Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity

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.

A rationally designed oral vaccine induces Immunoglobulin A in the murine gut that directs the evolution of attenuatedSalmonellavariants

“…Notably, in the murine streptomycin model of NTS, inactivated oral vaccines protected predominantly via induction of high-avidity O-antigen-specific secretory IgA (17,18). However, inactivated vaccines are typically associated with weak protection (18,19). Here we reveal that rapid IgA-driven within-host evolution of NTS strains in the gut lumen is both a contributor and a possible solution to the poor performance of inactivated S.Tm vaccines.…”

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…In the last case, L-lysine is usually the dibasic amino acid, while Gram-negative bacteria contain meso -diaminopimelic acid (DAP). Among the intracellular cytoplasmic PRRs, nucleotide-binding oligomerization domain-1 and -2 (NOD1/NOD2) share overlapping signaling pathways but different specificities in MAMPs/PAMPs recognition [ 26 , 27 , 28 , 29 , 30 , 31 ]. NOD1 recognizes and is activated by bacterial PGNs.…”

Robust microbe immune recognition in the intestinal mucosa

“…However, also nontoxic CT variants that have been developed for this purpose and have been shown to share this T H17 -polarizing effect, which depends on their residual toxicity [ 66 ]. Work carried out in our laboratory [ 67 ] systematically addressed the specific effect of bacterial epithelial invasiveness (rather than adhesiveness) in the microbial induction of protective mucosal immunity in non-typhoidal invasive salmonellosis. A transitory mucosal bacterial colonization model in germ-free mice [ 68 ] was applied to carry out mucosal immunizations with invasive and noninvasive versions of an non-replicative auxotrophic strain of Salmonella enterica serovar Typhimurium ( S .…”

“…A transitory mucosal bacterial colonization model in germ-free mice [ 68 ] was applied to carry out mucosal immunizations with invasive and noninvasive versions of an non-replicative auxotrophic strain of Salmonella enterica serovar Typhimurium ( S . Typhimurium) [ 67 ]. Being unable to proliferate inside host cells and tissues, invasive auxotrophic S .…”

“…Being unable to proliferate inside host cells and tissues, invasive auxotrophic S . Typhimurium was found to be a virulent but capable of transient epithelial-restricted cell invasion [ 67 ]. The high-affinity IgA-mediated [ 69 ] efficacy of auxotrophic S .…”