Reovirus Activated Cell Death Pathways

Abstract

Mammalian orthoreoviruses (ReoV) are non-enveloped viruses with segmented double-stranded RNA genomes. In humans, ReoV are generally considered non-pathogenic, although members of this family have been proven to cause mild gastroenteritis in young children and may contribute to the development of inflammatory conditions, including Celiac disease. Because of its low pathogenic potential and its ability to efficiently infect and kill transformed cells, the ReoV strain Type 3 Dearing (T3D) is clinical trials as an oncolytic agent. ReoV manifests its oncolytic effects in large part by infecting tumor cells and activating programmed cell death pathways (PCDs). It was previously believed that apoptosis was the dominant PCD pathway triggered by ReoV infection. However, new studies suggest that ReoV also activates other PCD pathways, such as autophagy, pyroptosis, and necroptosis. Necroptosis is a caspase-independent form of PCD reliant on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and its substrate, the pseudokinase mixed-lineage kinase domain-like protein (MLKL). As necroptosis is highly inflammatory, ReoV-induced necroptosis may contribute to the oncolytic potential of this virus, not only by promoting necrotic lysis of the infected cell, but also by inflaming the surrounding tumor microenvironment and provoking beneficial anti-tumor immune responses. In this review, we summarize our current understanding of the ReoV replication cycle, the known and potential mechanisms by which ReoV induces PCD, and discuss the consequences of non-apoptotic cell death—particularly necroptosis—to ReoV pathogenesis and oncolysis.

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti‐PD‐1/PD‐L1 cancer immunotherapy

“…As a potent inducer of ICD, necroptosis synergises with anti‐PD‐1/PD‐L1 antibodies, providing added therapeutic benefits in cancer treatment. 121 For instance, a study developed a biomimetic artificial necroptotic cancer cell (α‐HSP70p‐CM‐CaP) vaccine containing HSP70 peptide, cancer membrane proteins (CM), and adjuvant CpG. This vaccine's delivery of immunogenic antigen materials and CpG to lymph nodes enhances DC maturation and antigen presentation, resulting in robust cellular immunity.…”

Oncolytic viral therapy as promising immunotherapy against glioma

“…At present, other NDV‐based strategies for the treatment of malignant glioma are being explored, such as autologous tumor vaccine modified with nonlytic NDV (ATV‐NDV) 161 . Reovirus are nonenveloped virus with 9–12 linear double‐stranded RNA that occurs naturally in the mammalian respiratory and intestinal systems 162 . Reovirus has a targeted lytic effect on cells activated by the RAS pathway, such as malignant gliomas cells and breast cancer cells 163 .…”

“…161 Reovirus are nonenveloped virus with 9-12 linear double-stranded RNA that occurs naturally in the mammalian respiratory and intestinal systems. 162 Reovirus has a targeted lytic effect on cells activated by the RAS pathway, such as malignant gliomas cells and breast cancer cells. 163 Clinical trials and preclinical studies of Reovirus have shown great promise.…”

Structure of Orthoreovirus RNA Chaperone σNS, a Component of Viral Replication Factories

“…Infection by some reovirus strains appears to induce the development of celiac disease, a complex immune disorder characterized by an immune response to dietary gluten that can damage the intestinal lining and result in diarrhea and malabsorption 3 . Infection by some reovirus strains can induce apoptosis, necroptosis, and pyroptosis in tumor cells by activating programmed cell death pathways 4 . Because of these characteristics, reovirus was one of the first viruses used as an oncolytic agent 5 .…”