Some Antibiotics Rev Up Host Immune Response to Viruses

The antimicrobial drug neomycin protects mice from some viral infections, complicating the picture of the relationship between antibiotics and susceptibility to viruses.

Apr 9, 2018
Shawna Williams

A Pap stain shows the type of changes that can be induced by infection with herpes simplex virus.WIKIMEDIA, NEPHRONLast week, Paulo Verardi got a paper cut refilling the printer in his office at the University of Connecticut. The virologist started looking through a drawer for some Neosporin, and it got him thinking about what the cream really does. A study he was reading that same day found that treating mice topically with antibiotics in a class known as aminoglycosides—which include neomycin, the antibiotic in Neosporin—helped them fend off infection by some viruses. “This opens our mind to all of these other off-target effects that any drug can have, including antibiotics,” he explains.

In the study, out today (April 9) in Nature Microbiology, immunologist Akiko Iwasaki of Yale University and colleagues report that the drugs induced changes in gene expression in the host, stimulating an innate immune response in the areas where they were applied that helped the mice resist some viral pathogens.

“It does show an unexpected impact of antibiotics on viral diseases,” Iwasaki says.

Other groups had previously examined the effect of antibiotics on viral infections in either animals or cultured cells, with results that ranged from dramatically decreased to highly increased susceptibility, depending on the particular antibiotic and virus used. In some studies, the antibiotics’ effect on gut microbiota seemed to explain the changes in vulnerability.

See “Antibiotics Increase Mouse Susceptibility to Dengue, West Nile, and Zika

Iwasaki’s research team had found earlier that treating mice with an oral cocktail of antibiotics made them more susceptible to a flu virus. In the new study, the team wanted to find out whether local antibiotic treatment would affect response to a different virus, herpes simplex (HSV). They treated the vaginal mucosa of mice with a blend of antibiotics for two to six days then exposed them to the virus.

Compared to untreated controls, the antibiotic-treated mice initially had less viral replication in their mucosa, testing revealed, and although their levels of virus did approach those of the untreated mice after a few days, they were less likely to develop severe symptoms of disease, the researchers report.

The scientists tried using just one antibiotic rather than a cocktail, and found that only neomycin could produce the antiviral effect. To see whether this protective effect was explained by the death of bacteria, they also tried the experiment in germ-free mice (which lack gut microbiota), with similar results.

Having established that “the bacteria are not involved in this response, [coauthor Smita Gopinath] wanted to find out if the antibiotics have an effect on the mammalian host cells,” Iwasaki says. So Gopinath compared gene expression in the vaginal cells of neomycin-treated mice to that of controls—none of which had been exposed to herpes. Neomycin had ramped up the activity of some genes in the host, particularly those involved in a type of innate immune response associated with the interferon family of signaling proteins that is known to help repel viral attack. The research group found a similar effect of neomycin on gene expression in cultured human cells.

The results shouldn’t be interpreted to mean that antibiotics like neomycin could be used clinically as antivirals.

“It’s actually a very important study, I think,” because it shows that the drug acts directly on the host cells, says Nathalie Granvaux, a biochemist at the University of Montreal who was not involved in the study. “They really went from the big picture to the mechanism, and I think that makes their study very strong.”

Taken together with those of other studies on antibiotics and susceptibility to viruses, the results are “a reminder that antibiotics have not only that impact on the bacteria or on the microbiome . . . but it also has these general effects on gene expression” that can affect immunity either positively or negatively depending on factors such as the route of administration, the pathogen, and interactions with the microbiome, says Verardi.

In additional experiments, the researchers used germ-free mice to examine the effect of neomycin treatment of mucosa on influenza infection. They came to opposite results from their prior experiment that found mice were more vulnerable to flu when given oral antibiotics: After just one intranasal dose of neomycin, 40 percent of mice survived exposure (also through the nose) to a highly virulent flu strain that killed all of the control mice.

The results shouldn’t be interpreted to mean that antibiotics like neomycin could be used clinically as antivirals, Iwasaki cautions, because “the impact of killing good commensal bacteria may be more detrimental than the virus you’re trying to fight off.” Instead, she suggests that once more is known about how the antibiotic induces an antiviral response, a drug could be developed to replicate that effect without disrupting the microbiome.

The study may have more immediate implications for how some scientists conduct their research, Grandvaux says. “Antibiotics are used a lot in the tissue culture [and] cell culture we do in labs, and so if the antibiotics are triggering the antiviral defense, the gene regulation, that means that if you want to study the antiviral response appropriately, when you use these kind of antibiotics, you have to be careful to remove them from your experimental study.”

Similarly, there’s a need for caution in animal experiments that use antibiotics to deplete gut bacteria in order to study the effects of the microbiome, notes Noah Palm, who studies host-microbiota interactions at Yale but was not involved in the study. “When people do these kinds of experiments where they think they’re looking at just effects of the antibiotics on the microbiota, you certainly could be complicating things,” he says, “particularly for this class of antibiotics, which [the researchers] show engages some really core and powerful immune responses.”

S. Gopinath et al., “Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner,” Nat Microbiol, doi:10.1038/s41564-018-0138-2, 2018.