Salmonella Virulence Factor SsrAB Regulated Factor Modulates Inflammatory Responses by Enhancing the Activation of NF-κB Signaling Pathway

Abstract

Effector proteins encoded by Salmonella pathogenicity islands play a key role in promoting bacterial intracellular survival, colonization, and pathogenesis. In this study, we investigated the function of the virulence-associated effector SrfA (SsrAB regulated factor) both in macrophages in vitro and in infected mice in vivo. SrfA was secreted into the cytoplasm during S. Typhimurium infection and disassociated IL-1R–associated kinase-1 (IRAK-1) from the IRAK-1–Toll interacting protein (Tollip) complex by interacting with Tollip. The released IRAK-1 was phosphorylated and subsequently activated the NF-κB signaling pathway, which enhanced the LPS-induced expression of inflammatory cytokines, such as IL-8, IL-1β, and TNF-α. The coupling of ubiquitin to endoplasmic reticulum degradation aa 183–219 domain of Tollip is the binding region for SrfA, and both the MDaa207–226 and CTaa357–377 regions of SrfA mediate binding to Tollip and NF-κB signaling activation. Deletion of SrfA in S. Typhimurium had no notable effects on its replication but impaired the induction of NF-κB activation in infected macrophages. The mice infected with srfA-deficient bacteria exhibited a decreased inflammatory response and an increased survival rate compared with those infected with wild-type S. Typhimurium. We conclude that SrfA is a novel Salmonella virulence effector that helps modulate host inflammatory responses by promoting NF-κB signaling activation.

Salmonella enterica Serovar Typhimurium Increases Functional PD-L1 Synergistically with Gamma Interferon in Intestinal Epithelial Cells via Salmonella Pathogenicity Island 2

“…Therefore, one or multiple genes from SPI-2 are involved in PD-L1 induction of IECs. To further identify a single bacterial component important in PD-L1 induction, seven SPI-2encoded effector mutants were created and tested (⌬spvC, ⌬sspH1, ⌬slrp, ⌬sseJ, ⌬sseL, ⌬spvD, and ⌬srfA; see Table S2 in the supplemental material) based on their suggested effector functions (20,21,30). Each strain was inoculated at four doses (1 ϫ 10 7 , 3 ϫ 10 7 , 5 ϫ 10 7 , and 8 ϫ 10 7 CFU/well) to generate respective intracellular bacteria versus PD-L1 expression curves (Fig.…”

Comparison of Salmonella enterica Serovars Typhi and Typhimurium Reveals Typhoidal Serovar-Specific Responses to Bile

“…Typhi and downregulated in S . Typhimurium include lpxR (t1208/STM14_1612), a lipid A-modifying protein that modulates the ability of lipid A to stimulate Toll-like receptor 4 (TLR4) ( 32 ) and promotes Salmonella growth inside macrophages ( 33 ), and srfA and srfB , virulence factors expressed under SPI-1-inducing conditions ( 34 ) and reported to modulate inflammatory signaling ( 35 ). Additionally, several hypothetical proteins, t0944 (STM14_2352), t1774 (STM14_1312), and t2782 (STM14_3479), were upregulated in S .…”

SrfC of Pseudomonas cichorii JBC1 affects its attachment to the host surface and host tissue infection

“…Genome analysis suggested that the srfABC cluster was located in the horizontally acquired island adjacent to a putative lipoprotein transport system that is responsible for its secretion (Nykyri et al ., ). Among the proteins coded for by the cluster, SrfA was expected to be secreted to effect nuclear transcription (Worley et al ., ) and was determined to be a secreted virulence effector of Salmonella that modulates host inflammatory responses by promoting the activation of nuclear factor‐kappa B (NF‐κB) signalling pathways (Lei et al ., ). This is in contrast to the results for P. cichorii in the present study; this difference in SrfA function between mammalian and plant pathogens requires further study.…”