This picture illustrates an example of gut microbiota composition dictating how resident lung alveolar macrophages (AM) respond to viral infection. The presence of segmented filamentous bacteria, a commensal microbe present in some mice, reprograms AM gene expression, increasing complement expression and phagocytosis, thereby enabling AM to engulf and destroy viral pathogens without inflammatory signaling.
This picture illustrates an example of gut microbiota composition dictating how resident lung alveolar macrophages (AM) respond to viral infection. The presence of segmented filamentous bacteria, a commensal microbe present in some mice, reprograms AM gene expression, increasing complement expression and phagocytosis, thereby enabling AM to engulf and destroy viral pathogens without inflammatory signaling. [Dr. Andrew Gewirtz]

A study by researchers at Georgia State University Institute for Biomedical Sciences has shown that the composition of gut microbiota can influence both the susceptibility of mice to respiratory virus infections (RVIs) and the severity of these infections.

The research showed that segmented filamentous bacteria (SFB), a common bacterial species found in the mouse intestines, protected animals against influenza virus infection, whether these bacteria were naturally acquired or administered. SFB-related protection against viral infection was also observed against respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The collective study results indicated that to retain their protective capacity, the segmented filamentous bacteria required the presence of basally resident alveolar macrophage (AM) immune cells in the lungs. AMs are among the first cells to encounter inhaled threats including respiratory viruses. The team said that if the results are found to be applicable to human infections, they could have significant implications for risk assessing whether patients might advance to severe disease following infection.

Andrew Gewirtz, PhD, Regents’ Professor at the Institute for Biomedical Sciences at Georgia State, and Richard Plemper, PhD, Regents’ Professor and director of the Center for Translational Antiviral Research at Georgia State, are co-senior authors of the team’s published paper in Cell Host & Microbe, which is titled, “Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection,” in which they concluded, “These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.”

Dr. Andrew Gewirtz, co-senior author of the study and Regents’ Professor in the Institute for Biomedical Sciences at Georgia State University.
Andrew Gewirtz, PhD, co-senior author of the study and Regents’ Professor at the Institute for Biomedical Sciences at Georgia State University. [Georgia State University]

Susceptibility to respiratory virus infections such as RSV, SARS-Cov-2, and influenza A viruses (IAVs) varies widely between individuals, and can range from asymptomatic to lung pathology and potentially death, the authors wrote. And while the scientists pointed out that there are likely many different, and complex factors involved in determining these differing responses to respiratory virus infection, “…we hypothesized that one important factor is gut microbiota composition, which is now appreciated to have broad influence over a range of chronic inflammatory diseases and the immune responses with which such diseases are associated.”

To investigate this further in mice, the team looked more closely at whether differences in particular microbial species can impact outcomes of respiratory virus infections, and if so, how they might do so, which hasn’t been well defined previously.

The scientists first studied mice raised with discrete microbiome differences and then subsequently studied mice mice differing in only the presence or absence of segmented filamentous bacteria. Viral titers in the lung were measured several days after infection and varied significantly depending on the nature of the microbiome of the different animal groups.

The study found that in animals lacking segmented filamentous bacteria, basally resident alveolar macrophages were quickly depleted as influenza virus A infection progressed. However, in mice colonized with segmented filamentous bacteria, basally resident alveolar macrophages were altered to resist influenza virus infection depletion and inflammatory signaling. The basally resident alveolar macrophages disabled influenza virus, in large part by activating a component of the immune system referred to as the complement system. “AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis,” the scientists stated.

“We show herein that how AMs respond to respiratory viruses is dramatically altered by the composition of the intestinal microbiota,” they further commented. “Specifically, we report that colonization of the intestine by SFB, naturally acquired or exogenously administered, markedly attenuates IAV-induced AM pro-inflammatory gene expression while increasing ability of AMs to disable IAV.” Transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV in these animals.

The authors acknowledged establishment of the general concept that microbiota composition in total can influence immune phenotype and proneness to infection. However, Plemper commented, “We find it remarkable that the presence of a single common commensal bacterial species, amidst the thousands of different microbial species that inhabit the mouse gut, had such strong impacts in respiratory virus infection models and that such impacts were largely attributable to reprogramming of basally resident alveolar macrophages. If applicable to human infections, these findings will have major implications for the future risk assessment of a patient to advance to severe disease.” The authors further pointed out, “The extent to which SFB is present in humans is not well defined, but it has been reported to be frequently present in children in some regions and was unequivocally shown to be present in some adult individuals.”

Dr. Richard Plemper, co-senior author of the study, Regents’ Professor and director of the Center for Translational Antiviral Research at Georgia State University.
Richard Plemper, PhD, co-senior author of the study, Regents’ Professor, and director of the Center for Translational Antiviral Research at Georgia State University. [Georgia State University]

The authors pointed out that independent of a specific role for SFB, the findings “speak strongly” to the potential of gut microbiota to influence proneness to RVI, especially via programming of AMs. “Both AM pro-inflammatory gene expression and AM depletion are known to correlate with RVI severity in humans, but determinants of inter-individual heterogeneity in AM responses have not been defined.” They reason that it is “highly unlikely that SFB is the only gut microbe capable of impacting on AMs and susceptibility to RVI. “Rather, we posit that AMs are a key component of the gut-lung axis, wherein an individual’s microbiota in its entirety is a determinant of disease outcome following exposure to an array of respiratory viruses.”

Gewitz added, “We find it highly unlikely that segmented filamentous bacteria is the only gut microbe capable of impacting the phenotype of alveolar macrophages, and consequently, proneness to respiratory virus infection. Rather, we hypothesize that gut microbiota composition broadly influences proneness to respiratory virus infection. Microbiota mediated programming of basally resident alveolar macrophages may not only influence the severity of acute respiratory virus infection, but may also be a long-term post-respiratory virus infection health determinant.”

The authors further pointed out that deciphering how SFB impacts on lung AMs could potentially point to strategies for reducing disease burden caused by RVI. So, as well as mitigating primary RVI, AM persistence may help prevent secondary consequences of RVI, they suggested. “Many of the severe consequences of IAV infection in humans result from secondary bacterial infections, to which the lung is more permissive by loss of IAV-induced AM depletion.”

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