Massis, L. M. | Search bioRxiv

bioRxiv2022

Multi-omics reveal Salmonella-liberated dietary L-arabinose promotes expansion in superspreaders

Our understanding of specific metabolites that drive host-pathogen interactions in the guts of superspreader hosts is incomplete. In a mouse model of chronic, asymptomatic Salmonella enterica serovar Typhimurium (S. Tm) infection, we performed untargeted metabolomics on the feces of mice and found superspreader hosts possess distinct metabolic signatures compared to non-superspreaders, including differential levels of L-arabinose. RNA-seq on S. Tm in superspreader fecal samples showed increased expression of the L-arabinose catabolism pathway in vivo. By combining bacterial genetics and diet manipulation, we demonstrate that diet-derived L-arabinose provides S. Tm a competitive advantage in the gut. We show that expansion of S. Tm in the gut requires a previously uncharacterized alpha-N-arabinofuranosidase that can liberate L-arabinose from dietary polysaccharides. Ultimately, we demonstrate that pathogen-liberated L-arabinose from the diet provides a competitive advantage to S. Tm in vivo. These findings propose L-arabinose as a critical driver of S. Tm expansion in the guts of superspreader hosts.

microbiology↗

bioRxiv2021

Metabolomic analysis of diverse mice reveals hepatic arginase-1 as source of plasma arginase in Plasmodium chabaudi infection

Infections disrupt host metabolism, but the factors that dictate the nature and magnitude of metabolic change are incompletely characterized. To determine how host metabolism changes in relation to disease severity in murine malaria, we performed plasma metabolomics on eight Plasmodium chabaudi-infected mouse strains with diverse disease phenotypes. We identified plasma metabolic biomarkers for both the nature and severity of different malarial pathologies. A subset of metabolic changes, including plasma arginine depletion, match the plasma metabolomes of human malaria patients, suggesting new connections between pathology and metabolism in human malaria. In our malarial mice, liver damage, which releases hepatic arginase-1 (Arg1) into circulation, correlated with plasma arginine depletion. We confirmed that hepatic Arg1 was the primary source of increased plasma arginase activity in our model, which motivates further investigation of liver damage in human malaria patients. More broadly, our approach shows how leveraging phenotypic diversity can identify and validate relationships between metabolism and the pathophysiology of infectious disease. ImportanceMalaria is a severe and sometimes fatal infectious disease endemic to tropical and subtropical regions. Effective vaccines against malaria-causing Plasmodium parasites remain elusive, and malaria treatments often fail to prevent severe disease. Small molecules that target host metabolism have recently emerged as candidates for therapeutics in malaria and other diseases. However, our limited understanding of how metabolites affect pathophysiology limits our ability to develop new metabolite therapies. By providing a rich dataset of metabolite-pathology correlations, and by validating one of those correlations, our work is an important step toward harnessing metabolism to mitigate disease. Specifically, we showed that liver damage in P. chabaudi-infected mice releases hepatic arginase-1 into circulation, where it may deplete plasma arginine, a candidate malaria therapeutic that mitigates vascular stress. Our data suggest that liver damage may confound efforts to increase levels of arginine in human malaria patients.

pathology↗