Abstract
Autophagy is an evolutionarily ancient pathway that has been shown to be important in the innate immune defense against several viruses. However, little is known about the regulatory role of autophagy in transmissible gastroenteritis virus (TGEV) replication. In this study, we found that TGEV infection increased the number of autophagosome-like double- and single-membrane vesicles in the cytoplasm of host cells, a phenomenon that is known to be related to autophagy. In addition, virus replication was required for the increased amount of the autophagosome marker protein LC3-II. Autophagic flux occurred in TGEV-infected cells, suggesting that TGEV infection triggered a complete autophagic response. When autophagy was pharmacologically inhibited by wortmannin or LY294002, TGEV replication increased. The increase in virus yield via autophagy inhibition was further confirmed by the use of siRNA duplexes, through which three proteins required for autophagy were depleted. Furthermore, TGEV replication was inhibited when autophagy was activated by rapamycin. The antiviral response of autophagy was confirmed by using siRNA to reduce the expression of gene p300, which otherwise inhibits autophagy. Together, the results indicate that TGEV infection activates autophagy and that autophagy then inhibits further TGEV replication.
Highlights
Coronaviruses are enveloped, positive-stranded RNA viruses belonging to the family Coronaviridae in the order Nidovirales[1]
We examined the effect of the autophagy machinery on transmissible gastroenteritis virus (TGEV) replication by modifying the autophagy pathway with pharmacological inducer/inhibitors and RNA interference
We observed that the number of double- and single-membrane vesicles increased near the perinuclear region of TGEV-infected ST cells, and that such structures were rare in the mock-treated samples (Fig. 1a)
Summary
Coronaviruses are enveloped, positive-stranded RNA viruses belonging to the family Coronaviridae in the order Nidovirales[1]. The representative members in each genus are transmissible gastroenteritis virus (TGEV) from alphacoronavirus, mouse hepatitis virus (MHV) and severe acute respiratory syndrome virus (SARS-CoV) from betacoronavirus, infectious bronchitis virus (IBV) from gammacoronavirus, and Bulbut-CoV from Deltacoronavirus[4]. Members of this family cause acute and persistent infections and are broadly distributed among mammalian species (including humans) and avian species. DMVs are usually rare in normal cells, but large numbers of double-membrane structures called autophagosomes are usually induced by activation of the cellular autophagy machinery[9]. We found that autophagy primarily functions to restrict TGEV replication
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