Antibiotics won’t resolve a viral infection. And their misuse may contribute to antibiotic resistance. But, antibiotic resistance may not be the only problem. According to scientists from the Washington University School of Medicine in St. Louis, antibiotics deployed against a viral infection may weaken the immune response to subsequent viral infections.
Using a mouse model of West Nile virus, the scientists demonstrated that oral antibiotics not only alter bacterial abundance and community structure in the gut, they also impair the development of optimal antiviral T-cell responses.
Detailed results appeared March 27 in Cell Reports, in an article entitled, “Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections.” The article suggests that antibiotic use can account, at least in part, for the great differences in disease severity that are observed when people are infected by viruses.
People infected with West Nile virus can show a wide range of disease. Some develop life-threatening brain infections. Others show no signs of infection at all. One reason for the different outcomes may lie in the community of microbes that populate their intestinal tracts.
West Nile virus is not unusual in its ability to cause disease ranging from mild to severe. Many viral infections cause no symptoms in the majority of people, mild to moderate disease in some, and severe disease in an unlucky few.
But why people respond so differently to the same organism has never been entirely clear. Human genetics doesn't explain everything, and neither does the genetic makeup of the microbe itself, although both play a role.
“We observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota,” wrote the articles’ authors. “Abx treatment impaired the development of optimal T-cell responses, with decreased levels of WNV-specific CD8+ T cells associated with increased infection and immunopathology.”
Antibiotics kill off members of the normal bacterial community and allow some potentially harmful ones to overgrow. Since a healthy immune system depends on a healthy gut microbiome, the scientists reasoned, antibiotics may be hobbling the immune system, leaving the body unprepared to fight off a subsequent viral infection.
The researchers gave mice a placebo or a cocktail of four antibiotics—vancomycin, neomycin, ampicillin, and metronidazole—for two weeks before infecting the mice with West Nile virus. About 80% of the mice that received no antibiotics survived the infection, while only 20% of the antibiotic-treated mice did.
Subsequent experiments showed that the mice stayed at high risk for more than a week after the antibiotic treatment ended, and just three days of antibiotic treatment was enough to raise the mice's risk of dying from West Nile infection.
“Once you put a dent in a microbial community, unexpected things happen,” said Larissa Thackray, Ph.D., first author of the current paper and an assistant professor of medicine at Washington University. “Some groups of bacteria are depleted and different species grow out. So, increased susceptibility may be due to both the loss of a normal signal that promotes good immunity and the gain of an inhibitory signal.”
“The immune system is activated differently if the gut does not have a healthy microbiome,” added senior author Michael S. Diamond, M.D., Ph.D., the Herbert S. Gasser Professor of Medicine at Washington University. “If someone is sick with a bacterial infection, they absolutely should take antibiotics. But it is important to remember that there may be collateral effects. You might be affecting your immune response to certain viral infections.”
To look more deeply into how increased susceptibility to viral infection may be linked to changes in gut bacteria, the researchers tested the four antibiotics separately and in combination. Treatment with ampicillin or vancomycin alone made the mice more likely to die of West Nile, while neomycin did not. Metronidazole had no effect alone, but it amplified the effect of ampicillin or vancomycin. Further, different antibiotic treatments led to changes to the bacterial community in the gut that correlated with vulnerability to viral infection.
The researchers tested immune cells from mice treated with antibiotics and found that they had low numbers of an important immune cell known as killer T cells. Normally during an infection, T cells that recognize the invading virus multiply to high numbers and play a critical role in controlling the infection. Mice treated with antibiotics generated fewer such T cells.
The weak T-cell response is likely a byproduct of the changes to the bacterial populations caused by the antibiotics, not a direct effect of the drugs on the immune cells. For one thing, the mice still had trouble fending off viral infection a week or more after they stopped receiving antibiotics. For another, transferring gut bacteria from mice given antibiotics to other antibiotic-treated mice made the recipients even more vulnerable to viral infection, suggesting that something in the bacteria was undermining the mice's immune response.
“Our results,” the article’s authors concluded, “identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections.”
