Flaviviruses are a genus of arboviruses, including dengue virus (DENV), Zika virus, yellow fever virus, and West Nile virus, that have the potential to cause severe disease in humans and represent a tremendous and growing threat to public health. Like all arboviruses, flavivirus infection is contracted upon the bite of an infected vector, a process during which the virus and saliva are injected into the host skin. A large body of work has already reported the infection-enhancing ability of proteins derived from vector saliva, suggesting the existence of selective pressures on the vector-to-host viral transmission process. Through the work described herein, we demonstrated that flavivirus infection of Aedes aegypti modulates the protein cargo of extracellular vesicles, a potential avenue for the delivery of pro-viral factors during transmission. In doing so, we identified one protein, AAEL002675 (ARGIL1- Aedes aegypti Arginase-like 1 Protein), a putative arginase, within specific fractions of Aedes aegypti saliva that displayed infection-enhancing activity. We also observed this ARGIL1 protein within extracellular vesicles derived from dengue-infected Aedes aegypti cells.
Importantly, treatment of cells with ARGIL1 resulted in an arginase-dependent enhanced level of DENV infection in vitro. In mammals, arginase is an important regulator of excessive cellular inflammation. It catalyzes production of collagen and polyamines from L-arginine, therefore reducing the pool of L-arginine substrate available for inducible nitric oxide synthase (iNOS) to produce nitric oxide. Consistently, cells treated with ARGIL1 displayed decreased levels of iNOS upon DENV infection, suggesting that ARGIL1 treatment reshapes the cellular environment to be more permissive to viral replication upon mosquito bite. These findings provide further evidence that ARGIL1 is an arginase-like pro-viral factor enhancing vector-to-host DENV transmission. Altogether, a better understanding of the molecular processes driving DENV transmission, such as those described here, will be instrumental for the development of innovative preventative antiviral strategies against flaviviruses and arboviruses, including vaccines that target vector proteins.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47417 |
| Date | 02 November 2023 |
| Creators | Gold, Alexander S. |
| Contributors | Douam, Florian |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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