Sustained Autophagy Contributes to Measles Virus Infectivity

Abstract

The interplay between autophagy and intracellular pathogens is intricate as autophagy is an essential cellular response to fight against infections, whereas numerous microbes have developed strategies to escape this process or even exploit it to their own benefit. The fine tuned timing and/or selective molecular pathways involved in the induction of autophagy upon infections could be the cornerstone allowing cells to either control intracellular pathogens, or be invaded by them. We report here that measles virus infection induces successive autophagy signallings in permissive cells, via distinct and uncoupled molecular pathways. Immediately upon infection, attenuated measles virus induces a first transient wave of autophagy, via a pathway involving its cellular receptor CD46 and the scaffold protein GOPC. Soon after infection, a new autophagy signalling is initiated which requires viral replication and the expression of the non-structural measles virus protein C. Strikingly, this second autophagy signalling can be sustained overtime within infected cells, independently of the expression of C, but via a third autophagy input resulting from cell-cell fusion and the formation of syncytia. Whereas this sustained autophagy signalling leads to the autophagy degradation of cellular contents, viral proteins escape from degradation. Furthermore, this autophagy flux is ultimately exploited by measles virus to limit the death of infected cells and to improve viral particle formation. Whereas CD150 dependent virulent strains of measles virus are unable to induce the early CD46/GOPC dependent autophagy wave, they induce and exploit the late and sustained autophagy. Overall, our work describes distinct molecular pathways for an induction of self-beneficial sustained autophagy by measles virus.

Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

“…One recent observation is that the expression of MeV-C is required for the induction of late autophagy in infected HeLa cells, subsequent to MeV replication [16]. In the present study, we found that PPRV-C significantly increased the level of LC3-II and promoted the degradation of p62.…”

“…In recent years, an increasing number of studies have demonstrated that the infection processes of morbilliviruses are closely related with autophagic flux [16,17]. However, the coxsackievirus B3, herpes simplex virus and influenza A virus have been shown to induce autophagosome formation but block the fusion of autophagosomes with lysosomes [48–50].…”

“…However, the coxsackievirus B3, herpes simplex virus and influenza A virus have been shown to induce autophagosome formation but block the fusion of autophagosomes with lysosomes [48–50]. More importantly, MeV infection induces successive autophagic signalling, leading to a sustained increase in autophagic flux [16]. Our data are consistent with those of MeV; indeed, E64d treatment increased the amount of LC3-II in both rapamycin-treated and virus-infected EECs, indicating that there was increased autophagic flux.…”

“…In contrast, low basal levels of LC3-II were present in mock-infected cells, indicating that basal autophagy in normal EECs was essential for maintaining homeostasis. Recent studies show that several members of the Paramyxoviridae family, including MeV [16], human respiratory syncytial virus [52], canine distemper virus [53] and Newcastle disease virus [35], can utilize an autophagy mechanism to facilitate replication. To further determine what role autophagy plays in the replication of PPRV, we examined viral replication ability by exposing EECs to rapamycin, an inducer of autophagy that specifically inhibits the action of mTOR [54].…”

“…Autophagy also contributes to innate and adaptive immunity against a wide variety of intracellular microbial pathogens, including bacteria, viruses and protozoa [14,15]. An increasing amount of evidences suggest that the autophagy processes are also exploited by many viruses for their replication, such as the measles virus (MeV) [16], PPRV [17], hepatitis C virus [18], classical swine fever virus (CSFV) [19], porcine reproductive and respiratory syndrome virus (PRRSV) [20], avian reovirus [21], and influenza A virus [22]. However, it has been demonstrated that autophagy is involved in the elimination of the herpes simplex virus [23], foot-and-mouth disease virus [24], human rotavirus [25] and cytomegalovirus [26].…”