Tailored intestinal IgA responses can set an evolutionary trap for Salmonella Typhimurium
Beth M. Stadtmueller,
Marjan W. van der Woude,
Patrick H. Viollier,
Beat H. Meier,
Posted 31 Oct 2019
bioRxiv DOI: 10.1101/824821
Posted 31 Oct 2019
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 naive 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. ### Competing Interest Statement Diard M, Hardt W-D and Slack, E are coauthors of a patent application for an oligovalent Salmonella vaccine capable of setting and evolutionary trap.
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