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 May 17, 2018
Citation Information: J Clin Invest. 2018;128(8):3535-3545. https://doi.org/10.1172/JCI97065.
View: Text | PDF
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 2

Microbiota depletion impairs antibacterial defense in the lung by decreasing pulmonary IgA production.

Options: View larger image (or click on image) Download as PowerPoint
Microbiota depletion impairs antibacterial defense in the lung by decrea...
(A–D) Total levels of (A) IgM (n = 8 for Conv; n = 5 for ABx mice), (B) IgG (n = 5 for Conv; n = 4 for ABx mice), and (C) IgA (n = 14 for Conv; n = 14 for ABx mice) in the BALF or (D) in plasma (n = 9 for Conv; n = 7 for ABx mice) were measured. (E) Lung IgA+ plasma cells were identified by FACS as IgAhi (E, left) and B220lo CD138hi cells (E, right). (F) Total lung IgA+ cells and (G) IgA+ plasma cells were quantified by FACS (n = 10 for Conv and ABx mice). (H) Levels of P. aeruginosa–binding IgA were quantified by coating P. aeruginosa to ELISA plates and measuring bound IgA (n = 7 for Conv and ABx mice). (I, J) WT and IgA–/– mice were pretreated or not with antibiotics, and afterwards infected with 1 × 105 CFU per mouse P. aeruginosa. Bacterial loads in the (I) lungs and (J) blood were measured at 24 hours after infection (n = 24 for Conv WT; n = 28 for Conv IgA–/–; n = 9 for WT ABx; n = 12 for IgA–/– ABx mice). Mann-Whitney U tests were applied to the data set. Values are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005.