Neuropilin‐1‐Mediated SARS‐CoV‐2 Infection in Bone Marrow‐Derived Macrophages Inhibits Osteoclast Differentiation

In humans, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection can cause medical complications across various tissues and organs. Despite the advances to understanding the pathogenesis of SARS‐CoV‐2, its tissue tropism and interactions with host cells have not been fully understood. Existing clinical data have revealed disordered calcium and phosphorus metabolism in Coronavirus Disease 2019 (COVID‐19) patients, suggesting possible infection or damage in the human skeleton system by SARS‐CoV‐2. Herein, SARS‐CoV‐2 infection in mouse models with wild‐type and beta strain (B.1.351) viruses is investigated, and it is found that bone marrow‐derived macrophages (BMMs) can be efficiently infected in vivo. Single‐cell RNA sequencing (scRNA‐Seq) analyses of infected BMMs identify distinct clusters of susceptible macrophages, including those related to osteoblast differentiation. Interestingly, SARS‐CoV‐2 entry on BMMs is dependent on the expression of neuropilin‐1 (NRP1) rather than the widely recognized receptor angiotensin‐converting enzyme 2 (ACE2). The loss of NRP1 expression during BMM‐to‐osteoclast differentiation or NRP1 neutralization and knockdown can significantly inhibit SARS‐CoV‐2 infection in BMMs. Importantly, it is found that authentic SARS‐CoV‐2 infection impedes BMM‐to‐osteoclast differentiation. Collectively, this study provides evidence for NRP1‐mediated SARS‐CoV‐2 infection in BMMs and establishes a potential link between disturbed osteoclast differentiation and disordered skeleton metabolism in COVID‐19 patients.