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

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Figure 5

Local application of IgA enhances the antibacterial defense against P. aeruginosa in antibiotic-treated animals.

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Local application of IgA enhances the antibacterial defense against P. a...
(A–D) IgA was purified from ex vivo murine lamina propria culture, and purified lamina propria IgA (IgALP) or PBS was intranasally applied to animals pretreated with antibiotic 30 minutes prior to infection with P. aeruginosa. Bacterial loads (n = 12 for mice with and without IgA treatment) in (A) lung and (B) blood, and (C) body temperature (n = 8 for mice with and without IgA treatment) were measured 24 hours after infection, or survival was monitored over 4 days (n = 17 for mice with and without IgA treatment) (D). (E) Pooled hybridoma IgA (IgAH) preparations were tested in vitro for their binding to P. aeruginosa. (F and G) High and non–P. aeruginosa–binding IgA prepared from IgA hybridoma were administrated intranasally 30 minutes prior to infection and P. aeruginosa loads were measured 24 hours later in lung (F) and blood (G) (n = 9 mice for PBS group, n = 12 mice for high P. aeruginosa–binding IgA, n = 10 mice for non–P. aeruginosa–binding IgA). Values are mean ± SD, each dot corresponds to the data from one mouse. Mann-Whitney U tests were applied to the data set, except for survival and body temperature data. A t test with Welch’s correction was applied to body temperature data (see Methods). The Gehan-Breslow Wilcoxon test was applied to the survival data. *P < 0.05.