Impact of GUT microbiota on alveolar macrophages and respiratory viral infection severity

The National Institute of Allergy and Infectious Diseases awarded Georgia State University Research Foundation Inc. $795,962 on August 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate how gut microbiota composition influences respiratory viral infection outcomes and alveolar macrophage function.

The research examines the protective mechanisms by which segmented filamentous bacteria (SFB) colonization in the intestine confers resistance to severe respiratory viral infections in mice, independent of interferon and adaptive immunity. Prior work demonstrated that SFB-colonized mice maintain resident alveolar macrophages during viral challenge, whereas SFB-negative mice experience rapid macrophage depletion. Alveolar macrophages from SFB-positive mice exhibit enhanced capacity to neutralize influenza virus through complement production and phagocytosis and resist infection-induced inflammatory signaling. The funded research comprises two aims: defining the mechanisms by which SFB colonization triggers alveolar macrophage reprogramming (Aim 1) and characterizing the phenotypic consequences and mechanistic underpinnings of this reprogramming (Aim 2), using mouse models to identify additional immune-modulating bacteria beyond SFB as examples.

Work is performed in Atlanta, Georgia. The period of performance runs through July 31, 2031.

Abstract

Annual and sporadic influenza virus (IAV) outbreaks and the recent sars/COV-2 pandemic highlight that respiratory viral infections (rvis) remain a scourge of humanity, affecting all societies and strata therein. Yet, impacts of RVI are highly heterogeneous. Indeed, infection disparities are frequently observed even amongst individuals with similar genetics and viral exposures. Furthermore, some individuals with high initial viral loads develop minimal clinical disease while others become severely ILL. Our recently published work demonstrates that in mice, GUT microbiota composition can strongly influence RVI outcomes 1. Specifically, we reported that carriage of the commensal microbe segmented filamentous bacteria (SFB) in the ileum, naturally acquired or exogenously administered, protects mice against severe RVI, as assessed by viral titers, histopathology, and clinical disease features. Such protection is independent of interferon and adaptive immunity but requires basally resident alveolar macrophages (am), which are quickly depleted in SFB- mice, but persist in SFB+ mice, as RVI progresses. Examination of am from SFB+ mice revealed that they are intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, am from SFB+ mice are not quiescent. Rather, they exhibit enhanced ability to neutralize IAV via complement production and phagocytosis. Further, transplant of am isolated from SFB+ mice into SFB- mice recapitulates the IAV resistance of SFB+ mice, providing a compelling link between intestinal microbiota, am phenotype, and RVI severity. We will now use our tractable mouse model to define how SFB colonization results in am reprogramming (aim 1) and discern the mechanistic underpinnings and phenotypic consequences of SFB-induced am reprogramming (aim 2). SFB is one important example of an immune modulating bacteria that we will use as a tool to discover specific, potentially harnessable, mechanisms by which GUT bacteria influence RVI severity. Yet, our overarching hypothesis is that am are a key component of the GUT-lung axis by which an individual's microbiome in its entirety is a determinant of RVI outcome. To interrogate this hypothesis in humans, we will conduct a research bronchoscopy study to investigate the extent to which GUT microbiota composition in stool influences am phenotype among humans with and without a history of severe RVI (aim 3). Together, these interrelated but independently achievable aims will advance understanding of the GUT-lung axis and may result in novel strategies to improve clinical outcomes from RVI.