Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling

The microbiota primes immune defences but the identity of specific commensal microbes which protect against infection is unclear. Conversely, how pathogens compete with the microbiota to establish their host niche is also poorly understood. Here, we investigate the antagonism between the microbiota and Klebsiella pneumoniae during colonization and transmission. We discover that maturation of the microbiota drives the development of distinct immune defence programs in the upper airway and intestine to limit K. pneumoniae colonization within these niches. Immune protection in the intestine depends on the development of Bacteroidetes, IL-36 signalling and macrophages. This effect of Bacteroidetes requires their conserved commensal colonization factor (CCF) polysaccharide utilization locus. Conversely, in the upper airway, Proteobacteria prime immunity through IL-17A, but K. pneumoniae overcomes these defences through encapsulation to effectively colonize this site. Ultimately, we find that host-to-host spread of K. pneumoniae occurs principally from its intestinal reservoir, and that CCF-producing Bacteroidetes are sufficient to prevent transmission between hosts through IL-36. Thus, our study provides mechanistic insight into when, where and how commensal Bacteroidetes protect against K. pneumoniae colonization and contagion, providing insight into how these protective microbes could be harnessed to confer population-level protection against K. pneumoniae infection.