Close Relationship between cIAP2 and Human ARDS Induced by Severe H7N9 Infection

Abstract

Background. cIAP2 is involved in necroptosis as a key upstream regulation factor. We aimed to investigate the role of cIAP2 in ARDS/ALI induced by H7N9 virus through regulating the RIPK1/3 necroptosis pathway. Methods. Lung tissues of 11 patients who died from ARDS-complicated H7N9 infection between 2013 and 2016 were obtained as the H7N9-ARDS group. Lung tissues near benign lung nodules were acquired as the control group. Histological changes were evaluated by H&E staining. Protein levels of cIAP2, RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL in the lung tissues were detected by Western Blot. The mRNA levels of cIAP2, RIPK1, and RIPK3 were detected by real-time PCR. Results. H7N9 virus infection had a high mortality, with ARDS being the leading cause of death. The protein level of cIAP2 in the experimental group was lower than that in the control group (P<0.05). However, the experimental group showed higher RIPK1, RIPK3, and p-RIPK3 protein levels than the control group (P<0.05), as well as the expression level of MLKL and p-MLKL protein, which is a key downstream protein in necroptosis (P<0.05). Conclusion. In tissues from patients with fatal H7N9, downregulation of cIAP2 and induction of necroptosis was observed. We could speculate that necroptosis of the pulmonary epithelium is associated with severe H7N9 infection leading to ARDS. Thus, necroptosis inhibition may be a novel therapy for H7N9 influenza virus.

Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death

“…As previously discussed, TRAIL has been shown to be expressed by PR8-infected alveolar macrophages in vivo and to induce epithelial cell apoptosis [53]. In addition to the significant cell death of bystander cells to IAV-induced death receptor ligands, patients with fatal ARDS-like H7N9 disease have been shown to express significantly less expression of the inhibitor of apoptosis protein, cIAP2, in lung tissue samples [143]. Correspondingly, mice lacking cIAP2 displayed increased susceptibility to PR8 infection, where use of bone-marrow chimeras revealed that this hypersusceptibility was largely attributable to RIPK3-dependent necrosis in the non-haemopoietic compartment, such as bronchial epithelial cells [155].…”

“…Likewise, necroptotic signalling responses were observed in human blood-derived monocytes upon H7N9 infection and were sufficient to promote pro-inflammatory cytokines gene expression, e.g., IFNβ, IL-6, and RANTES/CCL5 and costimulatory protein CD80, CD83 and CD86 expression on monocyte-derived DC and T cell proliferation [83]. Patients with fatal ARDS-like H7N9 disease also display increased total levels of necrosome components RIPK1, RIPK3 and MLKL in lung tissue samples, as well as active phosphorylated forms of RIPK3 and MLKL [143]. Similarly, pMLKL has also been detected in lung tissues following PR8 infection of mice [82].…”

Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

“…Interestingly, virulent human coronaviruses have been shown to promote multiple form of necrotic cell death such as RIPK3-dependent necroptosis and caspase-1-dependent pyroptosis 35 . These pathways have also been implicated in influenza-induced ARDS in mice and humans 36,37 . Therefore, inflammatory cell death (e.g.…”

Benefits and Perils of Necroptosis in Influenza Virus Infection

“…Although these findings were observed when the threshold for RIPK3 activation was artificially lowered (by cIAP2 ablation), they presaged the possibility that necroptosis can have pathological, even fatal, consequences when hyperactivated during IAV infections. Indeed, a recent study has shown that lower cIAP2 levels (which, presumably result in increased RIPK3 activity) are correlated with the severity of ARDS outcomes in humans following H7N9 infections (46). Conversely, RIPK3 deficiency was found to be protective following infection of mice with an H7N9 strain of virulent IAV (47).…”