Similarly to how we use buses, trains, or Uber to get to places, viruses like Dengue virus (DENV) also travel from one place to another by their own form of public transport – mosquitoes. When a mosquito takes a blood meal from an infected human, the virus from that infected human ‘travels’ to other humans when the mosquito next takes a blood meal. DENV poses as a major threat to global health, causing 100-400 million infections each year. There are currently no drugs available for treating dengue and the only licensed vaccine does not always work, so the main defence against dengue infection is to combat the mosquitoes with insecticides or wearing protective clothing, but mosquitoes are beginning to develop resistance to insecticides.
Mosquitoes carry the virus without the virus causing harm to the mosquito, making mosquitoes the perfect transport system for the spread of DENV – but this begs the question, why is it that mosquitoes can carry these potentially life-threatening viruses without dying? Well, this is attributed to the mosquito’s innate immune system that fights off the viral infection and limits its replication; however, these systems aren’t efficient enough to eliminate the virus completely and only reduces viral load just enough so that it does not harm the mosquito, therefore allowing the mosquito to continuously spread the virus.
The mosquito innate immune system can eliminate a wide range of microorganisms, including bacteria, viruses and yeast. One of the ways mosquitoes can fight off infection is through the activation of signalling pathways within cells that leads to the production of antimicrobial peptides (AMPs), which are proteins secreted in the blood that eliminates microbes either by directly killing them or by recruiting immune cells to do so. Much like how we have traffic lights to signal cars to go, the presence of microbes act as a green go signal to mosquito cells to produce specific AMPs, depending on the type of microbe present.
IMD pathway activation by viruses. The virus binds to the surface of the cell and is internalised. The virus is released into the cytoplasm and uncoats, releasing the viral DNA. The viral DNA binds to a protein which stimulates the IMD pathway, leading to AMP gene expression.
My research project focuses on one of these AMP-producing pathways, called the Immunodeficiency (IMD) pathway. This particular pathway has captured our interest because, for a long time, it was known to be activated only by bacteria to fight off bacterial infections, but our lab has recently discovered that it can also be activated by dengue virus! However, the protein that recognises dengue virus to activate the pathway is unknown. Furthermore, whether or not other types of viruses can also activate this pathway is currently unexplored. My project aims to address these remaining questions.
In summary, this project takes a unique turn in that instead of trying to find ways to eliminate the mosquitoes that spread these dangerous viruses, we aim to better understand the immune systems within mosquitoes that allow them to transmit viruses. This could provide novel targets for the development of genetically-modified mosquitoes more capable of sensing viral infection in the future. In this way, the mosquito will have a stronger antiviral response, resulting in complete elimination of the virus and therefore transmission-incompetent mosquitoes.
References for further reading:
Katzelnick, L., Coloma, J. and Harris, E. (2017) Dengue: knowledge gaps, unmet needs, and research priorities. The Lancet Infectious Diseases, 17(3), pp.e88-e100.
Lee, W., Webster, J., Madzokere, E., Stephenson, E. and Herrero, L. (2019) Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection. Parasites & Vectors, 12(1).
Merkling, S. and van Rij, R. (2013) Beyond RNAi: Antiviral defense strategies in Drosophila and mosquito. Journal of Insect Physiology, 59(2), pp.159-170.
Sim, S., Jupatanakul, N. and Dimopoulos, G. (2014) Mosquito Immunity against Arboviruses. Viruses, 6(11), pp.4479-4504.
