Comparative analysis of Salmonella genomes identifies a metabolic network for escalating growth in the inflamed gut

Abstract

The Salmonella genus comprises a group of pathogens associated with illnesses ranging from gastroenteritis to typhoid fever. We performed an in silico analysis of comparatively reannotated Salmonella genomes to identify genomic signatures indicative of disease potential. By removing numerous annotation inconsistencies and inaccuracies, the process of reannotation identified a network of 469 genes involved in central anaerobic metabolism, which was intact in genomes of gastrointestinal pathogens but degrading in genomes of extraintestinal pathogens. This large network contained pathways that enable gastrointestinal pathogens to utilize inflammation-derived nutrients as well as many of the biochemical reactions used for the enrichment and biochemical discrimination of Salmonella serovars. Thus, comparative genome analysis identifies a metabolic network that provides clues about the strategies for nutrient acquisition and utilization that are characteristic of gastrointestinal pathogens. IMPORTANCE While some Salmonella serovars cause infections that remain localized to the gut, others disseminate throughout the body. Here, we compared Salmonella genomes to identify characteristics that distinguish gastrointestinal from extraintestinal pathogens. We identified a large metabolic network that is functional in gastrointestinal pathogens but decaying in extraintestinal pathogens. While taxonomists have used traits from this network empirically for many decades for the enrichment and biochemical discrimination of Salmonella serovars, our findings suggest that it is part of a "business plan" for growth in the inflamed gastrointestinal tract. By identifying a large metabolic network characteristic of Salmonella serovars associated with gastroenteritis, our in silico analysis provides a blueprint for potential strategies to utilize inflammation-derived nutrients and edge out competing gut microbes.

FIG 1

Central anaerobic metabolism of the gastrointestinal pathovar. Black text denotes genes unaffected by degradation in the extraintestinal pathovar, while blue text denotes genes putatively affected by disruptions or deletions in the extraintestinal pathovar. Due to space restrictions, not all intermediates, products, cofactors, or stoichiometries are shown for every reaction; the production of carbon dioxide and the involvement of nucleoside polyphosphate, vitamin B₁₂, or adenine dinucleotide cofactors are always shown. The table displays genes whose products regulate processes involved in central anaerobic metabolism.

FIG 2

Degradation of central anaerobic metabolism. Boxes contain the names of all hypothetically disrupted or deleted coding DNA sequences (CDSs) involved in central anaerobic metabolism for each genome analyzed. Entries with numbers represent abbreviated STM locus tags (e.g., 4308 = STM4308).