Abstract
BackgroundSystemic bacterial infections are highly regulated and complex processes that are orchestrated by numerous virulence factors. Genes that are coordinately controlled by the set of regulators required for systemic infection are potentially required for pathogenicity.ResultsIn this study we present a systems biology approach in which sample-matched multi-omic measurements of fourteen virulence-essential regulator mutants were coupled with computational network analysis to efficiently identify Salmonella virulence factors. Immunoblot experiments verified network-predicted virulence factors and a subset was determined to be secreted into the host cytoplasm, suggesting that they are virulence factors directly interacting with host cellular components. Two of these, SrfN and PagK2, were required for full mouse virulence and were shown to be translocated independent of either of the type III secretion systems in Salmonella or the type III injectisome-related flagellar mechanism.ConclusionsIntegrating multi-omic datasets from Salmonella mutants lacking virulence regulators not only identified novel virulence factors but also defined a new class of translocated effectors involved in pathogenesis. The success of this strategy at discovery of known and novel virulence factors suggests that the approach may have applicability for other bacterial pathogens.
Highlights
Systemic bacterial infections are highly regulated and complex processes that are orchestrated by numerous virulence factors
serovar Typhimurium (STM) is an intracellular pathogen that can replicate in a variety of cell types, but is most frequently found in monocytes and neutrophils following infection where it is located within a specialized host-membrane bound body, the Salmonella-containing vacuole (SCV) [8,9]
Rationale for strains used and study design To date, more than 300 genes have been annotated as regulatory genes in Salmonella and of those tested (83) we showed that 14 regulators including SpvR, FruR, IHF, PhoP/PhoQ, SsrA/SsrB, SlyA, Hnr, RpoE, SmpB, CsrA, RpoS, CRP, OmpR/EnvZ, and Hfq are required for virulence regulation during systemic infection in an acute mouse infection model [24]
Summary
Systemic bacterial infections are highly regulated and complex processes that are orchestrated by numerous virulence factors. Salmonella enterica serovar Typhimurium (STM) is a facultative intracellular bacterial pathogen with a broad host range capable of infecting birds, reptiles, mice, humans and other mammals. In humans, it is a leading causative agent of gastroenteritis with significant impacts on childhood mortality in the developing world [4] and among HIV positive patients in Sub-Saharan Africa [4,5]. Because its symptoms resemble human typhoid fever caused by the S. enterica serovar Typhi, which only infects man, STM-mediated systemic infection in mice represents an established model system to investigate the pathogenesis and immunology of typhoid fever in humans [6,7]. STM is able to avoid lysosomal fusion with the SCV and evade destruction [10,11]
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