AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

TLDR

COVID‑19, caused by SARS‑CoV‑2, primarily uses the ACE2 receptor for entry, yet ACE2 expression is low in respiratory tissues, raising questions about alternative entry pathways. The study aimed to identify additional host receptors that facilitate SARS‑CoV‑2 entry into respiratory epithelial cells. The authors demonstrated that AXL binds the N‑terminal domain of the viral spike protein and that overexpressing AXL in HEK293T cells supports viral entry while AXL knockout in pulmonary and primary lung cells markedly reduces infection. Soluble AXL inhibited infection, AXL expression correlated with spike protein levels in patient bronchoalveolar lavage cells, and these results establish AXL as a novel SARS‑CoV‑2 receptor and a potential therapeutic target.

Abstract

The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to the host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression is extremely low in various human tissues, especially in the respiratory tract. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system may exist. In this study, we found that the tyrosine-protein kinase receptor UFO (AXL) specifically interacts with the N-terminal domain of SARS-CoV-2 S. Using both a SARS-CoV-2 virus pseudotype and authentic SARS-CoV-2, we found that overexpression of AXL in HEK293T cells promotes SARS-CoV-2 entry as efficiently as overexpression of ACE2, while knocking out AXL significantly reduces SARS-CoV-2 infection in H1299 pulmonary cells and in human primary lung epithelial cells. Soluble human recombinant AXL blocks SARS-CoV-2 infection in cells expressing high levels of AXL. The AXL expression level is well correlated with SARS-CoV-2 S level in bronchoalveolar lavage fluid cells from COVID-19 patients. Taken together, our findings suggest that AXL is a novel candidate receptor for SARS-CoV-2 which may play an important role in promoting viral infection of the human respiratory system and indicate that it is a potential target for future clinical intervention strategies.