Parallel Exploitation of Diverse Host Nutrients Enhances Salmonella Virulence

Abstract

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 Salmonella nutrition and growth in a mouse typhoid fever model. The data revealed that Salmonella 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. Salmonella adapted to this situation by expressing versatile catabolic pathways to simultaneously exploit multiple host nutrients. A genome-scale computational model of Salmonella in vivo metabolism based on these data was fully consistent with independent large-scale experimental data on Salmonella 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, Salmonella metabolism, and Salmonella 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.

Shigella reroutes host cell central metabolism to obtain high-flux nutrient supply for vigorous intracellular growth

“…However, comparison of the Shigella data with our recent study on Salmonella enterica metabolism in a mouse typhoid fever model (37) reveals commonalities and striking differences. Shigella, like Salmonella and many other pathogens (37), exploits the fact that most biomass components are readily available in infected host environments. Uptake of these biomass components can save substantial biosynthesis costs.…”

“…Uptake of these biomass components can save substantial biosynthesis costs. However, Shigella has access to a high-flux supply for pyruvate that provides sufficient energy to drive fast growth, whereas intracellular Salmonella has access to many diverse but only scarce energy sources that together just support slow nutrient-limited growth (37). This striking difference may reflect the fact that Shigella reside directly in the host cytoplasm, whereas intracellular Salmonella are surrounded by a phagosomal membrane with apparently poor permeability in macrophages (their main target cell type during systemic infections).…”

Bacterial peptide transporters: Messengers of nutrition to virulence

“…This may slow down the growth but does not affect survival and therefore leave little scope for the development of resistance. Metabolism associated genes of pathogens have been consistently linked with virulence of major pathogens, [1][2][3][4][5][6][7][8][9] such as, role of carbon metabolism related pathways like glycolysis 10 and TCA cycle 11 in virulence of Salmonella Typhimurium and requirement of metabolism associated pathways for protection of Mycobacterium tuberculosis from host immune system. 9 Salmonella is even known to modulate host to exploit the limited supply of nutrients.…”

“…9 Salmonella is even known to modulate host to exploit the limited supply of nutrients. 8,12 Coupling of nutrition with virulence reveals metabolism associated genes that can be targeted for antimicrobial therapy. Peptide transporters represent one such class of genes known to be required for virulence of Gram negative as well as Gram positive pathogens.…”

CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants

“…The network revealed a wide-ranging distribution of CovS-regulated genes in pathways relevant to nutritional derivation. By examining nutritional genes at the genome-wide scale, we found that the nutritional derivation of pathogenic GAS is highly redundant and that many nutrients can be supplied by multiple genetic loci or physical sources with regard to extracellular nutrient uptake or de novo biosynthesis (55). As examples, two loci for ␤-glucoside transport were simultaneously downregulated by CovS ϩ at LP and upregulated at SP and de novo biosynthesis of cysteine and the cysteine transporter system were both upregulated at SP by CovS ϩ .…”