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One of such reprogramming events is the dynamic cross\u2010talk 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\u2010apoptotic programmed death events has remained elusive in context of RV infection. Here, we report that RV\u2010induced apoptosis accompanies another non\u2010apoptotic mode of programmed cell death pathway called necroptosis to promote host cellular demise at late phase of infection. Phosphorylation of mixed lineage kinase domain\u2010like (MLKL) protein indicative of necroptosis was observed to concur with caspase\u2010cleavage (apoptotic marker) beyond 6\u00a0hr of RV infection. Subsequent studies demonstrated phosphorylated\u2010MLKL 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\u2010cleavage and apoptosis could not fully rescue virus\u2010induced cell death but rather potentiated the necroptotic trigger. Interestingly, preventing both apoptosis and necroptosis by small molecules significantly rescued virus\u2010induced host cytopathy by inhibiting viral dissemination.<\/jats:p>","DOI":"10.1111\/mmi.14874","type":"journal-article","created":{"date-parts":[[2021,12,26]],"date-time":"2021-12-26T06:19:22Z","timestamp":1640499562000},"page":"818-836","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Rotavirus activates MLKL\u2010mediated host cellular necroptosis concomitantly with apoptosis to facilitate dissemination of viral progeny"],"prefix":"10.1111","volume":"117","author":[{"given":"Urbi","family":"Mukhopadhyay","sequence":"first","affiliation":[{"name":"Division of Virology ICMR\u2010National Institute of Cholera and Enteric Diseases  Kolkata India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upayan","family":"Patra","sequence":"additional","affiliation":[{"name":"Division of Virology 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