Antibiotic treatment-induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia

J Clin Invest. 2018 Aug 1;128(8):3535-3545. doi: 10.1172/JCI97065. Epub 2018 Jul 16.

Abstract

Broad-spectrum antibiotics are widely used with patients in intensive care units (ICUs), many of whom develop hospital-acquired infections with Pseudomonas aeruginosa. Although preceding antimicrobial therapy is known as a major risk factor for P. aeruginosa-induced pneumonia, the underlying mechanisms remain incompletely understood. Here we demonstrate that depletion of the resident microbiota by broad-spectrum antibiotic treatment inhibited TLR-dependent production of a proliferation-inducing ligand (APRIL), resulting in a secondary IgA deficiency in the lung in mice and human ICU patients. Microbiota-dependent local IgA contributed to early antibacterial defense against P. aeruginosa. Consequently, P. aeruginosa-binding IgA purified from lamina propria culture or IgA hybridomas enhanced resistance of antibiotic-treated mice to P. aeruginosa infection after transnasal substitute. Our study provides a mechanistic explanation for the well-documented risk of P. aeruginosa infection following antimicrobial therapy, and we propose local administration of IgA as a novel prophylactic strategy.

Keywords: Bacterial infections; Infectious disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Humans
  • Iatrogenic Disease
  • IgA Deficiency / drug therapy*
  • IgA Deficiency / genetics
  • IgA Deficiency / immunology
  • IgA Deficiency / pathology
  • Immunoglobulin A / pharmacology*
  • Mice
  • Mice, Knockout
  • Pneumonia, Bacterial / drug therapy*
  • Pneumonia, Bacterial / genetics
  • Pneumonia, Bacterial / immunology
  • Pneumonia, Bacterial / pathology
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / genetics
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / pathology
  • Pseudomonas aeruginosa / immunology*

Substances

  • Anti-Bacterial Agents
  • Immunoglobulin A

Grants and funding

to B.O., C.C., M.M.H., M.W., N.S.