Mosquito-borne viruses, including Zika, dengue and yellow fever, affect humans and animals and are huge killers globally. Mosquitoes have complex effects on disease transmission: the biting process appears to promote disease progression in ways that are not seen when mosquitoes are not involved. However, researchers remain unclear about exactly how mosquito bites exacerbate such diseases. In a new PLOS Neglected Tropical Diseases study, Rebecca Rico-Hesse, virologist at Baylor College of Medicine, and colleagues investigated the effects of mosquito saliva on human immune cells. I interviewed Rico-Hesse via email to find out more.
What drew you to study virology?
RRH: I was raised in a small city in northern Mexico and there saw the impact of two viruses in particular. Rabies virus affected animals and humans locally, and I also experienced the extensive effects of an epidemic of Venezuelan equine encephalitis virus on horses in Mexico and Texas. I decided I wanted to become a virologist when I was in high school; I ended up working on Venezuelan equine encephalitis for my Ph.D. thesis at Cornell University.
What role do mosquitoes play in transmitting infectious diseases to humans?
RRH: The World Health Organization has estimated that hundreds of millions of humans are infected by mosquito-borne diseases each year. Mosquitoes can transmit many different types of viruses, parasites, bacteria and even some worms (via eggs) to humans and animals; the best known mosquito-borne viruses that cause human disease are Zika, dengue, yellow fever and chikungunya.
Why do scientists believe that mosquito bites exacerbate the effects of such diseases?
RRH: During research into mosquito-borne viruses, scientists noted that injection via syringe of these viruses only resulted in infection and disease symptoms in a small proportion of subjects. Subsequent studies in mice and chickens showed that most mosquito-borne viruses cause more infection and disease symptoms when delivered naturally via mosquito bite. It appears that not only do mosquitoes deliver virus directly to susceptible cells, but factors injected during blood-feeding may enhance disease.
In your study, you wanted to examine how the saliva of uninfected mosquitoes affects the human immune system. How did you go about this?
RRH: We had previously studied the effects of mosquito bites when examining dengue infection in humanized mice (immunodeficient mice engrafted with human stem cells). We decided to measure responses to mosquito bites alone in the human cells in these mice, using sophisticated methods for measuring specific cell types and some proteins secreted by them. This took us about four years to do, since we hadn’t anticipated the complexity of the immune responses in humanized mice.
What did you find?
RRH: We found that mosquito saliva proteins had significant, long-lasting effects on human immune cells. Following the mosquito bites, human immune cells moved to tissues including blood, spleen, skin and bone marrow, and activated other cells via their secreted proteins. At the mosquito bite site, we found human cells quickly moving away from skin tissues and activating cells in the spleen and bone marrow, and some cell types later moved out of the bone marrow and back to the skin.
What most surprised or interested you about your findings?
RRH: We were surprised that just four mosquito bites could cause a reaction in human immune cells as deep as the bone marrow, even up to a week after the bite. Our results also imply that we should include mosquito bites and saliva in our research on viruses such as dengue, since they have major effects on virus delivery, on human immune responses, and ultimately on how disease is caused.
What do you hope your findings might lead to, and what are the next steps for your research?
RRH: We are hoping to begin to narrow down which mosquito saliva proteins have the most effect on enhancing mosquito-borne viral diseases. If we could find common threads in the way mosquitoes infect humans by bite, we might also uncover targets for interrupting the transmission of viruses including dengue and Zika.
Research Article: Vogt MB, Lahon A, Arya RP, Kneubehl AR, Spencer Clinton JL, Paust S, et al. (2018) Mosquito saliva alone has profound effects on the human immune system. PLoS Negl Trop Dis 12(5): e0006439. https://doi.org/10.1371/journal.pntd.0006439
Images Credits: NIAID, Flickr; Rebecca Rico-Hesse