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

Abstract

<jats:title>Abstract</jats:title><jats:p>Secretory antibody responses (Immunoglobulin A, IgA) against repetitive bacterial surface glycans, such as O-antigens, can protect against intestinal pathogenic bacteria. However, vaccines that rely predominantly on secretory IgA for protection against non-Typhoidal salmonellosis often fail. Here we demonstrate that a major contributor to this failure is rapid immune escape, due to strong selective pressure exerted by high-avidity intestinal IgA. Interestingly, we found that IgA-escape initially occurs via a predictable narrow spectrum of <jats:italic>Salmonella</jats:italic> O-antigen variants that are fitness-neutral in naïve hosts. This could be attributed both to phase-variation, and to loss-of-function mutations in O-antigen-modifying enzymes. Via a vaccination regimen that simultaneously induced IgA against all observed O-antigen variants, rapid bacterial evolution could be switched from a hindrance into an advantage. Here, IgA generated a selective pressure resulting in fixation of mutations causing loss of polymerized O-antigen. When transmitted into naive hosts, these short O-antigen variants display compromised fitness and virulence, i.e. IgA-mediated pressure generates an evolutionary trade-off. Rational induction of IgA specificities that set “evolutionary traps” could reduce virulent enteropathogen reservoirs, even when sterilizing immunity cannot be achieved. This may become a powerful tool in the management of increasingly drug-resistant enteropathogenic bacteria.</jats:p><jats:sec><jats:title>One sentence summary</jats:title><jats:p>Intestinal IgA responses that recognize all rapidly-evolvable O-antigen variants of a <jats:italic>Salmonella</jats:italic> Typhimurium strain can drive evolutionary trade-offs for the pathogen.</jats:p></jats:sec>

High microbiota reactivity of adult human intestinal IgA requires somatic mutations

“…In contrast, hypermutated antibodies abundant in the human gut are likely to be the result of ongoing selection for high-affinity binding. Cross-species reactivity of high-affinity antibodies might rely on epitopes shared between different bacterial species such as conserved glycan structures or highly conserved peptides ( Rollenske et al, 2018 ; Bunker et al, 2019 ; Diard et al, 2019 Preprint ; Sterlin et al, 2020 ). The identification of epitopes targeted by IgA across multiple members of the microbiota is the crucial next step to further understand the phenomenon of cross-species reactivity and to dissect pathways of how cross-species reactivity is achieved.…”