Antibiotic treatment–induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia
Oliver H. Robak, … , Catherine Chaput, Bastian Opitz
Oliver H. Robak, … , Catherine Chaput, Bastian Opitz
Published August 1, 2018; First published May 17, 2018
Citation Information: J Clin Invest. 2018;128(8):3535-3545. https://doi.org/10.1172/JCI97065.
View: Text | PDF
Categories: Research Article Infectious disease

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

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.

Authors

Oliver H. Robak, Markus M. Heimesaat, Andrey A. Kruglov, Sandra Prepens, Justus Ninnemann, Birgitt Gutbier, Katrin Reppe, Hubertus Hochrein, Mark Suter, Carsten J. Kirschning, Veena Marathe, Jan Buer, Mathias W. Hornef, Markus Schnare, Pascal Schneider, Martin Witzenrath, Stefan Bereswill, Ulrich Steinhoff, Norbert Suttorp, Leif E. Sander, Catherine Chaput, Bastian Opitz

×

Figure 1

Antibiotic-mediated microbiota depletion impairs antibacterial defense against P. aeruginosa.

Options: View larger image (or click on image) Download as PowerPoint
Antibiotic-mediated microbiota depletion impairs antibacterial defense a...
(A–D) Conventionally colonized mice (Conv) and mice that were treated with an antibiotic cocktail for 6–8 weeks (ABx) were infected with P. aeruginosa. (A) Bacterial loads in BALF (n = 9), (B) lung tissue (n = 11 for Conv mice; n = 9 for ABx mice), and (C) blood (n = 11 for Conv mice; n = 9 for ABx mice) were counted at the indicated time points, or (D) survival was monitored (n = 11 for Conv mice; n = 12 for ABx mice). (E–M) Mice were intranasally infected with P. aeruginosa or treated with PBS for 6 hours. Production of inflammatory mediators was measured by ELISA (n = 10 for uninfected Conv and ABx mice; n = 10 for infected Conv mice; n = 11 for infected ABx mice) and qRT-PCR (n = 8 for uninfected Conv and ABx mice; n = 10 for infected Conv mice; n = 9 for infected ABx mice). (N and O) Alveolar macrophages (n = 9 for uninfected Conv and ABx mice; n = 9 for infected Conv mice; n = 7 for infected ABx mice) and neutrophils (n = 9 for uninfected Conv and ABx mice; n = 9 for infected Conv mice; n = 8 for infected ABx mice) were counted by FACS analysis after staining of BALF samples. (P) Lung vascular permeability of control and microbiota-depleted animals was measured by Evans blue dye leakage in the lungs (n = 8 for Conv; n = 8 for ABx mice). Mann-Whitney U tests were applied to the data set, except for the survival curve (D), which was submitted to log-rank test. Values are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005.