The lipopolysaccharide modification regulator PmrA limitsSalmonellavirulence by repressing the type three-secretion system Spi/Ssa

Abstract

The regulatory protein PmrA controls expression of lipopolysaccharide (LPS) modification genes in Salmonella enterica serovar Typhimurium, the etiologic agent of human gastroenteritis and murine typhoid fever. PmrA-dependent LPS modifications confer resistance to serum, Fe 3+ , and several antimicrobial peptides, suggesting that the pmrA gene is required for Salmonella virulence. We now report that, surprisingly, a pmrA null mutant is actually hypervirulent when inoculated i.p. into C3H/HeN mice. We establish that the PmrA protein binds to the promoter and represses transcription of ssrB , a virulence regulatory gene required for expression of the Spi/Ssa type three-secretion system inside macrophages. The pmrA mutant displayed heightened expression of SsrB-dependent genes and faster Spi/Ssa-dependent macrophage killing than wild-type Salmonella . A mutation in the ssrB promoter that abolished repression by the PmrA protein rendered Salmonella as hypervirulent as the pmrA null mutant. The antivirulence function of the PmrA protein may limit the acute phase of Salmonella infection, thereby enhancing pathogen persistence in host tissues.

The Iron-Sensing Fur Regulator Controls Expression Timing and Levels of Salmonella Pathogenicity Island 2 Genes in the Course of Environmental Acidification

“…This idea could be supported by the finding that ectopic expression of the SPI-2 genes caused by the lack of YdgT-or EIIA Ntr -mediated regulation leads to Salmonella virulence attenuation in mice infected intraperitoneally (8,10). Finally, because both Fur and PmrA regulators control SPI-2 expression in a similar fashion, Fur might delay SPI-2-mediated macrophage killing as PmrA does for macrophages (21). However, even if this were the case, Fur ultimately contributes to Salmonella virulence, in contrast to the finding that PmrA-controlled macrophage killing limits Salmonella virulence (21).…”

“…Interestingly, the PmrA protein repressed SPI-2 expression in a manner similar to the Fur regulator; PmrA was shown to bind to a region overlapping with the SsrB-binding site on the ssrB promoter (Fig. 4A) and repress ssrB transcription (21). Therefore, the reason Salmonella uses two iron-sensing regulatory systems to control SPI-2 expression remains a question.…”

“…The PmrA protein controls expression of the lipopolysaccharide modification genes (19). Recently, the PmrA response regulator has been reported to repress SPI-2 expression in the presence of iron (21), suggesting that PmrA could be an iron mediator to repress expression of the SPI-2 genes. Here, we report that the iron-sensing Fur regulator also controls expression of the SPI-2 genes.…”

Dual RNA-seq of pathogen and host

“…Rather STnc440 may be activated through the major regulatory To some extent, this may be linked to the mis-regulation of SPI-2 expression in the absence of STnc440. It has been reported before that premature SPI-2 induction has an adverse effect on Salmonella growth within its host cell niche and therefore negative regulators of SPI-2, such as YdgT (Coombes et al, 2005) or PmrA (Choi and Groisman, 2013), are required for the contextual activation of virulence factors from this island ( Fig. 1.2).…”

“…Upon its stimulation, HilD transcriptionally activates two further regulators, HilC and RtsA, which amplify the signal, leading to the rapid induction of the entire SPI-1 locus. Choi and Groisman, 2013, Ellermeier and Slauch, 2007, and Fass and Groisman, 2009 In contrast, the T3SS-2 routes effectors across the vacuolar membrane of Salmonella's intracellular replication niche, the so-called Salmonella-containing vacuole (SCV). Thus, expression of SPI-2 has to be tightly controlled to ensure its activation only within the host cell environment.…”