Abstract
The intestinal resident Candida glabrata opportunistically infects humans. However few genetic factors for adaptation in the intestine are identified in this fungus. Here we describe the C. glabrata CYB2 gene encoding lactate dehydrogenase as an adaptation factor for survival in the intestine. CYB2 was identified as a virulence factor by a silkworm infection study. To determine the function of CYB2, we analysed in vitro phenotypes of the mutant Δcyb2. The Δcyb2 mutant grew well in glucose medium under aerobic and anaerobic conditions, was not supersensitive to nitric oxide which has fungicidal-effect in phagocytes, and had normal levels of general virulence factors protease, lipase and adherence activities. A previous report suggested that Cyb2p is responsible for lactate assimilation. Additionally, it was speculated that lactate assimilation was required for Candida virulence because Candida must synthesize glucose via gluconeogenesis under glucose-limited conditions such as in the host. Indeed, the Δcyb2 mutant could not grow on lactate medium in which lactate is the sole carbon source in the absence of glucose, indicating that Cyb2p plays a role in lactate assimilation. We hypothesized that Cyb2p-mediated lactate assimilation is necessary for proliferation in the intestinal tract, as the intestine is rich in lactate produced by bacteria flora, but not glucose. The Δcyb2 mutant showed 100-fold decreased adaptation and few cells of Saccharomyces cerevisiae can adapt in mouse ceca. Interestingly, C. glabrata could assimilate lactate under hypoxic conditions, dependent on CYB2, but not yeast S. cerevisiae. Because accessible oxygen is limited in the intestine, the ability for lactate assimilation in hypoxic conditions may provide an advantage for a pathogenic yeast. From those results, we conclude that Cyb2p-mediated lactate assimilation is an intestinal adaptation factor of C. glabrata.
Highlights
Candida albicans and Candida glabrata are commensal yeasts that live in association with human mucosal surfaces including the intestine and vagina, and often turn pathogenic in immnunocompromised individuals, such as AIDS, leukemia or diabetes patients and cause a high rate of mortality [1,2,3,4]
This report concludes that the glyoxylate cycle is a critical adaptation factor for C. albicans to survive in the host environment, especially in the macrophage where nutrient availability is low for pathogens
This study demonstrates that Cyb2p plays an essential role in lactate assimilation and identifies it as a novel adaptation factor for survival in the intestine, as well as substantiating the previous speculation that lactate assimilation is required for Candida infection [7]
Summary
Candida albicans and Candida glabrata are commensal yeasts that live in association with human mucosal surfaces including the intestine and vagina, and often turn pathogenic in immnunocompromised individuals, such as AIDS, leukemia or diabetes patients and cause a high rate of mortality [1,2,3,4]. This report speculated that the lactate assimilation as an alternative pathway can support the glyoxylate cycle, because the transcripts for CYB2 (encoding L-lactate dehydrogenase, converting L-lactate to pyruvate), JEN1 and JEN2 (lactate transporters and its homolog) were induced 15.7-fold, 5.5-fold and 159.5-fold, respectively, in macrophages [10] (Figure S1). To clarify this speculation, the Djen1/Djen double knock out mutant of C. albicans was constructed and analysed for virulence. The importance of lactate assimilation in disease is unclear
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