Gut microbes stimulate antiviral signals protecting against flu virus

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Commensal gut microbes stimulate antiviral signals in non-immune lung cells to protect against the flu virus during early stages of infection, researchers report July 2nd in the journal Cell Reports.

Enhanced baseline type I interferon (IFNα/β) signaling, which drives antiviral responses, reduced flu virus replication and weight loss in mice, but this protective effect was attenuated by antibiotic treatment.

“This 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,” says senior study author Andreas Wack of the Francis Crick Institute in the UK.

“In some countries, the livestock industry uses antibiotics a lot, prophylactically, so treated animals may become more susceptible to virus infections.”

IFNα/β signalling 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.

This trade-off is apparent in individuals with a genetic variant that results in high interferon production.

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 IFNα/β signalling strikes the right balance, maximizing antiviral protection while minimizing excessive inflammation.

This visual depicts the findings of Bradley and Finsterbusch et al. who identify lung stroma as the target of microbiota-driven signals that set the interferon signature in these cells. Antibiotic treatment reduces gut microbiota and the lung stromal interferon signature and facilitates early influenza virus replication in lung epithelia, effects that can be reversed by fecal transplantation. Credit: Bradley and Finsterbusch et al./Cell Reports

To address this question, Wack and his team used mice with enhanced baseline IFNα/β signalling 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 IFNα/β signalling 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 IFNα/β signalling in the lungs.

Antibiotics weaken flu defenses in the lung
Scanning electron micrograph of epithelial cells lining the inside of the lung. Different cell types with different shapes and different functions compose this inner lining, and the right balance between these cell types is important for a healthy lung. Credit: Andreas Wack, Francis Crick Institute

But the protective effect of enhanced baseline IFNα/β signalling was reduced by two to four weeks of antibiotic treatment, which decreased IFNα/β signalling 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 IFNα/β signalling in lung stromal cells, thereby enhancing protection against influenza virus infection.

The new findings are consistent with those from previous studies showing that mice treated with oral antibiotics are more susceptible to viral infections, including the influenza A virus.

“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,” says Wack.

Moving forward, the researchers plan to further investigate the exact origins and mechanisms underlying microbiota-driven antiviral resistance.

“Previous research has suggested that the microbiota-driven signal in lung stromal cells could originate either from the gut or the lung,” Wack says.

“However, in the work presented here, the results of the fecal transplant experiments strongly suggest a gut involvement in this effect.

We would love to understand the exact nature of the signal from the gut to the lung, and we are working on several hypotheses.”


Avian influenza viruses (AIV) are categorized into high (HPAI) and low (LPAI) pathogenicity viruses based on disease severity.

Some LPAI such as H9N2 subtype pose a significant public health threat as they can replicate in permissive mammalian tissues without prior adaptation13.

Furthermore, previous reassortant isolates in humans, such as H5N1, H7N9, H10N8 and H5N6, have been shown to carry a partial or a whole set of internal genes from avian H9N2 viruses47.

Therefore, control of avian H9N2 influenza virus in poultry can have a significant positive impact on the poultry industry and also public health.

As a LPAI virus, AIV subtype H9N2 has tropism for several tissues, including tissues of the upper respiratory tract and gastrointestinal tract (GIT) of chickens8.

Even though the interplay between bacterial pathogens and commensal gut microbiota of chickens and other animals has been studied extensively, there is a paucity of research on the role of commensal gut microbiota in viral infections.

We have recently shown that infection of chickens with AIV subtype H9N2 results in changes in the composition of the fecal microbiota without restoration to a pre-infection microbial composition after the virus was undetectable9.

Marek’s disease virus (MDV) infection of chickens has also been shown to result in a shift in the composition of gut microbiota with involvement of the immune system and metabolic pathways10,11.

These studies highlight a role for gut microbiota of chickens in viral infections.

Understanding the mechanism of immunity initiated by commensal gut microbiota is of paramount importance to utilize commensal gut microbiota in the form of probiotics or other strategies for shifting the composition to a state where it can allow the host to control AIV infection and shedding, thereby reducing transmission.

The GIT microbiota plays an important role in the induction and regulation of host responses to various pathogens including bacteria1214, fungi15 and viruses1618.

Recently, we showed that changes in the composition of the gut microbiota towards a dysbiotic condition resulted in higher oropharyngeal and cloacal shedding of AIV subtype H9N2 in chickens, which was also associated with compromised type I interferon (IFN) expression19.

However, altering the composition of gut microbiota using probiotics has shown beneficial effects on immunity to influenza virus infection20,21.

For instance, oral administration of a human isolate of Bifidobacterium longum MM-2 to influenza-infected mice reduced influenza virus associated mortality and inflammatory responses in the lower respiratory tract20.

The major mechanisms involved were shown to be the activation of natural killer (NK) cells both in the lungs and spleen and increased expression of various cytokines in the lungs20.

Furthermore, oral administration of heat-killed Lactobacillus plantarum L-137 to mice infected with influenza virus enhanced protection against the virus and reduced virus titre via a type I interferon dependent mechanism21.

Microbes and antigens of microbial origin are sensed by the GIT resident dendritic cells (DCs) resulting in migration of DCs to the draining lymph nodes followed by activation of T cell subsets and production of various cytokines and homing molecules, which are important for the trafficking of T cells to the respiratory system during infection16,22.

Therefore, understanding the mechanisms of innate immunity against AIV in chickens initiated by the gut microbiota could allow for the development of effective probiotics to enhance immunity against viruses.

We hypothesized that dysbiosis of the gut microbiota of chicken results in higher AIV subtype H9N2 shedding, compromised innate responses, and a recovery from dysbiosis using probiotics and fecal microbial transplant (FMT) administration can result in the recovery of innate responses against the virus and reduced virus shedding.

Therefore, in this study, a model was used in which a cocktail of antibiotics (ABX) was administered to chickens to induce dysbiosis of the gut microbiota. Subsequently, either a combination of five Lactobacillus species (PROB) or FMT was used to reconstitute the gut microbiota and to assess the ability of PROB and FMT to reverse the effects of antibiotics on the chicken immune system.


More information:Cell Reports, Bradley and Finsterbusch et al.: “Microbiota-driven tonic interferon signals in lung stromal cells protect from influenza virus infection” https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30744-2 , DOI: 10.1016/j.celrep.2019.05.105

Journal information: Cell Reports
Provided by Cell Press

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