The quick, piercing bite of a mosquito leaves behind a tiny amount of saliva under the skin of its prey. This saliva has been shown to have potent effects, such as numbing the pain of the bite and preventing blood from clotting. Curiously, a mosquito’s bite also can enhance the severity of an accompanying viral infection. Researchers have long been unsure why this is the case.
Now, by tracking how the mouse immune system responds to a mosquito bite, researchers in the United Kingdom have discovered that viruses incubate within host immune cells responding to the inflammation surrounding the bite, then detonate an explosion of viral particles. In this way, the host immune system actually helps an invading virus spread faster and farther, worsening the severity of disease.
Thanks to those immune cells, “the virus gets a really big boost to spread throughout the body,” says senior author Clive McKimmie, a research fellow with the University of Leeds’ Virus Host Interaction Team. “Instead of an otherwise avirulent infection, you get a lot of mice succumbing to and dying of the infection.” The findings appeared in the June 21 issue of Immunity.
The discovery points to new avenues of infectious disease research, says microbiologist David Schneider at Stanford University, who wrote an accompanying commentary about the work but was not involved in the study. “Now we can ask, what mosquito molecules are doing this, what is the host-side biology … and how can you interfere with that?”
McKimmie and colleagues injected small volumes of viral particles—as would be present in mosquito saliva—into mice of either un-manipulated skin or at the site of a mosquito bite. The virus reached higher concentrations in the blood of the mice when introduced at a bite site, so the team set out to define the molecular and cellular changes occurring within the itchy bump of a bite.
In response to a bite, the mouse skin cells produced a flood of chemokines and cytokines, signaling molecules that attracted invader-fighting neutrophils to the site. Those neutrophils, in turn, recruited macrophages, immune cells that typically gobble up microbes.
Yet, using fluorescent dye to label the viral particles, the team found that the virus preferentially infected and multiplied within macrophages. Within 6 to 8 hours after infection, the cells burst, spewing viral particles into the host’s surrounding blood and tissue and enabling the spread of virus around the body. Conversely, blocking the arrival of macrophages to the bite site suppressed infection, and more mice survived.
For now, the researchers do not know which particular factors in mosquito saliva actually instigate the immune response, but unrelated pro-inflammatory compounds—including a bacteria-like compound and a vaccine adjuvant—induced the same response, suggesting other inflammatory agents that recruit macrophages can similarly promote viral infection. “We think it is just an unfortunate accident that the mosquito bite is inflammatory, and the virus is making use of this,” says McKimmie. Whether the virus evolved to take advantage of the immune system, or just got lucky, remains unclear.
The team performed the experiments with two genetically distinct viruses, Semliki Forest virus and Bunyamwera virus, and found the same effect for each, suggesting the phenomenon may hold true for many mosquito-borne viruses, including dengue virus and Zika virus. More work will need to be done to determine if that extrapolation is correct, says Schneider. “As soon as you make a rule of how something works, that’s when you should start looking for the situation when the opposite is true,” he says.
Still, the results suggest there might be a simple way to prevent some mosquito-borne infections—intervene early by preventing inflammation at the bite site. This could be done as easily as applying a topical anti-inflammatory medication at the site, says McKimmie. But more lab work will need to be done first. “We don’t want people to go start medicating themselves now,” he adds. “But in the laboratory, where everything is controlled, we do have an impressive effect on the end-stage disease and end-stage survival.”