Abstract
Human respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide. Inflammation induced by RSV infection is responsible for its hallmark manifestation of bronchiolitis and pneumonia. The cellular debris created through lytic cell death of infected cells is a potent initiator of this inflammation. Macrophages are known to play a pivotal role in the early innate immune and inflammatory response to viral pathogens. However, the lytic cell death mechanisms associated with RSV infection in macrophages remains unknown. Two distinct mechanisms involved in lytic cell death are pyroptosis and necroptosis. Our studies revealed that RSV induces lytic cell death in macrophages via both of these mechanisms, specifically through the ASC (Apoptosis-associated speck like protein containing a caspase recruitment domain)-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome activation of both caspase-1 dependent pyroptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), as well as a mixed lineage kinase domain like pseudokinase (MLKL)-dependent necroptosis. In addition, we demonstrated an important role of reactive oxygen species (ROS) during lytic cell death of RSV-infected macrophages.
Highlights
Respiratory syncytial viruses (RSV) are among the most common causes of viral pneumonia in neonatal, elderly, and immunocompromised humans worldwide
Since inflammasome activation serves as a precursor for pyroptosis-mediated lytic cell death [12], these results suggest that pyroptosis may be involved in lytic cell death of respiratory syncytial virus (RSV)-infected macrophages
The release of cellular components (e.g., ATP, S100A9 protein, 25-hydroxycholesterol) during cell lysis act as danger associated molecular patterns (DAMPs) to further drive the amplification of inflammation through activation of pro-inflammatory signaling cascades in the surrounding tissue-resident cells [8,16,17,35]
Summary
Respiratory syncytial viruses (RSV) are among the most common causes of viral pneumonia in neonatal, elderly, and immunocompromised humans worldwide. RSV-induced pneumonia results from an exaggerated pro-inflammatory response triggered by excessive cytokine and chemokine release from infected inflammatory immune cells [6,7,8,9,10]. In the case of RSV, cell debris generated by this cell death results in the physical obstruction of small airways by accumulating cellular fragments and leads to the classic lesion of bronchiolitis [15]. We demonstrated that necroptosis induces lytic cell death in RSV-infected macrophages through the RIPK3-MLKL pathways. We show that ROS play a key role in positively regulating lytic cell death of RSV-infected macrophages. These results indicate that both pyroptosis and necroptosis are involved during ROS-dependent RSV-induced lytic cell death in macrophages
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