The Salmonella Pathogenicity Island (SPI)-2 and SPI-1 Type III Secretion Systems Allow Salmonella Serovar typhimurium to Trigger Colitis via MyD88-Dependent and MyD88-Independent Mechanisms

Abstract

Salmonella typhimurium can colonize the gut, invade intestinal tissues, and cause enterocolitis. In vitro studies suggest different mechanisms leading to mucosal inflammation, including 1) direct modulation of proinflammatory signaling by bacterial type III effector proteins and 2) disruption or penetration of the intestinal epithelium so that penetrating bacteria or bacterial products can trigger innate immunity (i.e., TLR signaling). We studied these mechanisms in vivo using streptomycin-pretreated wild-type and knockout mice including MyD88−/− animals lacking an adaptor molecule required for signaling via most TLRs. The Salmonella SPI-1 and the SPI-2 type III secretion systems (TTSS) contributed to inflammation. Mutants that retain only a functional SPI-1 (M556; sseD::aphT) or a SPI-2 TTSS (SB161; ΔinvG) caused attenuated colitis, which reflected distinct aspects of the colitis caused by wild-type S. typhimurium: M556 caused diffuse cecal inflammation that did not require MyD88 signaling. In contrast, SB161 induced focal mucosal inflammation requiring MyD88. M556 but not SB161 was found in intestinal epithelial cells. In the lamina propria, M556 and SB161 appeared to reside in different leukocyte cell populations as indicated by differential CD11c staining. Only the SPI-2-dependent inflammatory pathway required aroA-dependent intracellular growth. Thus, S. typhimurium can use two independent mechanisms to elicit colitis in vivo: SPI-1-dependent and MyD88-independent signaling to epithelial cells and SPI-2-dependent intracellular proliferation in the lamina propria triggering MyD88-dependent innate immune responses.

Heterogeneity of type III secretion system (T3SS)-1-independent entry mechanisms used by Salmonella Enteritidis to invade different cell types

“…For a long time it was assumed that cell invasion by Salmonella was only associated with its T3SS-1, which induces a Trigger mechanism. However, some studies have reported that Salmonella strains lacking SPI-1 are able to induce enterocolitis both in humans and in mouse and bovine models (Coombes et al, 2005;Hapfelmeier et al, 2005;Hu et al, 2008). The present study confirms that although T3SS-1 is the main in vitro Salmonella invasion factor for all the cell lines tested, T3SS-1-independent processes can play a not insignificant role.…”

“…For example, a Salmonella Senftenberg strain lacking T3SS-1 was isolated from a human clinical case and shown to be able to induce enterocolitis in a mouse model (Hu et al, 2008). Moreover, Salmonella Typhimurium T3SS-1-independent enteropathogenesis has also been demonstrated in murine and bovine infection models, and in chicken caecal and small-intestine explants (Coombes et al, 2005;Desin et al, 2009;Hapfelmeier et al, 2005). All these results indicate that in vivo T3SS-1-independent invasion mechanisms play an important role in Salmonella infection.…”

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

“…[8][9][10][11] Bacterial genes (SPI-1 and SPI-2 encoded factors) were also shown to be critical during this infection stage. [12][13][14][15] Besides the fact that this model of infection causes a systemic disease with typhoid-like symptoms in the majority of inbred strains, the Salmonella Typhimurium oral infection model remains relevant to study initial steps affecting the colonization of the host.…”

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

“…In addition to TLR, it is noteworthy that Salmonellae enterica encode 2 type 3 secretion systems that allow the secretion of effector proteins able to trigger proinflammatory host responses and their injection into host cells. 37 It is possible that this secretion system may also contribute to T-cell recruitment in the bladder since live Ty21a were more efficient than heat-killed bacteria, although the TLRagonist activities of the latter should be similar, or even increased in the case of flagellin. 38 NMIBC is the most prevalent form of bladder cancer, which in turn represents the second most common urogenital cancer with a lifetime risk of 1 in 26 for men and 1 in 87 for women in the United States.…”