Aerobic metabolism in Vibrio cholerae is required for population expansion during infection

Abstract

Vibrio cholerae is a bacterial pathogen that replicates to high cell density in the small intestine of human hosts leading to the diarrheal disease cholera. During infection, V. cholerae senses and responds to environmental signals that govern cellular responses. Spatial localization of V. cholerae within the intestine affects nutrient availability and therefore the metabolic pathways required for the replicative success of the pathogen. Metabolic processes used by V. cholerae to reach such high cell densities are not fully known. Here we seek to better define the metabolic traits that contribute to high levels of V. cholerae during infection by investigating mutant strains in key carbohydrate metabolism pathways. By disrupting the pyruvate dehydrogenase (PDH) complex and pyruvate formate-lyase (PFL), we could differentiate aerobic and anaerobic metabolic pathway involvement in V. cholerae proliferation. We demonstrate that oxidative metabolism is a key contributor to the replicative success of V. cholerae in vivo using an infant mouse model where PDH mutants were attenuated 100-fold relative to wild type for colonization. Additionally, metabolism of host substrates such as mucin were determined to support V. cholerae growth in vitro as a sole carbon source primarily in aerobic growth conditions. Mucin likely contributes to population expansion during human infection as it is a ubiquitous source of carbohydrates. These data highlight the importance of oxidative metabolism in the intestinal environment and warrants further investigation of how oxygen and other host substrates shape the intestinal landscape that ultimately influences bacterial disease. We conclude from our results that oxidative metabolism of host substrates such as mucin is a key driver of V. cholerae growth and proliferation during infection, leading to the substantial bacterial burden exhibited in cholera patients. ImportanceVibrio cholerae remains a challenge in the developing world and incidence of the disease it causes, cholera, is anticipated to increase with rising global temperatures and with emergent, highly infectious strains. At present, the underlying metabolic processes that support V. cholerae growth during infection are less well understood than specific virulence traits such as production of a toxin or pilus. In this study we determined that oxidative metabolism of host substrates such as mucin contribute significantly to V. cholerae population expansion in vivo. Identifying metabolic pathways critical for growth can provide avenues for controlling V. cholerae infection and the knowledge may be translatable to other pathogens of the gastrointestinal tract.