Table 1.
Receptors or proteins related to SARS-CoV-2 infection in the nervous system.
| Receptor or protein | Expression in nerve cells | Neuroanatomic areas of gene expression* | Pathological effects on the nervous system | References |
|---|---|---|---|---|
| ACE2 | Neurons, astrocytes, microglia, BECs, OLGs | PG, Acb, Hy, SC, Cd, SN, Cb, HiF, FroCx, Amg, Pu and ACC | The direct binding of SARS-CoV-2 to the ACE2 receptor could trigger microvascular dysfunction, disrupt coagulation processes, cause neuronal depolarization, and increase expression of glutamate and MMPs, resulting in neuroinflammation, seizures, and hemorrhages. | (56, 58, 69, 73–75) |
| TMPRSS2 | PG, Hy, Cb, Amg, Cd, HiF, SN, Acb, ACC, FroCx, Pu and SC. | It acts as a co-receptor for ACE2 and cleaves S protein, facilitating viral binding to the ACE2 receptor and its activation. Therefore, it promotes the same effects described for ACE-2. | (76–78) | |
| DPP4 | Astrocytes (in murine) | FroCx, SC, ACC, PG, SN, Hy, HiF, Amg, Cb, Acb, Cd and Pu. | It is strongly associated with MERS-CoV. The murine models for DPP4 receptor infected with MERS-CoV have shown neuronal damage and peripheral immune infiltrates. | (79–81) |
| TLR4 | Astrocytes, microglia | Cd, SN, Acb, Amg, Pu, SC, ACC, FroCx, y, HiF and Cb. | Molecular docking studies have demonstrated the binding of the native S protein of SARS-CoV-2 to TLR1, TLR4, and TLR6. However, TLR4 is most likely to recognize molecular patterns from SARS-CoV-2 to induce inflammatory responses. In CNS, it could promote the neuroinflammation environment. | (82, 83) |
| ATR1 | Neurons, astrocytes | PG, SN, Hy, Cb SC,HiF, Cd, Acb, Pu, Amg, FroCx and ACC | It has been suggested that SARS-CoV-2 causes lung damage by increasing Ang II production. The hyperactivation of Ang II/ATR1/ACE signaling results in increased expression of pro-inflammatory cytokines, macrophage activation, and possibly BBB dysfunction. | (84–87) |
| ITGB1 | Microglia | SC, PG, SN, Hy, HiF,Pu, Cd, Amg, FroCx, Acb, ACC and Cb. | It has been suggested that ITGB1 could bind to S protein through the RGD or KGE motif. ITGB1 mainly activates the MI3K/MAPK pathways, inducing an inflammatory response. | (24, 88, 89) |
| CatB and CatL | Microglia, neurons, astrocytes. | Cat B: FroCx, PG, SC, Cb, Hy, Acb, ACC, Cd, SN, Pu, HiF and Amg Cat: PG, SC, FroCx, Cb, SN, Hy, Cd, Acb, Pu, ACC, HiF and Amg | It has been suggested that S protein priming is partly dependent on the endosomal proteases, CatB and CatL. Nevertheless, TMPRSS2 is essential for viral entry into primary target cells and viral spread in the infected host. Also, CatB and CatL can contribute to the neuroinflammatory process. | (90, 91) |
| NLRP3 | Microglia, astrocytes, neurons | SC, FroCx, Acb, Hy, SN, ACC, HiF, Amg, Cd, PG, Pu, Cb | To date, it is unclear if SARS-CoV-2 activates the NLRP3 inflammasome. However, SARS-CoV expresses at least three proteins (viroporins) that activate the NLRP3 inflammasome: envelope (E), ORF3a, and ORF8b. The NLRP3 inflammasome activation could trigger inflammatory cell death. | (92–94) |
Neuroanatomic areas and nerve cells in which these receptors or proteins are expressed and their possible neuropathological effects.
Acb, nucleus accumbens; ACC, anterior cingulate cortex; ACE2, angiotensin-converting enzyme 2; Amg, amygdala; ATR1, angiotensin receptor type 1; BBB, blood-brain barrier; BECs, brain endothelial cells; Cat, cathepsin; Cb, cerebellum; Cd, caudate nucleus; DPP4, dipeptidyl peptidase-4; FroCx, frontal cortex; HiF, hippocampal formation; Hy, hypothalamus; ITGB1, integrin subunit beta 1; KGE, Lys-Gly-Glu; MAPK, Mitogen-Activated Protein Kinases; MERS-CoV, Middle East Respiratory Syndrome Coronavirus; MI3K, myo-inositol 3-kinase; MMPs, matrix metalloproteinases; NF-kB, nuclear factor kappa B; NLRP3, nucleotide-binding domain-, leucine-rich repeat-containing receptor, pyrin domain-containing 3; OLGs, oligodendrocytes; PG, pituitary gland; Pu, putamen; RGD, Arg-Gly-Asp; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SC, spinal cord (cervical c-1), SN, substantia nigra; TLR, Toll Like Receptor; TMPRSS2, transmembrane protease serine 2.
The GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2) was used to obtain the gene expression data (from highest to lowest expression) in several brain areas.