MICROBIOTA-IMMUNE SYSTEM INTERACTIONS IN THE INTESTINE

Interactions between the microbiota and the intestinal epithelium have a significant impact on mucosal adaptive immunity but the underlying mechanisms remain unclear. We have begun to unravel one potential molecular connection between epithelial cells and adaptive immunity by studying serum amyloid A (SAA) proteins. SAAs are induced in the intestinal epithelium by bacteria and are also major acute phase serum proteins. SAAs have been proposed to play a role in the inflammatory response to infection, but their exact functions were previously unclear. We have discovered that mouse and human SAAs are retinol binding proteins. Mouse and human SAAs bind retinol with nanomolar affinity, are associated with retinol in vivo, and limit the bacterial burden in tissues after acute infection. We determined the crystal structure of mouse SAA3 at a resolution of 2 Å, finding that it forms a tetramer with a hydrophobic binding pocket that can accommodate retinol. Retinol plays a vital role in the adaptive immune response to infection, yet proteins that mediate retinol transport during in response to microbial encounter have not been previously identified. Our results thus identify SAAs as a family of microbe-inducible retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and suggest how retinol is circulated during infection and in response to the microbiota.