Abstract
There is the notion that infection with a virulent intestinal pathogen induces generally stronger mucosal adaptive immunity than the exposure to an avirulent strain. Whether the associated mucosal inflammation is important or redundant for effective induction of immunity is, however, still unclear. Here we use a model of auxotrophic Salmonella infection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Although live auxotrophic Salmonella no longer causes inflammation, its mucosal virulence factors remain the main drivers of protective mucosal immunity; virulence factor-deficient, like killed, bacteria show reduced efficacy. Assessing the involvement of innate pathogen sensing mechanisms, we show MYD88/TRIF, Caspase-1/Caspase-11 inflammasome, and NOD1/NOD2 nodosome signaling to be individually redundant. In colonized animals we show that microbiota metabolite cross-feeding may recover intestinal luminal colonization but not pathogenicity. Consequent immunoglobulin A immunity and microbial niche competition synergistically protect against Salmonella wild-type infection.
Highlights
Mercedes Gomez de Agüero 3, Christian M
As the invading and tissue-overgrowing virulent bacteria responsible are subject to pronounced population bottle necks[3,22], we hypothesized that a strain of live serovar Typhimurium (STm) encoding functional virulence factors would retain its invasiveness with associated adaptive immunogenicity, despite being unable to replicate and overall avirulent
Like the homologous model in commensal Escherichia coli developed previously[15,16], STmAux colonized the gastrointestinal tract of germ-free mice only transiently, allowing rapid and full recovery to germ-free status, as neither host metabolism nor diet could substitute the auxotrophic requirement for these metabolites (Fig. 1a, b)
Summary
Mercedes Gomez de Agüero 3, Christian M. We use a model of auxotrophic Salmonella infection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Mounting a functional anti-microbial adaptive immune response depends on concomitant induction of an innate immunogenic response through pattern recognition receptor (PRR) activation[1]. PRRs sense conserved microbial molecular structures, such as bacterial lipopolysaccharide (LPS), peptidoglycan, and flagellin, that are conserved across pathogenic and non-pathogenic microorganisms[2]. Pathogenspecific virulence factors such as type 3 secretion system (T3SS) components[3] and intracellular toxin action have been shown to be sensed by PRRs4,5. PRR activation by pathogens may drive inflammation and innate anti-microbial defense
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
