MAJOR ARTICLE COVID-19 Immunoparalysis of Myeloid Cells • JID 2021:224 (1 August) • 395 The Journal of Infectious Diseases Received 13 October 2020; editorial decision 19 January 2021; accepted 22 January 2021; published online January 25, 2021. a A. B., L. G., and S. M. contributed equally to this work. Correspondence: Jean-Louis Mege, MD, PhD, Immunology Department, Hôpital de la Conception, 147 boulevard Baille, 13005 Marseille, France (jean-louis.mege@univ-amu.fr). The Journal of Infectious Diseases ® 2021;224:395–406 © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. DOI: 10.1093/infdis/jiab044 Monocytes and Macrophages, Targets of Severe Acute Respiratory Syndrome Coronavirus 2: Te Clue for Coronavirus Disease 2019 Immunoparalysis Asma Boumaza, 1,2,a Laetitia Gay, 1,2,3,a Soraya Mezouar, 1,2,a Eloïne Bestion, 1,2,4 Aïssatou Bailo Diallo, 1,2 Moise Michel, 1,2 Benoit Desnues, 1,2 Didier Raoult, 1,2 Bernard La Scola, 1,2 Philippe Halfon, 1,2,3 Joana Vitte, 1,2, Daniel Olive, 5 and Jean-Louis Mege 1,2,6 1 Aix-Marseille Université, Institut de recherche pour le développement, Assitance publique-hopitaux de Marseille, Microbe, Phylogeny and infection, Marseille, France, 2 Institut hospitalo-universitaire Méditerranée infection, Marseille, France, 3 ImCheck Therapeutics, Marseille, France, 4 Genoscience Pharma, Marseille, France, 5 Centre de recherche en cancérologie de Marseille, Inserm Unité mixte de recherche 1068, Centre National de la Recherche Scientifque Unité mixte de recherche 7258, Institut Paoli Calmettes, Marseille, France, and 6 Aix-Marseille Université, Assistance publique-hoptiaux de Marseille, Hopital de la Conception, Laboratoire d’Immunologie, Marseille, France Background. Coronavirus disease 2019 (COVID-19) clinical expression is pleiomorphic, severity is related to age and comorbidities such as diabetes and hypertension, and pathophysiology involves aberrant immune activation and lymphopenia. We wondered if the myeloid compartment was afected during COVID-19 and if monocytes and macrophages could be infected by se- vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods. Monocytes and monocyte-derived macrophages (MDMs) from COVID-19 patients and controls were infected with SARS-CoV-2 and extensively investigated with immunofuorescence, viral RNA extraction and quantifcation, and total RNA extrac- tion followed by reverse-transcription quantitative polymerase chain reaction using specifc primers, supernatant cytokines (inter- leukins 6, 10, and 1β; interferon-β; transforming growth factor–β1, and tumor necrosis factor–α), and fow cytometry. Te efect of M1- vs M2-type or no polarization prior to infection was assessed. Results. SARS-CoV-2 efciently infected monocytes and MDMs, but their infection is abortive. Infection was associated with immunoregulatory cytokines secretion and the induction of a macrophagic specifc transcriptional program characterized by the upregulation of M2-type molecules. In vitro polarization did not account for permissivity to SARS-CoV-2, since M1- and M2-type MDMs were similarly infected. In COVID-19 patients, monocytes exhibited lower counts afecting all subsets, decreased expression of HLA-DR, and increased expression of CD163, irrespective of severity. Conclusions. SARS-CoV-2 drives monocytes and macrophages to induce host immunoparalysis for the beneft of COVID-19 progression. Keywords. SARS-CoV-2; COVID-19; monocytes; macrophages; polarization. The severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) emerged in Wuhan, China, at the end of 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic, with 85 million cases and 1 800 000 deaths to date [1]. COVID-19 is char- acterized by a strikingly heterogeneous clinical presentation and prognosis. Most patients are pauci-symptomatic or have fever, cough, and fatigue, while a minority experience progression to an acute respiratory distress syndrome or other critically severe con- ditions. The severity of the disease is related to underlying con- ditions such as hypertension, diabetes, coronary heart disease, or obesity [2]. The mechanisms remain elusive, but evidence for a prominent role of the immune system is accumulating. The se- verity of COVID-19 pneumonia is associated with lymphopenia and a cytokine release syndrome (CRS) [3], which contributes to the massive migration of T cells into tissues, mainly the lung, and accumulation of T cells within lesions [4]. Tere is evidence that myeloid cells are involved in the path- ophysiology of coronavirus infection, either directly, as virus target, or indirectly, as CRS efectors [5]. Macrophages are susceptible to Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome corona- virus (SARS-CoV) infection [6]. Macrophage and monocyte accumulation in the alveolar lumen was demonstrated in a mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expressing human angiotensin-converting enzyme 2 (ACE2) [7]. SARS-CoV-2 nucleocapsid protein was detected in lymph nodes and spleen-associated CD169 + macro- phages from COVID-19 patients [8]. Finally, single-cell RNA sequencing (scRNA-seq) of pulmonary tissue from COVID-19 patients revealed an expansion of interstitial macrophages and monocyte-derived macrophages (MDMs) but not of alveolar Downloaded from https://academic.oup.com/jid/article/224/3/395/6119539 by guest on 19 September 2021