Abstract
Dengue is the most burdensome vector-borne viral disease in the world. Dengue virus (DENV), the etiological cause of dengue, is transmitted primarily by the Aedes aegypti mosquito. Like any arbovirus, the transmission cycle of dengue involves the complex interactions of a multitude of human and mosquito factors. One point during this transmission cycle that is rich in these interactions is the biting event by the mosquito, upon which its saliva is injected into the host. A number of components in mosquito saliva have been shown to play a pivotal role in the transmission of dengue, however one such component that is not as well characterized is extracellular vesicles. Here, using high-performance liquid chromatography in tandem with mass spectrometry, we show that dengue infection altered the protein cargo of Aedes aegypti extracellular vesicles, resulting in the packaging of proteins with infection-enhancing ability. Our results support the presence of an infection-dependent pro-viral protein packaging strategy that uses the differential packaging of pro-viral proteins in extracellular vesicles of Ae. aegypti saliva to promote transmission. These studies represent the first investigation into the function of Ae. aegypti extracellular vesicle cargo during dengue infection.
Highlights
Dengue virus (DENV) is a mosquito-borne virus responsible for a greater burden of human disease than any other arbovirus, causing an estimated 10,000 deaths and 100 million symptomatic infections per year in over 125 countries [1,2,3]
Previous studies examining the contents of Ae. aegypti saliva have shown that it contains over one hundred unique proteins, many of which have been shown to enhance or inhibit DENV infection [18,22,23]
Made up of a highly heterogenous population of membrane-bound vesicles of differing origin and cargo, Extracellular vesicles (EVs) are considered a mechanism of intercellular communication, and as a result are involved in a multitude of physiological and pathological functions [25,26]
Summary
Dengue virus (DENV) is a mosquito-borne virus responsible for a greater burden of human disease than any other arbovirus, causing an estimated 10,000 deaths and 100 million symptomatic infections per year in over 125 countries [1,2,3]. Previous studies examining the contents of Ae. aegypti saliva have shown that it contains over one hundred unique proteins, many of which have been shown to enhance or inhibit DENV infection [18,22,23] In order for these salivary proteins to potentially affect DENV infection in a mammalian host, they must either be secreted directly into the saliva or packaged in extracellular vesicles, which are secreted into the saliva. Made up of a highly heterogenous population of membrane-bound vesicles of differing origin and cargo, EVs are considered a mechanism of intercellular communication, and as a result are involved in a multitude of physiological and pathological functions [25,26] Lately was it demonstrated that a cell line from a medically important arthropod secreted EVs [27,28,29]. The identification of infection-enhancing molecules found in arthropod EVs points to novel transmission mechanisms, many of which could allow for the development of therapeutics and insect-based transmission vaccines against identified targets that would impede transmission and infection in humans
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