High-avidity IgA protects the intestine by enchaining growing bacteria

Oral-vaccine-induced IgA cross-links growing bacteria into clonal aggregates, inhibiting pathogenesis, adaption and the spread of antimicrobial resistance genes. Clumping antibody protects gut Immunoglobulin A (IgA) is a key component in the body's first line of defence against many infections, but the physical processes that drive its protective function in the gut are poorly defined. Kathrin Moor et al . show that IgA protects against Salmonella infection in the intestines of mice by enchaining the progeny of dividing bacteria into clonal or oligoclonal clumps. This clumping mechanism enables IgA to directly disarm potentially invasive species and prevent bacterial invasion, while avoiding immune processes that could cause damage to the host. 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’) 1 , 2 , 3 . 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 8 non-motile bacteria per gram). In typical infections, much lower densities 4 , 5 (10 0 –10 7 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.