Mitophagy Enhances Oncolytic Measles Virus Replication by Mitigating DDX58/RIG-I-Like Receptor Signaling

Abstract

The success of future clinical trials with oncolytic viruses depends on the identification and the control of mechanisms that modulate their therapeutic efficacy. In particular, little is known about the role of autophagy in infection by attenuated measles virus of the Edmonston strain (MV-Edm). We investigated the interaction between autophagy, innate immune response, and oncolytic activity of MV-Edm, since the antiviral immune response is a known factor limiting virotherapies. We report that MV-Edm exploits selective autophagy to mitigate the innate immune response mediated by DDX58/RIG-I like receptors (RLRs) in nonsmall cell lung cancer (NSCLC) cells. Both RNA interference (RNAi) and overexpression approaches demonstrate that autophagy enhances viral replication and inhibits the production of type I interferons regulated by RLRs. We show that MV-Edm unexpectedly triggers SQSTM1/p62-mediated mitophagy, resulting in decreased mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and subsequently weakening the innate immune response. These results unveil a novel infectious strategy based on the usurpation of mitophagy leading to mitigation of the innate immune response. This finding provides a rationale to modulate autophagy in oncolytic virotherapy. IMPORTANCE In vitro studies, preclinical experiments in vivo, and clinical trials with humans all indicate that oncolytic viruses hold promise for cancer therapy. Measles virus of the Edmonston strain (MV-Edm), which is an attenuated virus derived from the common wild-type measles virus, is paradigmatic for therapeutic oncolytic viruses. MV-Edm replicates preferentially in and kills

Mitophagy in Viral Infections

“…Following seasonal influenza A virus infection, receptor interacting protein kinase 2 (RIPK2)-mediated mitophagy reduces immunopathology by negatively regulating activation of NOD-like receptor family pyrin-containing domain protein 3 (NLRP3) signaling and inflammation (Lupfer et al, 2013). We have recently reported that measles virus Edmonston vaccine strain (MV-Edm) infection induces mitophagy in nonsmall cell lung cancer (NSCLC) cells leading to enhanced viral replication (Xia et al, 2014a). While MV-Edm infection induces innate immune responses by means of activation of DDX58/MAVS, it in parallel stimulates SQSTM1-mediated mitophagy to degrade mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS), a key adaptor protein of DDX58/IFIH1 signaling, and thus attenuates antiviral immune responses (Fig.…”

Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells

“…Some experimental evidences show that autophagy is an essential host defense response to fight infection by destroying infectious pathogens trapped within autophagosomes, and plays an important role in the induction of both innate and adaptive immune response [14, 18, 24-26], whereas some studies show that viruses also subvert autophagy to enhance viral replication and release, such as hepatitis C virus, dengue virus, and measles virus [27-31]. It has been shown recently that NDV strain Beaudette C triggers autophagy both in human U251 glioma cells and in chicken cells leading to enhanced virus replication [32, 33].…”

Autophagy dysfunction in autoinflammatory diseases

“…AGS7 is caused by gain-of-function variants in IFIH1 , the gene encoding MDA5, which lead to enhanced IFN-β transcription [99]. Autophagy can regulate the activation of mitochondrion-tethered MAVS by mitophagy [100] or other mechanisms [101,102], thus suppressesing type I IFN production. For DNA viruses, cyclic di-nucleotides generated by cyclic GMP–AMP synthase (cGAS) in the presence of dsDNA activate the adaptor protein stimulator of interferon genes (STING) to induce type I IFN expression [97].…”