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

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.

Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic

“…The first step in cellular infection by SARS-CoV-2 is the binding of S protein to the host cell surface entry factors such as the membrane associated and soluble ACE2 receptor (38) which may be preceded by weaker binding of the S protein to attachment factors such as heparan sulphate (39). Other entry factors that facilitate attachment or entry include neuropilin-1 (40,41), the tyrosine-protein kinase receptor UFO (AXL) (42), CD147 (43), high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) (44), integrins (45,46), angiotension II receptor 1 (AT1) and vasopressin receptor 2, but their role in natural infection is currently unclear. Proteases such as surface TMPRSS2 and endosomal cathespsin L (46) cleave the S protein to activate SARS-CoV-2 entry by endocytosis and membrane fusion (22).…”

Science’s Response to COVID-19

“…105 The receptor tyrosine kinase, AXL, may also be involved in virus entry through a direct interaction with the S-protein; importantly these studies showed that mouse AXL did not bind CoVID-19 S-protein. 106 Such nuances are hugely important for planning and evaluating in vitro and cellular/animal model studies of infection.…”

What can the neurological manifestations of COVID-19 tell us : a meta-analysis

“…(2) AXL and NRP1 It is worth noting that, in addition to ACE2, recent studies have shown that receptor tyrosine kinase AXL is a new phenotype receptor of choice for SARS-CoV-2, and AXL is widely expressed in almost all human organs, especially in human lung and bronchial epithelial tissues and cells, the expression of AXL is much higher than that of ACE2 [122] .AXL is also found in cells in the brain, including radiating glia, astrocytes, and microglia [123] .Another cellular mediator, neurociliary protein-1 (NRP1), also promotes the entry of SARS-CoV-2 into host cells, thereby increasing its infectivity.NRPs are involved in a variety of physiological processes, including neuronal development and axon control. Studies have observed high expression of NRP1 in olfactoric epithelial cells infected with SARS-CoV-2 [124][125] .Therefore, AXL and NRP1 provide us with new research directions and intervention targets.…”