Necroptosis blockade prevents lung injury in severe influenza.

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

Z-form nucleic acid-binding protein 1 (ZBP1) as a sensor of viral and cellular Z-RNAs: walking the razor's edge.

Z-form nucleic acid-binding protein 1 (ZBP1) detects viral Z-form RNAs (Z-RNAs), activates receptor-interacting protein kinase 3, and triggers cell death during both RNA and DNA virus infections. Such cell death promotes virus clearance by eliminating infected cells and galvanizing antiviral immunity, and is thus often targeted for evasion by virus-encoded suppressors. Recent evidence demonstrates that ZBP1 can also be activated by cellular Z-RNAs transcribed from endogenous retroelements within mammalian genomes. These cellular Z-RNAs, if not edited and neutralized by adenosine deaminase RNA-specific 1, trigger ZBP1-dependent cell death and inflammation, which may drive disease in Aicardi-Goutière's syndrome and related interferonopathies. Thus, while well-controlled activation of ZBP1 by viral Z-RNAs during infections is beneficial, the same pathway can have harmful consequences when inappropriately triggered by cellular Z-RNAs in other disease settings.

Reovirus Activated Cell Death Pathways.

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.