Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions with the gut tissues ('immune exclusion'). IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (≥10 non-motile bacteria per gram). In typical infections, much lower densities (10-10 colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo: IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo. Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance.
Supplemental Figure 1. Nutrient gradients and gene expression are reproducible across replicates. The figure shows the profiles of single cell growth rate (left), normalized ptsG expression (middle), and normalized acs expression (right) for wildtype (WT, top) and acs mutant populations (bottom), each line shows average values within a single replicate (six to ten chambers). Note that overall profiles are very similar between replicates, though some are shifted slightly towards higher or lower depth (e.g. dark gray line acs mutant). This is likely due to slight variation in the density of cells, chamber height, or flow pressure that can change how deep glucose can penetrate into the chamber before being depleted.
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