tetano
Editor, Senior Moderator
J Allergy Clin Immunol
. 2022 Jul 13;S0091-6749(22)00911-3.
doi: 10.1016/j.jaci.2022.06.020. Online ahead of print.
Angiotensin II induces reactive oxygen species, DNA damage, and T cell apoptosis in severe COVID-19
Lucy Kundura[SUP] 1 [/SUP], Sandrine Gimenez[SUP] 1 [/SUP], Renaud Cezar[SUP] 2 [/SUP], Sonia André[SUP] 3 [/SUP], Mehwish Younas[SUP] 1 [/SUP], Yea-Lih Lin[SUP] 1 [/SUP], Pierre Portales[SUP] 4 [/SUP], Claire Lozano[SUP] 4 [/SUP], Charlotte Boulle[SUP] 5 [/SUP], Jacques Reynes[SUP] 5 [/SUP], Vincent Thierry[SUP] 4 [/SUP], Clément Mettling[SUP] 1 [/SUP], Philippe Pasero[SUP] 1 [/SUP], Laurent Muller[SUP] 6 [/SUP], Jean-Yves Lefrant[SUP] 6 [/SUP], Claire Roger[SUP] 6 [/SUP], Pierre-Géraud Claret[SUP] 7 [/SUP], Sandra Duvnjak[SUP] 8 [/SUP], Paul Loubet[SUP] 9 [/SUP], Albert Sotto[SUP] 9 [/SUP], Tu-Anh Tran[SUP] 10 [/SUP], Jérôme Estaquier[SUP] 11 [/SUP], Pierre Corbeau[SUP] 12 [/SUP]
Affiliations
Abstract
Background: Lymphopenia is predictive of survival in Coronavirus disease 2019 (COVID-19) patients.
Objective: The aim of this study was to understand the cause of a lymphocyte count drop in severe forms of SARS-CoV-2 infection.
Methods: Monocytic production of reactive oxygen species (ROS) and T cell apoptosis were measured by flow cytometry, DNA damage in peripheral mononuclear blood cells (PBMCs) by immunofluorescence, and Angiotensin II (AngII) by ELISA in SARS-CoV-2-infected patients upon admission to Intensive Care Units (ICU, n=29) or non-ICU (n=29), and in age- and sex-matched healthy controls.
Results: We show that the monocytes of certain COVID-19 patients spontaneously released ROS able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs, and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, Angiotensin Converting Enzyme 2, a protease able to catabolize AngII. Accordingly, we observed in certain COVID-19 patients high plasma levels of AngII. Looking for the stimulus responsible for their monocytic ROS production, we unveiled that AngII triggers ROS production by monocytes via Angiotensin receptor I. ROS released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes.
Conclusion: We conclude that T cell apoptosis provoked via DNA damage due to the release of monocytic ROS could play a major role in COVID-19 pathogenesis.
Clinical implication: Unveiling this new pathogenic pathway opens up new therapeutic possibilities for COVID-19.
Keywords: ACE2; Angiotensin II receptor; DNA oxidation; SARS-CoV-2; antioxidant; lymphopenia; oxidative stress; programmed cell death.
. 2022 Jul 13;S0091-6749(22)00911-3.
doi: 10.1016/j.jaci.2022.06.020. Online ahead of print.
Angiotensin II induces reactive oxygen species, DNA damage, and T cell apoptosis in severe COVID-19
Lucy Kundura[SUP] 1 [/SUP], Sandrine Gimenez[SUP] 1 [/SUP], Renaud Cezar[SUP] 2 [/SUP], Sonia André[SUP] 3 [/SUP], Mehwish Younas[SUP] 1 [/SUP], Yea-Lih Lin[SUP] 1 [/SUP], Pierre Portales[SUP] 4 [/SUP], Claire Lozano[SUP] 4 [/SUP], Charlotte Boulle[SUP] 5 [/SUP], Jacques Reynes[SUP] 5 [/SUP], Vincent Thierry[SUP] 4 [/SUP], Clément Mettling[SUP] 1 [/SUP], Philippe Pasero[SUP] 1 [/SUP], Laurent Muller[SUP] 6 [/SUP], Jean-Yves Lefrant[SUP] 6 [/SUP], Claire Roger[SUP] 6 [/SUP], Pierre-Géraud Claret[SUP] 7 [/SUP], Sandra Duvnjak[SUP] 8 [/SUP], Paul Loubet[SUP] 9 [/SUP], Albert Sotto[SUP] 9 [/SUP], Tu-Anh Tran[SUP] 10 [/SUP], Jérôme Estaquier[SUP] 11 [/SUP], Pierre Corbeau[SUP] 12 [/SUP]
Affiliations
- PMID: 35841981
- PMCID: PMC9278992
- DOI: 10.1016/j.jaci.2022.06.020
Abstract
Background: Lymphopenia is predictive of survival in Coronavirus disease 2019 (COVID-19) patients.
Objective: The aim of this study was to understand the cause of a lymphocyte count drop in severe forms of SARS-CoV-2 infection.
Methods: Monocytic production of reactive oxygen species (ROS) and T cell apoptosis were measured by flow cytometry, DNA damage in peripheral mononuclear blood cells (PBMCs) by immunofluorescence, and Angiotensin II (AngII) by ELISA in SARS-CoV-2-infected patients upon admission to Intensive Care Units (ICU, n=29) or non-ICU (n=29), and in age- and sex-matched healthy controls.
Results: We show that the monocytes of certain COVID-19 patients spontaneously released ROS able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs, and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, Angiotensin Converting Enzyme 2, a protease able to catabolize AngII. Accordingly, we observed in certain COVID-19 patients high plasma levels of AngII. Looking for the stimulus responsible for their monocytic ROS production, we unveiled that AngII triggers ROS production by monocytes via Angiotensin receptor I. ROS released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes.
Conclusion: We conclude that T cell apoptosis provoked via DNA damage due to the release of monocytic ROS could play a major role in COVID-19 pathogenesis.
Clinical implication: Unveiling this new pathogenic pathway opens up new therapeutic possibilities for COVID-19.
Keywords: ACE2; Angiotensin II receptor; DNA oxidation; SARS-CoV-2; antioxidant; lymphopenia; oxidative stress; programmed cell death.