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Salmonella Typhimurium is an intracellular pathogenic gram-negative bacterium that colonizes predominantly the intestinal lumen, activates Toll-like receptors, and accounts for most of food borne illnesses. The transcription factor Stat2 is vital in type I interferon activated antiviral and antitumor immunity and yet less is known about its role in bacterial infection. In a recent study, we reported that Stat2 was protective when tested in a mouse model of lipopolysaccharide-induced sepsis as mortality was accelerated inStat2 knockout (KO) mice. In this study, we evaluated the effect of Stat2 in a clinically relevant inflammation model of Salmonella-induced colitis. We found that when mice were pretreated with streptomycin and then orally infected with Salmonella, compared to wild type mice, Stat2KO mice showed altered intestinal responses by experiencing lower intestinal bacterial burdens. No differences were found in bacterial burdens at systemic sites. Stat2-dependent responses were lethal to wild type mice while Stat2KO mice were found to be more resistant. In contrast, Stat1KO mice were more susceptible to Salmonella infection than wild type mice suggesting that Stat2 and Stat1 play different roles during pathogenic bacterial infection. Our results indicate that disruption of the intestinal microbiota allows Stat2-dependent responses to play an adverse role in host defense against Salmonella-induced colitis. To our knowledge, this is the first evidence of Stat2 dependent responses playing a negative role in the host defense against pathogenic Salmonella bacteria. Future studies will reveal if this observation applies to other gram negative pathogens.

A massive neutrophil influx in the intestine is the histopathological hallmark of Salmonella enterica serovar Typhimurium-induced enterocolitis in humans. Two major hypotheses on the mechanism leading to neutrophil infiltration in the intestinal mucosa have emerged. One hypothesis suggests that S. enterica serovar Typhimurium takes an active role in triggering this host response by injecting proteins, termed effectors, into the host cell cytosol which induce a proinflammatory gene expression profile in the intestinal epithelium. The second hypothesis suggests a more passive role for the pathogen by proposing that bacterial invasion stimulates the innate pathways of inflammation because the pathogen-associated molecular patterns of S. enterica serovar Typhimurium are recognized by pathogen recognition receptors on cells in the lamina propria. A review of the current literature reveals that, while pathogen recognition receptors are clearly involved in eliciting neutrophil influx during S. enterica serovar Typhimurium infection, a direct contribution of effectors in triggering proinflammatory host cell responses cannot currently be ruled out.

The genus Salmonella contains a group of closely related organisms that are pathogenic for humans and other vertebrates. The human disease manifestations caused most frequently by Salmonella serotypes worldwide are typhoid fever and gastroenteritis (reviewed in reference [102][1]). Both illnesses

Amyloid fibers are β-sheet-rich protein polymers that are highly resistant to denaturation. The distinguishing amyloid fold can be adopted by a variety of proteins, without a shared primary structure, and is found in nearly all cell types. Despite the fact that amyloids have a richly informed scientific history, the diverse biology contributed by amyloids is only beginning to be appreciated. Initial amyloid studies focused on the intimate association of amyloid formation with cytotoxicity and neurodegenerative diseases like Alzheimer's, Huntington's, and the prion encephalopathies. Despite amyloid's somewhat sinister past, recent work on “functional” amyloids has revealed numerous ways that amyloids contribute to normal cellular biology [1]. Included among the activities in which amyloids participate are melanin production, the ability to act as non-Mendelian inheritable genetic elements, and as extracellular molecular scaffolds that hold bacterial communities together. The amyloid fold is tailor-made for the extracellular space, as amyloid polymers can self-assemble without requiring exogenous energy and the polymers are resistant to a slew of harsh denaturants that would devastate most protein folds. This article will address questions involving the various roles of bacterial amyloids in host, polymicrobial, and environmental interactions.

SummaryResearch on the human microbiome has established that commensal and pathogenic bacteria can influence obesity, cancer, and autoimmunity through mechanisms mostly unknown. We found that a component of bacterial biofilms, the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation. This interaction accelerated amyloid polymerization and created potent immunogenic complexes that activated immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in systemic lupus erythematosus (SLE). When given systemically, curli-DNA composites triggered immune activation and production of autoantibodies in lupus-prone and wild-type mice. We also found that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibody titers compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity.