Parallel Exploitation of Diverse Host Nutrients Enhances <i>Salmonella</i> Virulence

Abstract

<div><p>Pathogen access to host nutrients in infected tissues is fundamental for pathogen growth and virulence, disease progression, and infection control. However, our understanding of this crucial process is still rather limited because of experimental and conceptual challenges. Here, we used proteomics, microbial genetics, competitive infections, and computational approaches to obtain a comprehensive overview of <i>Salmonella</i> nutrition and growth in a mouse typhoid fever model. The data revealed that <i>Salmonella</i> accessed an unexpectedly diverse set of at least 31 different host nutrients in infected tissues but the individual nutrients were available in only scarce amounts. <i>Salmonella</i> adapted to this situation by expressing versatile catabolic pathways to simultaneously exploit multiple host nutrients. A genome-scale computational model of <i>Salmonella</i> in vivo metabolism based on these data was fully consistent with independent large-scale experimental data on <i>Salmonella</i> enzyme quantities, and correctly predicted 92% of 738 reported experimental mutant virulence phenotypes, suggesting that our analysis provided a comprehensive overview of host nutrient supply, <i>Salmonella</i> metabolism, and <i>Salmonella</i> growth during infection. Comparison of metabolic networks of other pathogens suggested that complex host/pathogen nutritional interfaces are a common feature underlying many infectious diseases.</p></div