sugar concentrations. This pathway has been explored in great detail in S. cerevisiae, where it mainly reacts to osmotic stress (for review, see Saito et al, 2012, Brewster et al, 2014), and to other stress signals (Mollapour et al, 2006, Lawrence et al, 2004, Bilsland et al, 2004, Rodriguez‐Pena et al, 2010). We found that C. glabrata CgHog protects against the secreted metabolites of Lactobacillus spp. and allows it to compete with co‐colonising Lactobacillus spp

| RESULTS

M glycerol

| DISCUSSION

| EXPERIMENTAL PROCEDURES

Findings

| Ethics statement