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

Abstract

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.

NLRP3-dependent pyroptosis exacerbates coxsackievirus A16 and coxsackievirus A10-induced inflammatory response and viral replication in SH-SY5Y cells

“…For instance, dual inhibition of innate immunity and apoptosis by human cytomegalovirus protein UL37 × 1 enables efficient virus replication, but Caprine parainfluenza virus type 3N protein promotes viral replication via inducing apoptosis ( Ren et al, 2022 ). RIPK3-dependent necroptosis is induced and restricts viral replication in human astrocytes infected with Zika Virus ( Wen et al, 2021 ), while Rotavirus activates MLKL-mediated host cellular necroptosis concomitantly with apoptosis to facilitate dissemination of viral progeny ( Mukhopadhyay et al, 2022 ). Additionally, it was reported that AIM2 and NLRP3 inflammasome-mediated pyroptosis in EV-A71-infected neuronal cells restricts viral replication ( Hu et al, 2023 ; Yogarajah et al, 2017 ).…”

Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection

“…ferroptosis inhibitors Ferrostatin-1 and Liproxstatin-1 resulted in reduced RV infection as estimated by expression of VP6 and viral titres confirming significant role of ferroptosis in modulating RV infection. Concurrently, RV has been shown to induce programmed cell death apoptosis and necroptosis during late hours of infection for effective dissemination of infectious progeny ( Bagchi et al., 2010 ; Chaïbi et al., 2005 ; Martin-Latil et al., 2007 ; Mukhopadhyay et al., 2022 ). The current study added ferroptosis to the repertoire of RV induced cell death pathways.…”

Revisiting Regulated Cell Death Responses in Viral Infections

“…The phosphorylated form of MLKL oligomerizes and translocates to the plasma membrane of the cells infected by RV. This results in the loss of integrity of the host cell plasma membrane and the release of alarmin molecules such as HMGB1 which contribute to host cell death [202].…”