No abstract

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus, which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease.

A Candida glabrata calcineurin mutant exhibited increased susceptibility to both azole antifungal and cell wall-damaging agents and was also attenuated in virulence. Although a mutant lacking the downstream transcription factor Crz1 displayed a cell wall-associated phenotype intermediate to that of the calcineurin mutant and was modestly attenuated in virulence, it did not show increased azole susceptibility. These results suggest that calcineurin regulates both Crz1-dependent and -independent pathways depending on the type of stress.

The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings.