Abstract
Macroautophagy is an evolutionarily conserved cellular process critical for maintaining cellular homeostasis. It can additionally function as an innate immune response to viral infection as has been demonstrated for a number of arthropod-borne (arbo-) viruses. Arboviruses are maintained in a transmission cycle between vertebrate hosts and invertebrate vectors yet the majority of studies assessing autophagy-arbovirus interactions have been limited to the mammalian host. Therefore we evaluated the role of autophagy during arbovirus infection of the invertebrate vector using the tractable Aag2 Aedes aegypti mosquito cell culture system. Our data demonstrates that autophagy is significantly induced in mosquito cells upon infection with two divergent arboviruses: dengue virus-2 (DENV-2; Flaviviridae, Flavivirus) and chikungunya virus (CHIKV; Togaviridae, Alphavirus). While assessing the role of autophagy during arbovirus infection, we observed a somewhat paradoxical outcome. Both induction and suppression of autophagy via torin-1 and spautin-1, respectively, resulted in increased viral titers for both viruses, yet suppression of autophagy-related genes had no effect. Interestingly, chemical modulators of autophagy had either no effect or opposite effects in another widely used mosquito cell line, C6/36 Aedes albopictus cells. Together, our data reveals a limited role for autophagy during arbovirus infection of mosquito cells. Further, our findings suggest that commonly used chemical modulators of autophagy alter mosquito cells in such a way as to promote viral replication; however, it is unclear if this occurs directly through autophagic manipulation or other means.
Highlights
Arthropod-borne viruses, those of the families Flaviviridae and Togaviridae, cause significant morbidity and mortality and pose a continued public health threat worldwide. This is highlighted by the sustained transmission of dengue virus (DENV; Flaviviridae, Flavivirus) throughout the tropics, the emergent epidemics of Zika virus (ZIKV; Flaviviridae, Flavivirus), chikungunya virus (CHIKV; Togaviridae, Alphavirus) and West Nile virus (WNV; Flaviviridae, Flavivirus) in the Americas, and the sporadic outbreaks of yellow fever virus (YFV; Flaviviridae, Flavivirus) in Africa and South America
As a result we know very little about the role of autophagy during arbovirus infection within the invertebrate vector [22]. To address this knowledge gap we investigated the role of autophagy during dengue virus-2 (DENV-2) and CHIKV infection of Aag2 mosquito cells derived from the primary vector Aedes aegypti
Because autophagy has been understudied in mosquitoes it is unclear if traditional methods for manipulating and analyzing autophagy, such as the use of chemical compounds, will be effective and/ or toxic in mosquito cells
Summary
Arthropod-borne (arbo) viruses, those of the families Flaviviridae and Togaviridae, cause significant morbidity and mortality and pose a continued public health threat worldwide. This is highlighted by the sustained transmission of dengue virus (DENV; Flaviviridae, Flavivirus) throughout the tropics, the emergent epidemics of Zika virus (ZIKV; Flaviviridae, Flavivirus), chikungunya virus (CHIKV; Togaviridae, Alphavirus) and West Nile virus (WNV; Flaviviridae, Flavivirus) in the Americas, and the sporadic outbreaks of yellow fever virus (YFV; Flaviviridae, Flavivirus) in Africa and South America. Abnormal autophagic activity has been linked to a number of pathologies, including cancer and neurodegenerative diseases [3] This evolutionarily conserved pathway mediates the degradation and recycling of cellular components. Targeting aspects of the autophagy pathway has become a promising strategy for combatting a number of diseases [6, 7]
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