In a study of mice, an international team of scientists has discovered that signals from gut bacteria help to maintain a first line of defense in the lining of the lung: when mice with healthy gut bacteria were infected with influenza virus, around 80% of them survived; however, only a third survived if they were given antibiotics before being infected. The study was published in the journal Cell Reports.
“Our study supports that taking antibiotics inappropriately not only promotes antibiotic resistance and wipes out the commensals in your gut that are useful and protective, but it may also render you more susceptible to viral infections,” said Dr. Andreas Wack, a researcher at the Francis Crick Institute.
“In some countries, the livestock industry uses antibiotics a lot, prophylactically, so treated animals may become more susceptible to virus infections.”
Type I interferon (IFNα/β) signaling plays a central role in the immune defense against viral infections.
These pathways are fine-tuned to elicit antiviral protection while avoiding tissue damage due to inflammation.
They can mount enhanced immune responses against viruses, but the flip side is that they show signs of chronic auto-inflammation.
It has not been clear exactly how interferon signaling strikes the right balance, maximizing antiviral protection while minimizing excessive inflammation.
To address this question, Dr. Wack and colleagues used mice with enhanced baseline interferon signaling due to a mutation that increases expression levels of the IFNα/β receptor.
These mice were more resistant to influenza virus infection, with less weight loss, lower virus gene expression eight hours after infection, and reduced influenza virus replication two days later.
Given that the viral load was controlled early, subsequent interferon signaling and antiviral immune responses were never fully set in motion.
The results suggest that regulating expression levels of the IFNα/β receptor could be key to fine-tuning interferon signaling in the lungs.
But the protective effect of enhanced baseline interferon signaling was reduced by two to four weeks of antibiotic treatment, which decreased interferon signaling mainly in lung stromal cells, non-immune cells that make up the structural tissue of organs.
Conversely, fecal transplant reversed the antibiotic-induced susceptibility to influenza virus infection, suggesting a potential role for gut microbes.
Taken together, the results suggest that microbiota increase interferon signaling in lung stromal cells, thereby enhancing protection against influenza virus infection.
“This and previous studies demonstrate that microbiota-driven signals can act at multiple levels, inducing an antiviral state in non-immune cells to control infection early on, and enhancing the functionality of immune cells later in infection,” Dr. Wack said.
Konrad C. Bradley et al. 2019. Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection. Cell Reports 28 (1): 245-256; doi: 10.1016/j.celrep.2019.05.105