Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia
Marilia Sanches Santos Rizzo Zuttion, … , David M. Underhill, Peter Chen
Marilia Sanches Santos Rizzo Zuttion, … , David M. Underhill, Peter Chen
Published September 10, 2024
Citation Information: J Clin Invest. 2024;134(21):e180986. https://doi.org/10.1172/JCI180986.
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Research Article Infectious disease Pulmonology

Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia

Abstract

A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated that antibiotic treatment during influenza infection caused a fungal dysbiosis that drove lung eosinophilia and impaired MRSA clearance. Finally, we evaluated 3 cohorts of hospitalized patients and found that eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs, thereby increasing the risk of developing a secondary bacterial infection.

Authors

Marilia Sanches Santos Rizzo Zuttion, Tanyalak Parimon, Stephanie A. Bora, Changfu Yao, Katherine Lagree, Catherine A. Gao, Richard G. Wunderink, Georgios D. Kitsios, Alison Morris, Yingze Zhang, Bryan J. McVerry, Matthew E. Modes, Alberto M. Marchevsky, Barry R. Stripp, Christopher M. Soto, Ying Wang, Kimberly Merene, Silvia Cho, Blandine L. Victor, Ivan Vujkovic-Cvijin, Suman Gupta, Suzanne L. Cassel, Fayyaz S. Sutterwala, Suzanne Devkota, David M. Underhill, Peter Chen

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Figure 3

Antibiotic treatment of mice during influenza infection attenuates interstitial macrophage numbers and causes transcriptomic changes in alveolar macrophages consistent with an immunosuppressive phenotype.

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Antibiotic treatment of mice during influenza infection attenuates inter...
(A) Mice were infected with influenza (PR8, 250 PFU) at day 0. Control or antibiotics (VNAM) were started 7 days before PR8 infection to allow mice to equilibrate to the treatment and discontinued at day 7. (B–O) Lungs from mice sacrificed at day 10 were processed for scRNA-Seq (B, C, and H–O) and flow cytometry (D–G). (B) UMAP visualization of the major cell populations identified in the transcriptomic data set. (C and D) Relative numbers of alveolar macrophages (AM), interstitial macrophages (IM), and monocyte-derived macrophages (MoM) between control and VNAM groups in the scRNA-Seq data (C) and by flow cytometry analysis (D). (E–G) Flow cytometry analysis (n = 5) for total number of interstitial macrophages (*P < 0.05 by 2-tailed Student’s t test) (E), alveolar macrophages (F), and monocyte-derived macrophages (G). (H) Heatmap of the top 20 (by lowest FDR) differentially expressed genes (DEGs) in alveolar macrophages between control and VNAM-treated mice. The entire DEG list is provided in Supplemental Table 1. (I) DEGs in tissue-resident alveolar macrophages between control and VNAM groups were evaluated with Ingenuity Pathway Analysis (IPA). Disease and Function analysis was performed, and only nonredundant, downstream functional pathways (|z score| > 2) were visualized. The complete Disease and Function analysis is provided in Supplemental Table 2. (J–O) Tissue-resident alveolar macrophage expression of the phagocytosis receptors in control (n = 319) and VNAM (n = 316) conditions: Cd14 (J), Marco (K), Clec4d (L), Fcgr1 (M), Fcgr2b (N), and Fcgr3 (O). The complete list of DEGs between control and VNAM in alveolar macrophages is given in Supplemental Table 1. Adjusted P value: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. mϕ, macrophage.