Fibrotic lung disease inhibits immune responses to staphylococcal pneumonia via impaired neutrophil and macrophage function
Helen I. Warheit-Niemi, … , David N. O’Dwyer, Bethany B. Moore
Helen I. Warheit-Niemi, … , David N. O’Dwyer, Bethany B. Moore
Published January 6, 2022
Citation Information: JCI Insight. 2022;7(4):e152690. https://doi.org/10.1172/jci.insight.152690.
View: Text | PDF
Research Article Immunology Pulmonology

Fibrotic lung disease inhibits immune responses to staphylococcal pneumonia via impaired neutrophil and macrophage function

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized patients with IPF. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like humans with IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared with uninfected fibrotic mice. We determine that fibrosis conferred a defect in MRSA clearance compared with nonfibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibited neutrophil intracellular killing of MRSA through impaired neutrophil elastase release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments of antimicrobial responses upon pulmonary fibrosis development, and our findings suggest a possible mechanism for why patients with IPF are at greater risk of morbidity and mortality related to infection.

Authors

Helen I. Warheit-Niemi, Summer J. Edwards, Shuvasree SenGupta, Carole A. Parent, Xiaofeng Zhou, David N. O’Dwyer, Bethany B. Moore

×

Figure 2

Fibrotic lung disease impairs MRSA clearance 14 and 21 days after bleomycin treatment.

Options: View larger image (or click on image) Download as PowerPoint
Fibrotic lung disease impairs MRSA clearance 14 and 21 days after bleomy...
(A) Mice were treated with bleomycin or saline 14 days prior to infection with MRSA (7 × 107 CFU/mouse). Lung bacterial burden was quantified 1–4 days after infection. (B) Lung bacterial burden from mice described in A. Bacterial burden was quantified at specified time points (n = 5 mice per group). Representative of 2 independent experiments. Data represent the means ± SD. Statistical analysis by multiple Student’s t tests. *P < 0.05, **P < 0.01, ***P < 0.001. (C) Mice were treated with saline or bleomycin and then infected with 1 × 107 CFU MRSA 14 or 20 days after bleomycin treatment. Lung bacterial burden was quantified 24 hours postinfection (day 15 or day 21). Saline-treated mice were infected on day 20 and MRSA was quantified on day 21. (D) Lung bacterial burden from mice described in C (saline + MRSA n = 5, bleomycin + MRSA day 14 n = 6, bleomycin + MRSA day 20 n = 4). Representative of 2 independent experiments. Data represent the means ± SD. Statistical analysis by Kruskal-Wallis test with Dunn’s multiple comparisons. *P < 0.05. (E) Spleen bacterial burden from mice infected with 1 × 107 CFU MRSA 20 days after bleomycin (n = 9) or saline (n = 10) treatment. CFU measured 24 hours postinfection. Data from 2 combined independent experiments. Data represent the means ± SD. Statistical analysis by Mann-Whitney U test. ****P < 0.0001. LOD, limit of detection.