COVID-19 SARS-CoV-2 spike protein promotes latent infection through analgesia

At present, COVID-19 triggered by COVID-19 SARS-CoV-2 is still rampaging around the world. Most sars-cov-2 infected people show mild to severe respiratory symptoms, such as fever, cough and shortness of breath. However, there are also some recessive infections with no obvious clinical symptoms but positive nucleic acid detection. These recessive infections have caused great difficulties in epidemic control.

In January 2021, the Rajesh Khanna Laboratory of Arizona State University reported that the spike protein of sars-cov-2 virus can block the binding of vascular endothelial growth factor-A (VEGF-A) and its receptor, neuropilin-1 receptor (NRP-1), and play an analgesic role, Therefore, the analgesic effect mediated by spike protein may be one of the reasons for virus recessive infection. 

In order to evaluate the role of spike protein in VEGF-A/NRP-1 pathway, the researchers first carried out enzyme-linked immunosorbent assay. The results showed that the binding of NRP-1 increased with the increase of the concentration of recombinant spike protein. Using microelectrode array (MEA) to record the discharges of dorsal root ganglion (DRG) neurons, they found that VEGF-A treatment could significantly increase the spontaneous discharges of DRG neurons, and this effect could be blocked by the S1 domain of spike protein or NRP-1 inhibitor eg00229. Further protein structure analysis showed that VEGF-A and spike protein had a common binding site on NRP-1, so they may compete for the binding with NRP-1. So can spike protein affect pain behavior by competitive inhibition of VEGF-A/NRP-1 signal?

The researchers injected PBS, VEGF-A, VEGF-A + spike protein or vefg-a + eg0029 into the hind foot of rats respectively. It was found that the injection of VEGF-A could reduce the mechanical foot contraction threshold, shorten the thermal pain threshold and play a pain inducing role. When spike protein or eg00229 is mixed with VEGF-A, it can block the above effects of VEGF-A, indicating that spike protein can play a similar role as NRP-1 inhibitor and block the pain inducing effect of VEGF-A/NRP-1 signal pathway.

In order to further understand the mechanism of VEGF-A sensitizing nociceptive neurons, the researchers found that VEGF-A can significantly increase the Na + and Ca2 + currents of neurons and increase the frequency of spontaneous excitatory post synaptic current (sepsc) of colloidal neurons, That is to enhance the excitatory synaptic transmission from dorsal root to spinal dorsal horn neurons. 

The above effects can be blocked by CO incubation with spike protein or NRP-1 inhibitor. These results suggest that spike protein can interfere with the effect of VEGF-A/NRP-1 signaling pathway on downstream ion channels, so as to inhibit the sensitization of DRG neurons by vegf-a. Finally, the researchers proved that in the spared nerve injury (SNI) model of chronic pathological pain, VEGF-A stimulation can cause the phosphorylation of y1175 site of its receptor vgfr2 (epithelial growth factor receptor 2), while intrathecal injection of spike protein can reduce the phosphorylation of vegfr2-y1175, increase the foot contraction threshold in a dose-dependent manner and exert analgesic effect.

In summary, novel coronavirus pneumonia patients generally have elevated VEGF-A in the study, which can act on NRP-1. Through a series of cascade reactions in cells, Na+ channels and Ca2+ channel activities can be increased, resulting in sensitization of nociceptive neurons and aggravating pain. However, some sars-cov-2 infected people participate in the formation of asymptomatic recessive infection because spike protein competes with VEGF-A for NRP-1 and silences the pain caused by VEGF-A/NRP-1 pathway.

 

Cindy