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

Abstract

As of January 25, 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has caused more than 340 million infections with over 5.5 million deaths. [1] Coronavirus disease 2019 (COVID-19) patients may develop various clinical manifestations, including severe acute pulmonary disease, [2][3][4] hepatic dysfunction, [3,4] kidney injury, [4] heart damage, [3,4] gastrointestinal, [5] pancreatic symptoms, [6] and olfactory dysfunction. [7] However, due to the lagged, yet possibly long-lasting effects, [8] the impact of COVID-19 on the skeleton system has not been well characterized. Bone is the major reservoir for body calcium and phosphorus. [9] Preliminary clinical data have uncovered COVID-19-associated calcium metabolic disorders and osteoporosis. [10,11] Importantly, severe COVID-19 patients are found to have decreased blood calcium and phosphorus levels, in comparison with moderate COVID-19 patients. [12] These observations suggest a possible link between SARS-CoV-2 infection and damage in the skeleton system. 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 wildtype 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.

Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis

“…Many studies have focused on the impact of Omicron infection on musculoskeletal diseases [ 17 , 18 ]. Inflammation can influence bone remodeling, and researchers have reported that chronic obstructive pulmonary disease, asthma, and cystic fibrosis can disrupt bone metabolism and lead to pathological bone loss [ 36 , 37 ].…”

“…This bone loss may be caused by the accumulation of circulating proinflammatory cytokines and activated osteoclast differentiation. Gao et al [ 17 ] found that SARS-CoV-2 can also directly infect bone marrow macrophages through non-canonical receptor Nrp1 rather than through ACE2, which in turn inhibits their differentiation into osteoclasts. These studies suggest that SARS-CoV-2 has the potential to cause complications that so far have been neglected, suggesting that we will need to follow-up on patients with COVID-19 for a longer duration to determine the impact of the virus on target organs outside the respiratory system.…”

“…Recently, increasing attention has been paid to the effects of SARS-CoV-2 infection on bone metabolism [ 17 , 18 ]. However, to date, no study has reported whether the use of these novel antivirals will initiate or accelerate the progression of degenerative diseases of the musculoskeletal system.…”

Ferroptosis Is a Potential Therapeutic Target for Pulmonary Infectious Diseases

“…It is reported that alveolar epithelial cells are sensitive to SARS-CoV-2 and alveolar macrophages also suffer from the infection of SARS-CoV-2 [131,132]. In addition, MHV-A59 infects mouse bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs) [133], while neuropilin-1 (NRP1) mediates SARS-CoV-2 to infect mouse BMDMs [134]. Accordingly, the infection of coronavirus is closely related with ferroptosis, which may provide a new therapeutic target for the treatment of COVID-19.…”

The Role of Vitamin D in the Restriction of the Progress and Severity of COVID-19 Infection

“…As of May 13, 2022, the SARS-CoV-2 outbreak has caused more than 519.9 million infections with over 6.3 million deaths [1] (https://www.worldometers.info/coronavirus). The SARS-CoV-2 infected or COVID-19 patients may develop various clinical manifestations,including severe acute pulmonary disease [2,3], heart damage [4], kidney injury [4], hepatic dysfunction [4], pancreatic symptoms [5], gastrointestinal [6] and olfactory dysfunction [7]. However, the impact of COVID-19 may have long-lasting effects on the physiological systems.…”