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Rotavirus activates MLKL‐mediated host cellular necroptosis concomitantly with apoptosis to facilitate dissemination of viral progeny

Reprogramming the host cellular environment is an obligatory facet of viral pathogens to foster their replication and perpetuation. One of such reprogramming events is the dynamic cross‐talk between viruses and host cellular death signaling pathways. Rotaviruses (RVs) have been reported to develop multiple mechanisms to induce apoptotic programmed cell death for maximizing viral spread and pathogenicity. However, the importance of non‐apoptotic programmed death events has remained elusive in context of RV infection. Here, we report that RV‐induced apoptosis accompanies another non‐apoptotic mode of programmed cell death pathway called necroptosis to promote host cellular demise at late phase of infection. Phosphorylation of mixed lineage kinase domain‐like (MLKL) protein indicative of necroptosis was observed to concur with caspase‐cleavage (apoptotic marker) beyond 6 hr of RV infection. Subsequent studies demonstrated phosphorylated‐MLKL to oligomerize and to translocate to plasma membrane in RV infected cells, resulting in loss of plasma membrane integrity and release of alarmin molecules e.g., high mobility group box protein 1 (HMGB1) in the extracellular media. Moreover, inhibiting caspase‐cleavage and apoptosis could not fully rescue virus‐induced cell death but rather potentiated the necroptotic trigger. Interestingly, preventing both apoptosis and necroptosis by small molecules significantly rescued virus‐induced host cytopathy by inhibiting viral dissemination.