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https://www.arca.fiocruz.br/handle/icict/55534
INFLAMMASOME ACTIVATION IN INFECTED MACROPHAGES DRIVES COVID-19 PATHOLOGY
Author
Sefik, Esen
Qu, Rihao
Junqueira, Caroline
Kaffe, Eleanna
Mirza, Haris
Zhao, Jun
Brewer, J Richard
Han, Ailin
Steach, Holly R.
Israelow, Benjamin
Velazquez, Sofia E.
Chen, Y Grace
Halene, Stephanie
Iwasaki, Akiko
Meffre, Eric
Nussenzweig, Michel
Lieberman, Judy
Wilen, Craig B.
Kluger, Yuval
Flavell, Richard A.
Qu, Rihao
Junqueira, Caroline
Kaffe, Eleanna
Mirza, Haris
Zhao, Jun
Brewer, J Richard
Han, Ailin
Steach, Holly R.
Israelow, Benjamin
Velazquez, Sofia E.
Chen, Y Grace
Halene, Stephanie
Iwasaki, Akiko
Meffre, Eric
Nussenzweig, Michel
Lieberman, Judy
Wilen, Craig B.
Kluger, Yuval
Flavell, Richard A.
Affilliation
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/ Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/ Computational Biology and Bioinformatics Program. Yale University. New Haven, CT, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/ Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Pathology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Pathology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Surgery. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/Section of Hematology. Yale Cancer Center and Department of Internal Medicine. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Howard Hughes Medical Institute. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA
Laboratory of Molecular Immunology. The Rockefeller University. New York, NY, USA/Howard Hughes Medical Institute. The Rockefeller University. New York, NY, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Laboratory Medicine. Yale University School of Medicine. New Haven, CT, USA.
Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/Program of Applied Mathematics. Yale University, New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Howard Hughes Medical Institute. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/ Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/ Computational Biology and Bioinformatics Program. Yale University. New Haven, CT, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/ Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Pathology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Pathology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Surgery. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA.
Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/Section of Hematology. Yale Cancer Center and Department of Internal Medicine. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Howard Hughes Medical Institute. Yale University School of Medicine. New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA
Laboratory of Molecular Immunology. The Rockefeller University. New York, NY, USA/Howard Hughes Medical Institute. The Rockefeller University. New York, NY, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Department of Laboratory Medicine. Yale University School of Medicine. New Haven, CT, USA.
Department of Pathology. Yale University School of Medicine. New Haven, CT, USA/Program of Applied Mathematics. Yale University, New Haven, CT, USA.
Department of Immunobiology. Yale University School of Medicine. New Haven, CT, USA/Howard Hughes Medical Institute. Yale University School of Medicine. New Haven, CT, USA.
Abstract
Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system1-20. Blocking either viral replication with remdesivir21-23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.
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