TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral Yersinia infection

Enteroinvasive bacterial pathogens are responsible for an enormous
worldwide disease burden that critically affects the young and
immunocompromised. Yersinia pseudotuberculosisis a Gram-negative enteric
pathogen, closely related to the plague agent Y. pestis, that colonizes
intestinal tissues, induces the formation of pyogranulomas along the
intestinal tract, and disseminates to systemic organs following oral
infection of experimental rodents. Prior studies proposed that systemic
tissues were colonized by a pool of intestinal replicating bacteria
distinct from populations within Peyer’s patches and mesenteric lymph
nodes. Whether bacteria within intestinal pyogranulomas serve as the
source for systemic dissemination, and the relationship between bacterial
populations within different tissue sites, is poorly defined. Moreover,
the factors regulating Yersinia colonization and dissemination are
poorly understood. Here, we demonstrate, using Sequence Tag-based
Analysis of Microbial Populations in R (STAMPR), that remarkably small
founder populations independently colonize intestinal and systemic
tissues. Notably, intestinal pyogranulomas contain clonal populations of
bacteria that are restricted and do not spread to other tissues. However,
populations of Yersinia are shared among systemic organs and the blood,
suggesting that systemic dissemination occurs via hematogenous spread.
Finally, we demonstrate that TNF signaling is a key contributor to the
bottlenecks limiting both tissue colonization and lymphatic dissemination
of intestinal bacterial populations. Altogether, this study reveals
previously undescribed aspects of the infection dynamics of enteric
bacterial pathogens.