The body’s microbiota are fundamental to health, but how these noninvasive microbes communicate with the rest of the body to influence host physiology is not fully understood. Researchers from Stockholm, Umeå, and Gothenburg universities now report on studies in mice suggesting that gut microbiota are essential for supporting natural resistance to viral infections. Their research showed that the release of membrane vesicles from gut microbiota leads to the systemic delivery of bacterial DNA to host cells, which then triggers the cytosolic cGAS-STING-IFN-I pathway for innate immune DNA sensing, to protect distal organs against viral infections.

Reporting their results in Immunity, the team, headed by Nelson Gekara, PhD, at Stockholm University, noted that the study also uncovers “an underappreciated risk of antibiotic use during viral infections.” As Gekara pointed out, “A relevant and perhaps timely message in the current times of a global viral pandemic is that overuse of antibiotics can exacerbate viral infections.” The investigators’ published paper is titled, “The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis.”

The surfaces of all multicellular organisms are populated by commensal microbes—collectively known as the microbiota—which influence many host physiological processes, the authors explained. The vast majority of microbiota are extracellular bacteria that reside within the gut. These microbes are vital for the development and maturation of the immune system, and they also protect against bacterial and fungal pathogens by outcompeting them for nutrients or sites of attachment, and by producing antimicrobial substances. But how the microbiota within the gut lumen mediate systemic immune modulation, and their impact on viral infections, are not fully understood. “Although well acknowledged to provide a competitive hindrance to bacterial and fungal pathogens at barrier sites, how the microbiota impact viral infections is still contentious,” the team continued. “Depending on the context, they can promote or protect against viral invasion.”

Type I interferons (IFN-Is) are vital for antiviral immunity, and over the last few decades, “ …growing literature has indicated a role for the microbiota in IFN-I priming,” the researchers continued. However, efforts to understand how the microbiota prime the IFN-I system have arrived at “conflicting conclusions.” Moreover, “how these obligate extracellular microbes at host barrier surfaces communicate with distal immune cells to mediate systemic immune modulation is unresolved.

For their newly reported work, the team investigated how gut commensal bacteria might modulate systemic immunity and response to viral infection. First author Saskia Erttmann, PhD, at Umeå University, said, “We were interested in the influence of gut bacteria on viral infections. So, we treated mice with antibiotics and then infected them with two different types of virus—a DNA virus, herpes simplex virus type 1 (HSV-1), or an RNA virus, vesicular stomatitis virus (VSV). We found that antibiotic treatment made mice more susceptible to these viruses and that this was due to a decrease in basal expression of antiviral immune molecules called the type I interferon (IFN-Is).”

The immune system detects microbes via several families of innate receptors. These include cell surface-localized toll-like receptors (TLRs) that survey the extracellular environment, and cytosolic receptors such as cyclic GMP-AMP Synthase (cGAS) that alert the immune system to the presence of foreign or misplaced DNA inside the cell. Upon sensing DNA, cGAS synthesizes cyclic GMP-AMP (cGAMP), which then signals via the stimulator of interferon genes (STING) to induce the expression of IFN-Is.

To understand how microbiota induce basal expression of IFN-Is, the authors analyzed mice defective in different innate immune pathways. They found that induction of IFN-Is by the microbiota involves tonic activation of the cGAS-STING pathway and that this did not require direct bacteria-host cell contact. “The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions,” they wrote. “… by analyzing several knockout mice, our results showed that in vivo TLRs had minor or redundant contributions to IFN-I priming.” In contrast, mice ablated in the cGAS-STING-pathway were less responsive to and were more susceptible to HSV-1 and VSV infections.

“Innate immune sensing of extracellular microbes including the gut microbiota is generally assumed to occur via cell surface receptors such as TLRs, while activation of cytosolic immune receptors such as cGAS only occurs in response to invasive DNA viruses, pathogenic bacteria, or parasites equipped with virulence factors allowing them to invade and replicate inside the cell,” said Gekara.

“Thus, the finding that the intracellular cGAS-STING pathway is a sensor of extracellular gut bacteria was unexpected. Moreover, it was unclear to us how gut bacteria, physically separated from host cells by barriers such as the mucus and gut epithelial layer, are nonetheless able to trigger a systemic cGAS-STING-IFN-I response to protect distal organs against viruses.”

Bacterial membrane vesicles (MVs) are small lipid bilayer vesicles that are released from bacteria and likely can traverse tissue as well as cell membrane barriers. Gekara and colleagues considered MVs as possible vehicles that would allow gut bacteria to deliver DNA into distant host cells, thereby mediating a systemic cGAS-STING-IFN-I response. Their studies subsequently confirmed that DNA-containing membrane vesicles from gut microbiota were present in blood circulation, and when incubated with cells in vitro or inoculated into mice, such MVs promoted the clearance of viruses. “… membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells,” the team noted. “DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner.”

“This study fills an important gap in our understanding of how the gut microbiota mediates systemic immune modulation,” Gekara stated. The results also “… underscore the underappreciated risk of antibiotics,” he added. Antibiotics are commonly taken by self-medicating patients to “treat” undiagnosed illnesses and are sometimes prescribed to patients, as a precaution against bacterial infections that often emerge after viral infection. “Our results show that by perturbing the microbiota, antibiotics can adversely impair our ability to fight viral infections.”

The authors further concluded, “These findings highlight the importance of the microbiota in maintaining the immune system in a state of constant preparedness against viruses and underscore an underappreciated risk of unwarranted use of antibiotics during viral infection.”

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