Mucosal infection rewires TNFɑ signaling dynamics to skew susceptibility to recurrence

Elife. 2019 Aug 20;8:e46677. doi: 10.7554/eLife.46677.

Abstract

A mucosal infectious disease episode can render the host either more or less susceptible to recurrent infection, but the specific mechanisms that tip the balance remain unclear. We investigated this question in a mouse model of recurrent urinary tract infection and found that a prior bladder infection resulted in an earlier onset of tumor necrosis factor-alpha (TNFɑ)-mediated bladder inflammation upon subsequent bacterial challenge, relative to age-matched naive mice. However, the duration of TNFɑ signaling activation differed according to whether the first infection was chronic (Sensitized) or self-limiting (Resolved). TNFɑ depletion studies revealed that transient early-phase TNFɑ signaling in Resolved mice promoted clearance of bladder-colonizing bacteria via rapid recruitment of neutrophils and subsequent exfoliation of infected bladder cells. In contrast, sustained TNFɑ signaling in Sensitized mice prolonged damaging inflammation, worsening infection. This work reveals how TNFɑ signaling dynamics can be rewired by a prior infection to shape diverse susceptibilities to future mucosal infections.

Keywords: E. coli; immunology; infectious disease; inflammation; microbiology; mouse; mucosal infection; mucosal remodeling; recurrent infection; tumor necrosis factor alpha; urinary tract infection; uropathogenic E. coli.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Immunity, Mucosal*
  • Immunologic Factors / metabolism*
  • Mice
  • Recurrence
  • Secondary Prevention
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Urinary Tract Infections / immunology*

Substances

  • Immunologic Factors
  • Tumor Necrosis Factor-alpha

Associated data

  • GEO/GSE117532