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      A Not-So-Good Way to Die? Respiratory Syncytial Virus–induced Necroptotic Cell Death Promotes Inflammation and Type 2–mediated Pathology

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          Abstract

          Respiratory syncytial virus (RSV) is a significant cause of acute respiratory infection in infants, and most children have been infected at least once before the age of 2 years (1). A small percentage of these children develop viral bronchiolitis and pneumonia associated with intense inflammation in their lower airways. Accordingly, RSV is one of the most significant causes of infant hospitalization in the developed world and a significant cause of infant mortality in the developing world. RSV-dependent lower respiratory tract infections in early life are also associated with an increased prevalence of wheeze and asthma in later life. Despite over 60 years of research into RSV, there is currently no licensed vaccine. In addition, although prophylactic administration of a monoclonal antibody against the RSV F protein can successfully prevent RSV bronchiolitis, its administration after infection has limited benefit. What drives severe disease during RSV-dependent lower respiratory tract infections and which pathways might be therapeutically targeted after infection therefore remain significant questions. Airway epithelial cell (AEC) death is prevalent with respiratory viral infection, but the type of death elicited can profoundly impact host immunity and ensuing pathology. Apoptosis is an ordered, noninflammatory cell death that is an efficient method of removing virally infected cells (2). Many viruses, including RSV through its two nonstructural proteins (NS1 and NS2), therefore actively suppress apoptosis to promote viral replication (3). Necroptosis is another form of programmed cell death that, unlike apoptosis, leads to release of cellular contents into the extracellular environment, promoting inflammation (4). Necroptosis is caspase independent and occurs via receptor-mediated activation of RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and RIPK3 and formation of the necrosome complex. Ensuing oligomerization of MLKL (mixed lineage kinase domain-like pseudokinase) disrupts the cell membrane, allowing release of damage-associated molecular patterns such as HMGB1 (high mobility group box 1) (5) (Figure 1). The consensus therefore is that necroptosis is a “fail-safe” form of cell death, limiting viral spread while alerting the immune system to danger. Indeed, as with apoptosis, many viruses have evolved strategies to limit necroptosis to promote replication (6). Figure 1. Can respiratory syncytial virus (RSV)-dependent necroptosis be targeted for therapeutic benefit? Simpson and colleagues demonstrate that RSV infection readily induces necroptosis in RSV-infected airway epithelial cells. The subsequent release of HMGB1 into the extracellular space results in the recruitment of proinflammatory and type 2–skewed immune responses, exacerbated disease, and an ensuing heightened susceptibility to asthma. This newly described pathway could potentially be targeted at multiple levels for therapeutic intervention during RSV bronchiolitis, as depicted by the red inhibitory arrows. GATA3 = GATA3 binding protein; HMGB1 = high mobility group box 1; IFNaR = IFN-α receptor; ILC2 = group 2 innate lymphoid cell; MLKL = mixed lineage kinase domain-like pseudokinase; Nec1s = 7-Cl-O-Necrostatin 1; NS1 = nonstructural protein 1; NS2 = nonstructural protein 2; NSA = necrosulfonamide; P = phosphorylated; RAGE = receptor for advance glycation end products; RIPK1 = receptor-interacting serine/threonine-protein kinase 1; RIPK3 = receptor-interacting serine/threonine-protein kinase 3; TLR4 = Toll-like receptor 4; TNFR = tumor necrosis factor receptor; TSLP = thymic stromal lymphopoietin. In this issue of the Journal (pp. 1358–1371), Simpson and colleagues (7) challenge this classical dogma, arguing that in the context of RSV infection, necroptosis is detrimental to viral clearance and accentuates immunopathology and ensuing propensity to develop asthma. The authors show that HMGB1 is elevated in the nasopharynx of children specifically infected with RSV compared with those infected with other viruses. Subsequently, in vitro infection of healthy infant–derived AECs elicited necroptosis-dependent HMGB1 translocation and release that was associated with a reduction in viral titers. In a series of complementary studies, the authors show that pneumovirus (mPV; murine RSV ortholog) infection of neonatal mice also results in epithelial necroptosis and HMGB1 release, especially in mice deficient for the central IFN-stimulated gene IRF7 (IFN regulatory factor 7). Subsequent pharmacological inhibition or genetic ablation of necroptosis markedly attenuated AEC sloughing and HMGB1 release while importantly reducing viral titers, neutrophilic and type 2 inflammation, and airway remodeling. Furthermore, pharmacological inhibition of necroptosis during primary mPV infection protected mice from subsequent development of experimental asthma. This study importantly identifies necroptosis as a prominent cell death pathway initiated by RSV infection and delineates its downstream consequences in terms of immunity and pathology. Inevitably, however, unanswered questions persist that should remain the focus of future studies. The underlying mechanism by which RSV elicits AEC necroptosis, particularly the role of RSV proteins, remains unexplored. Findings derived from the mPV model suggest that augmented viral titers are associated with heightened necroptosis, and the authors understandably speculate a role for viral TLRs (Toll-like receptors) or inflammatory cytokines in necroptosis induction. Although both influenza A virus and RSV NS proteins function to suppress AEC apoptosis, it is intriguing that influenza A virus NS1 has also been shown to operate to induce necroptosis (8). Do RSV NS proteins therefore display dual roles in defining the apoptosis–necroptosis balance? If RSV-induced necroptosis is more prevalent in the context of impaired antiviral innate immunity, then host determinant factors are likely critical in defining the scale of necroptosis and ensuing adverse sequelae. Polymorphisms in key IFN and innate immune genes are the most significantly associated with compromised viral control and severe RSV bronchiolitis (9), genes that are also heavily linked to the development of asthma. Could impaired antiviral responses of asthmatic AECs (10) potentiate necroptosis and also be of relevance to virus-driven asthma exacerbations with associated augmentation of neutrophilia and type 2 inflammation? The authors convincingly demonstrated the marked capacity of RSV/mPV to induce AEC necroptosis/HMGB1 release and the profound benefits of inhibiting necroptosis. It will be important, however, to delineate if and how HMGB1 is responsible for driving all purported downstream effects of necroptosis. HMGB1 binds a range of receptors, including RAGE (receptor for advance glycation end products) and TLR4, to promote the activation and recruitment of innate immune cells, including macrophages and neutrophils (5). Moreover, HMGB1 can act via RAGE to induce pulmonary group 2 innate lymphoid cell (ILC2) accumulation by promoting these cells’ proliferation and survival (11). Thus, it is easy to rationalize the necroptosis dependency of neutrophilic, ILC2, and eosinophilic inflammation and ensuing airway remodeling after mPV infection. Virally induced necroptosis also likely facilitates the release of prototypical alarmins associated with induction of type 2 responses, such as IL-33, IL-25, and TSLP (thymic stromal lymphopoietin) (12), and thus it would be intriguing to evaluate their significance within this pathway. It is also clear that necroptosis during RSV infection can play a role beyond the epithelium, because RSV-exposed neutrophils (potentially recruited secondarily to HMGB1) can undergo necroptosis and ensuing NETosis (13), with neutrophil extracellular traps also having been demonstrated to be potentiators of type 2–driven immunopathology (14). It also remains to be determined how inhibition of necroptosis improves viral clearance independent of an augmented IFN response. Moreover, given that necroptosis has conversely been demonstrated to be beneficial to control of numerous other viruses (6), it would be important to ascertain what defines this virus-specific role for necroptosis in host immunity. In the future, it will be important to extend clinical aspects of this study to unequivocally demonstrate that severe RSV-driven bronchiolitis in infants directly correlates with evidence of heightened AEC necroptosis. Although inherent challenges exist in elucidating the cause and effect in such a scenario, initial evidence suggests that local HMGB1 levels may correlate with disease severity (15), but its association with viral titers and the relevant inflammatory markers is unclear. Moreover, although clearly challenging, it would be intriguing to delineate whether evidence of a robust necroptotic response during primary RSV infection associates with a greater risk of developing asthma later in life. Given the findings of the study by Simpson and colleagues (7), there is a clear opportunity to target necroptosis at various levels for therapeutic intervention during severe RSV bronchiolitis (Figure 1). The added specificity of targeting downstream mediators such as HMGB1 would seem preferable if, as discussed above, it can be shown to be the instigator of all adverse sequelae attributed to RSV-driven AEC necroptosis. Given the aforementioned conflicting beneficial roles attributed to necroptosis for distinct viral infections, it would, of course, be prudent to validate that such strategies do not render children more susceptible to other infections.

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          Most cited references 15

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          Apoptosis: a review of programmed cell death.

          The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
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            Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

            Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-β mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-β protein. In infected asthmatic cells, exogenous interferon-β induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-β, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.
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              Necroptosis in development, inflammation and disease

              Several years after the characterization of the role of receptor-interacting serine/threonine protein kinase 1 (RIPK1) in cell survival, inflammation and disease, RIPK1 was implicated in the regulation of a newly identified type of cell death known as necroptosis. This Timeline article describes the discoveries that shed light on the roles of RIPK1, RIPK3, mixed-lineage kinase domain-like protein (MLKL) and other regulators of necroptosis in controlling cell fate.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                1 June 2020
                1 June 2020
                1 June 2020
                1 June 2020
                : 201
                : 11
                : 1321-1323
                Affiliations
                [ 1 ]National Heart and Lung Institute

                Imperial College London

                London, United Kingdom
                Author notes
                [*]

                R.J.S. is Associate Editor of AJRCCM. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

                Article
                202003-0533ED
                10.1164/rccm.202003-0533ED
                7258638
                32182121
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/).

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                Figures: 1, Tables: 0, Pages: 3
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