When a mosquito infects you with a viral disease such as Zika or dengue, it does more than just deliver a few virus particles under your skin. The saliva it injects also causes an inflammation that helps the virus multiply and quickly spread to other parts of your body, according to a new study. The research suggests that there might be a surprisingly easy way to prevent infections in people who have just been bitten: applying an anti-inflammatory cream to the bite site.
When mosquitoes bite, they inject a tiny amount of their saliva (less than a microliter), which contains a specialized, potent cocktail of molecules that numb the pain of the bite and stop the blood from clotting. Many pathogens hitch a ride in the saliva, and they, too, seem to benefit: Mice develop more severe infections when a virus is injected by a mosquito than by a researcher using a needle. But, until now, it had been unclear why.
Clive McKimmie, an immunologist at the University of Leeds in the United Kingdom, and his colleagues set out to find the answer. They infected mice with a relatively harmless variety of the Semliki Forest virus (SFV), a relative of chikungunya. When the strain was injected into the skin, none of the mice got very sick, and all of them survived. But when injected into a mosquito bite on the skin, the virus spread faster and more easily to the rest of the body. Four of 11 mice died from the infection.
Apparently, the virus needed mosquito saliva to get going in its new host. But why? One theory has been that compounds in the saliva suppress the immune system. But the researchers found that that is not the case. Instead, saliva triggers an inflammation, essentially a warning that the body’s defenses have been breached. A class of cells known as neutrophils, which act as the body's first responders, rush to the bite site. These in turn recruit macrophages, cells whose job it is to gobble up microbes or anything else that does not belong in the body.
Using SFV labeled with a fluorescent dye, the researchers discovered that the macrophages are themselves infected by the virus and start spreading the disease further, like policemen joining a mob they are meant to control. When the researchers infected a strain of mice lacking macrophages with SFV, the mice fared similarly well whether they had been infected at a bite site or not. This shows that the virus actually uses the macrophages to replicate and disseminate quickly in the body, the authors write in Immunity today.
The paper is exciting because "it is the first example I know of where the virus is using the host response to increase the success of transmission to a new host,“ says David Schneider, a microbiologist at Stanford University in Palo Alto, California, who was not involved in the study. Mosquito-borne viruses face a particular challenge, he says, because they need to establish an infection from the few virus particles transmitted by a mosquito bite, and then become abundant enough to be taken up again when the next mosquito bites. “It just goes to show you that for every host defense mechanism, you can be sure some pathogen will be trying to exploit it,” says Andrew Read, an evolutionary biologist at Pennsylvania State University, University Park, who was not involved in the study.
McKimmie hopes that dampening the immune response after a bite, for instance by applying an anti-inflammatory cream, could make severe infections of mosquito-borne viruses less likely. "Obviously this needs a lot more work before we start recommending any form of public health advice,“ he says.
Schneider warns that suppressing an immune reaction may have drawbacks: “The risk there is always that there is a hidden secondary infection that will now be able to grow out of control and hurt the patient,“ he says. And widespread use of such a therapy could even lead to the evolution of more virulent pathogens that make do without the immune system’s help, he argues.
But McKimmie says there's no evidence that the strategy would drive virus evolution in any way. And there is no need to suppress the immune system as a whole, he says—just local inflammation. And even if it should prove to work one day, the treatment would only be a plan B, he says: "The best way to not be infected is not to be bitten.”