SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses
Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems do not recapitulate the histoarchitecture and cellular composition of respiratory tissues. To address this, we developed an innovative ex vivo model of whole human lung infection with SARS-CoV-2, leveraging a lung transplantation technique. Through single-cell RNA-seq, we identified that alveolar and monocyte-derived macrophages (AMs and MoMacs) were initial targets of the virus. Exposure of isolated lung AMs, MoMacs, classical monocytes and non-classical monocytes (ncMos) to SARS-CoV-2 variants revealed that while all subsets responded, MoMacs produced higher levels of inflammatory cytokines than AMs, and ncMos contributed the least. A Wuhan lineage appeared to be more potent than a D614G virus, in a dose-dependent manner. Amidst the ambiguity in the literature regarding the initial SARS-CoV-2 cell target, our study reveals that AMs and MoMacs are dominant primary entry points for the virus, and suggests that their responses may conduct subsequent injury, depending on their abundance, the viral strain and dose. Interfering on virus interaction with lung macrophages should be considered in prophylactic strategies.
Authors
- Luc Jouneau (ORCID: https://orcid.org/0000-0002-5094-7302)
- Julien De Wolf (ORCID: https://orcid.org/0000-0002-7871-2943)
- Delphyne Descamps (ORCID: https://orcid.org/0000-0002-4883-6910)
- Edouard Sage
- Claudia Bevilacqua (ORCID: https://orcid.org/0000-0003-0423-4624)
- Marc Dalod (ORCID: https://orcid.org/0000-0002-6436-7966)
- Thien‐Phong Vu Manh (ORCID: https://orcid.org/0000-0002-0294-342X)
- Florentina Pascale (ORCID: https://orcid.org/0000-0003-3942-3521)
- Meriadeg Ar Gouilh (ORCID: https://orcid.org/0000-0002-3672-9974)
- Matthieu Glorion (ORCID: https://orcid.org/0000-0002-3233-860X)
- Laurent Hannouche (ORCID: https://orcid.org/0009-0007-8160-1009)
- Isabelle Schwartz-Cornil (ORCID: https://orcid.org/0000-0002-3485-1765)
- Quentin Marquant
- Christophe Chevalier (ORCID: https://orcid.org/0000-0003-3231-9027)
- Bruno R. da Costa (ORCID: https://orcid.org/0000-0002-1786-6332)
- Jérôme Estephan
- A. Magnan (ORCID: https://orcid.org/0000-0002-9282-6656)
- Morgan Le Guen (ORCID: https://orcid.org/0000-0002-6789-1237)
- Céline Urien
- Carla Gouin
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Aix-Marseille Université (FR)
- AgroParisTech (FR)
- Université Paris-Saclay (FR)
- Microbiologie de l’alimentation au service de la santé (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Virologie et Immunologie Moléculaires (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Hôpital Foch (FR)
- Biologie de la Reproduction, Environnement, Epigénétique et Développement (FR)
- Dynamique Microbienne associée aux Infections Urinaires et Respiratoires
- Université de Caen Normandie (FR)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1007/s00018-024-05322-z
- Citations
- 4
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.56
Funders
- European Commission
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- AgroParisTech
- Université Paris-Saclay
- Région Occitanie Pyrénées-Méditerranée
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement