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Tailored intestinal IgA responses can set an evolutionary trap for Salmonella Typhimurium
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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 Salmonella 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.
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