The body’s microbiota is fundamental to health, but how these non-invasive microbes communicate with the rest of the body to influence host physiology is not fully understood. Researchers from the universities of Stockholm, Umeå and Gothenburg are now reporting studies in mice suggesting that the gut microbiota is essential for supporting natural resistance to viral infections. Their research showed that the release of membrane vesicles from the 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 sensing of DNA, in order to protect the distal organs against viral infections. .
Report their results in Immunity, the team, led by Nelson Gekara, PhD, at Stockholm University, noted that the study also reveals “an underestimated risk of antibiotic use during viral infections”. As Gekara pointed out, “A relevant and perhaps timely message in the current era of a global viral pandemic is that overuse of antibiotics can exacerbate viral infections.” The paper published by the researchers is titled “Gut Microbiota Overrides Systemic Antiviral Immunity via the cGAS-STING-IFN-I Axis.”
The surfaces of all multicellular organisms are populated with commensal microbes, collectively known as microbiota, which influence many host physiological processes, the authors explained. The vast majority of microbiota are extracellular bacteria that reside in 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 displacing them for nutrients or attachment sites, and producing antimicrobial substances. But how the microbiota in the gut lumen mediates systemic immune modulation and its impact on viral infections is not fully understood. “Although well recognized for providing a competitive barrier to bacterial and fungal pathogens at barrier sites, the impact of microbiota on viral infections is still controversial,” the team continued. “Depending on the context, they can promote or protect against viral invasion.”
Type I interferons (IFN-I) are vital for antiviral immunity, and over the past 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 come to “conflicting conclusions”. Additionally, “how these obligate extracellular microbes at host barrier surfaces communicate with distal immune cells to mediate systemic immune modulation is unresolved.
For their recently 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, herpes simplex virus vesicular stomatitis (VSV). We found that antibiotic treatment made mice more susceptible to these viruses and that this was due to a decrease in the basal expression of antiviral immune molecules called type I interferon (IFN-I).
The immune system detects microbes via several families of innate receptors. These include cell surface-localized toll-like receptors (TLRs) that monitor the extracellular environment and cytosolic receptors such as Cyclic GMP-AMP Synthase (cGAS) that alert the immune system to the presence of DNA foreign or misplaced inside the cell. Upon DNA detection, cGAS synthesizes cyclic GMP-AMP (cGAMP), which then signals through the interferon gene stimulator (STING) to induce IFN-I expression.
To understand how the microbiota induces the basal expression of IFN-I, the authors analyzed mice defective in different innate immune pathways. They discovered that the induction of IFN-I by the microbiota involves a tonic activation of the cGAS-STING pathway and that this does not require direct bacteria-host cell contact. “The microbiota-induced tonic IFN-I response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions,” they wrote. “…by analyzing multiple knockout mice, our results showed that in vivo TLRs had minor or redundant contributions to IFN-I priming.” In contrast, mice abducted in the cGAS-STING pathway were less susceptible and more susceptible to HSV-1 and VSV infections.
“Innate immune sensing of extracellular microbes, including gut microbiota, is generally thought to occur via cell surface receptors such as TLRs, while activation of cytosolic immune receptors such as cGAS only occurs by response to invasive DNA viruses, pathogenic bacteria or parasites with virulence. factors allowing them to invade and replicate inside the cell,” Gekara said.
“Thus, the finding that the intracellular cGAS-STING pathway is a sensor for extracellular gut bacteria was unexpected. Moreover, we did not know how gut bacteria, physically separated from host cells by barriers such as mucus and the intestinal epithelial layer, are nevertheless able to elicit a systemic cGAS-STING-IFN-I response to protect distal organs. against viruses.
Bacterial membrane vesicles (MV) are small lipid bilayer vesicles that are released by bacteria and can likely cross tissues 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 went on to confirm that membrane vesicles containing gut microbiota DNA were present in the bloodstream, and when incubated with cells in vitro or inoculated into mice, these MVs promoted virus clearance. “…membrane vesicles (MV) of extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells,” the team noted. “MVs containing DNA from gut microbiota were found in circulation and promoted the clearance of DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses from a cGAS-dependent manner.
“This study fills an important gap in our understanding of how gut microbiota mediate systemic immune modulation,” Gekara said. The findings “…also highlight the underestimated 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 appear after a viral infection. “Our results show that by disrupting the microbiota, antibiotics can impair our ability to fight viral infections.”
The authors further concluded: “These results highlight the importance of the microbiota in maintaining the immune system in a constant state of readiness against viruses and highlight an underestimated risk of inappropriate antibiotic use during a viral infection.