Autophagy Protects against Sindbis Virus Infection of the Central Nervous System

Abstract

Autophagy functions in antiviral immunity. However, it is not yet known whether endogenous autophagy genes protect against viral disease in vertebrates. Using three different approaches to inactivate the autophagy gene Atg5 in virally-infected neurons, we found that loss of Atg5 function increases mouse susceptibility to lethal Sindbis virus CNS infection. This phenotype is associated with delayed clearance of viral proteins, increased accumulation of the cellular p62 adaptor protein, and increased cell death in neurons, but not with altered levels of CNS viral replication. In vitro, p62 interacts with Sindbis virus capsid protein and genetic knockdown of p62 blocks the targeting of viral capsid to autophagosomes. Moreover, p62 or autophagy gene knockdown increases viral capsid accumulation and accelerates virus-induced cell death without affecting virus replication. These results suggest a novel function for autophagy in mammalian antiviral defense: a cell-autonomous mechanism in which p62 adaptor-mediated autophagic viral protein clearance promotes cell survival.

Selective autophagy limits cauliflower mosaic virus infection by NBR1-mediated targeting of viral capsid protein and particles

“…NBR1 provides antiviral roles in CaMV infection, and bulk autophagy significantly extends the lifespan of infected plants and virus particle production. Autophagy has been observed to increase host viability during some metazoan virus infections as well (10,12,31). This survival function of autophagy benefits CaMV infection by increasing the likelihood that infected plants will provide particles for transmission.…”

Disease tolerance and immunity in host protection against infection

“…Autophagy is an evolutionary conserved damage response that supports cell function under stress conditions that elicit damage to cellular organelles (Figure 2) 62 . Autophagy regulates inflammatory responses and modulates disease tolerance to infections such as Sindbis virus 63 , S. aureus 64 and polymicrobial 17 infections in mice. Of note, autophagy can act as a resistance mechanism against intracellular pathogens, i.e.…”

Selective autophagy and viruses

“…First, we performed in vitro studies to determine whether SIN induces autophagy, whether SIN is targeted to autophagosomes, and whether autophagy controls SIN replication. 3 We found that SIN infection induces autophagy in vitro, as evidenced by the induction of GFP-LC3 puncta, and the degradation of p62 in SIN-infected murine embryonic fibroblasts (MEFs) and mouse neuronal cells. In contrast to the findings of Shelly et al, 2 SINinduced autophagy requires viral replication, as autophagy is not observed in cells infected with UV-inactivated SIN.…”