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

Mucosal infection rewires TNFɑ signaling dynamics to skew susceptibility to recurrence.

Author information

1
Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, United States.
2
The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.
3
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
4
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, United States.
5
Department of Genetics, Washington University School of Medicine, St Louis, United States.
#
Contributed equally

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

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