Intestinal Microbiota Programming of Alveolar Macrophages Influences Severity of Respiratory Viral Infection

Abstract

Investigating the influence of intestinal microbiota composition on respiratory viral infection (RVI) revealed that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection, as assessed by viral titers, histopathology, and clinical disease features. Such protection, which also applied to RSV and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM), which, in SFB-negative mice, were quickly depleted as RVI progressed. Examination of AM from SFB-colonized mice revealed that they were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Transplant of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV mechanistically linking intestinal microbiota, AM phenotype, and RVI severity.

Note:
Funding Information: This work was supported, in part, by Public Health Service grants AI141222 (to RKP), AI171403 (to RKP), and AI170014 (to ATG) from the NIH/NIAID. T

Declaration of Interests: RKP reports contract testing from Enanta Pharmaceuticals and Atea Pharmaceuticals, and research support from Gilead Sciences, outside of the described work. All other authors declare that they have no competing interests.

Ethical Approval Statement: The Institutional Animal Care and Use Committee of Georgia State University approved animal studies.

Keywords: gut-lung axis, Segmented filamentous bacteria, inflammatory anergy, Influenza, phagocytosis, complement