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Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID 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.
A Wuhan lineage appeared to be more potent than a DG 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.
Keywords: Ex vivo lung perfusion, Viral nebulization, 10X genomics, Azimuth software. The SARS-CoV-2 virus is responsible for a large variety of clinical manifestations affecting the respiratory tract, going from a- or pauci-symptomatic state, to a pneumonia and an acute respiratory distress syndrome.
In order to develop effective intervention strategies, several independent studies investigated the precise cell types targeted by the virus, from blood and broncho-alveolar lavages BAL at different stages of advanced diseases [ 1 ] and from lungs at autopsy [ 2 ]. In the BAL, SARS-CoV-2 was found associated with epithelial cells and macrophages [ 1 ], and in the lung of deceased patients, with mononuclear phagocytic cells, endothelial cells, pneumocytes and airway cells [ 2 β 4 ].
