Abstract
Sindbis virus (SINV) is a mosquito-borne virus in the genus Alphavirus, family Togaviridae. Like most alphaviruses, SINVs exhibit lytic infection (apoptosis) in many mammalian cell types, but are generally thought to cause persistent infection with only moderate cytopathic effects in mosquito cells. However, there have been several reports of apoptotic-like cell death in mosquitoes infected with alphaviruses or flaviviruses. Given that apoptosis has been shown to be an antiviral response in other systems, we have constructed recombinant SINVs that express either pro-apoptotic or anti-apoptotic genes in order to test the effects of inducing or inhibiting apoptosis on SINV replication in mosquito cells. Recombinant SINVs expressing the pro-apoptotic genes reaper (rpr) from Drosophila or michelob_x (mx) from Aedes aegypti caused extensive apoptosis in cells from the mosquito cell line C6/36, thus changing the normal persistent infection observed with SINV to a lytic infection. Although the infected cells underwent apoptosis, high levels of virus replication were still observed during the initial infection. However, virus production subsequently decreased compared with persistently infected cells, which continued to produce high levels of virus over the next several days. Infection of C6/36 cells with SINV expressing the baculovirus caspase inhibitor P35 inhibited actinomycin D-induced caspase activity and protected infected cells from actinomycin D-induced apoptosis, but had no observable effect on virus replication. This study is the first to test directly whether inducing or inhibiting apoptosis affects arbovirus replication in mosquito cells.
Highlights
Each year several million people die of arthropod-borne diseases including malaria, yellow fever, and dengue fever (Hill et al, 2005)
There are a number of reports of cell death in mosquitoes infected with arboviruses, some of which are consistent with apoptosis (Bowers et al, 2003, Girard et al, 2005, Mims et al, 1966, Weaver et al, 1992, Weaver et al, 1988)
Correlation between apoptosis and resistance to West Nile virus infection has been observed in midgut cells of a refractory lab strain of Culex pipiens pipiens (Vaidyanathan & Scott, 2006), and apoptosis that occurs in the salivary glands of Culex pipiens quinquefasciatus late in infection correlates with reduced transmission potential for West Nile virus (Girard et al, 2005, Girard et al, 2007)
Summary
Each year several million people die of arthropod-borne diseases including malaria, yellow fever, and dengue fever (Hill et al, 2005). Correlation between apoptosis and resistance to West Nile virus infection has been observed in midgut cells of a refractory lab strain of Culex pipiens pipiens (Vaidyanathan & Scott, 2006), and apoptosis that occurs in the salivary glands of Culex pipiens quinquefasciatus late in infection correlates with reduced transmission potential for West Nile virus (Girard et al, 2005, Girard et al, 2007) Despite these intriguing observations, no causative data exist that directly link apoptosis to effects on viral vector competence in mosquitoes
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