COVID-19
Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19

https://doi.org/10.1016/j.jaci.2022.06.020Get rights and content

Background

Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19).

Objective

The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods

Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n = 29) or not admitted to an ICU (n = 29) and in age- and sex-matched healthy controls.

Results

We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs 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, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs 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 ROSs could play a major role in COVID-19 pathogenesis.

Key words

SARS-CoV-2
ACE2
oxidative stress
antioxidant
angiotensin II receptor
DNA oxidation
programmed cell death
lymphopenia

Abbreviations used

ACE2
Angiotensin-converting enzyme 2
AngII
Angiotensin II
AT1
Angiotensin receptor type 1
AU
Arbitrary unit
COVID-19
Coronavirus disease 2019
DCFH-DA
Dichlorodihydrofluorescein diacetate
DPI
Diphenyleneiodonium
HD
Healthy donor
ICU
Intensive care unit
IQR
Interquartile range
NAC
N-acetylcysteine
NADP
Nicotinamide adenine dinucleotide phosphate
NK
Natural killer
ROS
Reactive oxygen species
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2

Cited by (0)

Supported by the University Hospital of Nîmes (grant NIMAO/2020/COVID/PC-01 [to P.C.]), the Fondation pour la Recherche Médicale, and the Agence Nationale de Recherche (grant 216261 [to J.E.]).

Disclosure of potential conflict of interest: P. Corbeau received a grant from AbbVie. The rest of the authors declare that they have no relevant conflicts of interest.

These authors contributed equally to this work.

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