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JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1435144


Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.

COVID-19/metabolism , Interleukin-8/metabolism , Lung/immunology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/etiology , Animals , COVID-19/complications , COVID-19/pathology , Humans , Lung/pathology , Mice , Neutrophil Activation , Neutrophils/pathology , Phenotype , Thrombosis/pathology
Int J Health Plann Manage ; 35(5): 1240-1245, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-607516


This short communication recognizes the underbelly of weak and conflict-prone health systems in the Middle East and North Africa region in the wake of COVID-19 pandemic. The communication highlights how the lack of basic resources, absence of a well-functioning health system and the dearth of well-coordinated communication channels, can bode ill for the successful fight against COVID-19. The article elucidates COVID-19 potential health, social, and economic implications for such countries. The communication cautions that if COVID-19 is left to incubate and makes a home in weak systems, it will have a much better chance of mutating and coming back to infect many people globally. The communication calls on the international institutions in collaboration with developed nations to be prepared to probe up health systems in weak and conflict-prone health systems with much-needed resources in order to nip COVID-19 in the bud.

Armed Conflicts , Coronavirus Infections/epidemiology , Delivery of Health Care , Pneumonia, Viral/epidemiology , Africa, Northern/epidemiology , Betacoronavirus , COVID-19 , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Delivery of Health Care/organization & administration , Developing Countries , Humans , Middle East/epidemiology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/therapy , Risk Factors , SARS-CoV-2 , Socioeconomic Factors