Neuropilin‑1 as a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19

Davies,Julie; Randeva,Harpal S.; Chatha,Kamaljit; Hall,Marcia; Spandidos,Demetrios A.; Karteris,Emmanouil; Kyrou,Ioannis

doi:10.3892/mmr.2020.11510

Neuropilin‑1 as a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19

Authors:
- Julie Davies
- Harpal S. Randeva
- Kamaljit Chatha
- Marcia Hall
- Demetrios A. Spandidos
- Emmanouil Karteris
- Ioannis Kyrou
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Affiliations: Centre for Genome Engineering and Maintenance, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK, Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece
Published online on: September 15, 2020 https://doi.org/10.3892/mmr.2020.11510
Pages: 4221-4226
Copyright: © Davies et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Infection by the severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2) is the cause of the new viral infectious disease (coronavirus disease 2019; COVID‑19). Emerging evidence indicates that COVID‑19 may be associated with a wide spectrum of neurological symptoms and complications with central nervous system (CNS) involvement. It is now well‑established that entry of SARS‑CoV‑2 into host cells is facilitated by its spike proteins mainly through binding to the angiotensin‑converting enzyme 2 (ACE‑2). Preclinical studies have suggested that neuropilin‑1 (NRP1), which is a transmembrane receptor that lacks a cytosolic protein kinase domain and exhibits high expression in the respiratory and olfactory epithelium, may also be implicated in COVID‑19 by enhancing the entry of SARS‑CoV‑2 into the brain through the olfactory epithelium. In the present study, we expand on these findings and demonstrate that the NRP1 is also expressed in the CNS, including olfactory‑related regions such as the olfactory tubercles and paraolfactory gyri. This furthers supports the potential role of NRP1 as an additional SARS‑CoV‑2 infection mediator implicated in the neurologic manifestations of COVID‑19. Accordingly, the neurotropism of SARS‑CoV‑2 via NRP1‑expressing cells in the CNS merits further investigation.

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1	Domingo P, Mur I, Pomar V, Corominas H, Casademont J and de Benito N: (2020). The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19). EBioMedicine. 58. Elsevier B.V.; 2020, View Article : Google Scholar : PubMed/NCBI
2	World Health Organisation (WHO), . Coronavirus disease 2019 (COVID-19): Weekly Epidemiological Update. 21 August 2020. simplewww.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reportsLast accessed August 22, 2020.
3	Gavriatopoulou M, Korompoki E, Fotiou D, Ntanasis- Stathopoulos I, Psaltopoulou T, Kastritis E, Terpos E and Dimopoulos MA: Organ-specific manifestations of COVID-19 infection. Clin Exp Med. https://doi.org/10.1007/s10238-020-00648-x PubMed/NCBI
4	De Felice FG, Tovar-Moll F, Moll J, Munoz DP and Ferreira ST: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System. Trends Neurosci. 43:355–357. 2020. View Article : Google Scholar : PubMed/NCBI
5	Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, et al: Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 77:6832020. View Article : Google Scholar : PubMed/NCBI
6	Mao XY and Jin WL: The COVID-19 Pandemic: Consideration for brain infection. Neuroscience. 437:130–131. 2020. View Article : Google Scholar : PubMed/NCBI
7	Needham EJ, Chou SHY, Coles AJ and Menon DK: Neurological implications of COVID-19 infections. Neurocrit Care. 32:667–671. 2020. View Article : Google Scholar : PubMed/NCBI
8	Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu N-H, Nitsche A, et al: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 181:271–280.e8. 2020. View Article : Google Scholar : PubMed/NCBI
9	Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A and Li F: Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA. 117:11727–11734. 2020. View Article : Google Scholar : PubMed/NCBI
10	Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M and Nagata N: TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol. 93:e01815–18. 2019. View Article : Google Scholar : PubMed/NCBI
11	Katopodis P, Anikin V, Randeva HS, Spandidos DA, Chatha K, Kyrou I and Karteris E: Pan-cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS-CoV-2 infection leading to COVID-19. Int J Oncol. 57:533–539. 2020. View Article : Google Scholar : PubMed/NCBI
12	Cui C, Huang C, Zhou W, Ji X, Zhang F, Wang L, Zhou Y and Cui Q: AGTR2, one possible novel key gene for the entry of SARS-CoV-2 into human cells. IEEE/ACM Trans Comput Biol Bioinformatics. Jul 14–2020.(Epub ahead of print). View Article : Google Scholar
13	Kerkeni M and Gharbi J: RAGE receptor: May be a potential inflammatory mediator for SARS-COV-2 infection? Med Hypotheses. 144:1099502020. View Article : Google Scholar : PubMed/NCBI
14	Kerslake R, Hall M, Randeva HS, Spandidos DA, Chatha K, Kyrou I and Karteris E: Co-expression of peripheral olfactory receptors with SARS-CoV-2 infection mediators: Potential implications beyond loss of smell as a COVID-19 symptom. Int J Mol Med. 46:949–956. 2020. View Article : Google Scholar : PubMed/NCBI
15	Xia P and Dubrovska A: Tumor markers as an entry for SARS CoV 2 infection? FEBS J. Aug 1–2020.(Epub ahead of print). View Article : Google Scholar
16	Bittmann S, Weissenstein A, Moschüring-Alieva E and Villalon G and Villalon G: Neuropilin-1 in transmission process of COVID-19. J Regen Biol Med. 2:1–2. 2020.
17	Cantuti-Castelvetri L, Ojha R, Pedro L, Djannatian M, Franz J, Kuivanen S, Kallio K, Kaya T, Anastasina M, Smura T, et al: Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system. bioRxiv. https://doi.org/10.1101/2020.06.07.137802
18	Daly JL, Simonetti B, Antón-Plágaro C, Kavanagh Williamson M, Shoemark DK, Simón-Gracia L, Klein K, Bauer M, Hollandi R, Greber UF, et al: Neuropilin-1 is a host factor for SARS-CoV-2 infection. bioRxiv. https://doi.org/10.1101/2020.06.05.134114
19	Guo HF and Vander Kooi CW: Neuropilin Functions as an Essential Cell Surface Receptor. J Biol Chem. 290:29120–29126. 2015. View Article : Google Scholar : PubMed/NCBI
20	Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK and Datta K: Multifaceted role of neuropilins in the immune system: potential targets for immunotherapy. Front Immunol. 8:12282017. View Article : Google Scholar : PubMed/NCBI
21	Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MSB, Li G, et al: Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 89:37–53. 2016. View Article : Google Scholar : PubMed/NCBI
22	Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, et al FANTOM Consortium and the RIKEN PMI and CLST (DGT), : A promoter-level mammalian expression atlas. Nature. 507:462–470. 2014. View Article : Google Scholar : PubMed/NCBI
23	Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, Alm T, Asplund A, Björk L, Breckels LM, et al: A subcellular map of the human proteome. Science. 356:eaal33212017. View Article : Google Scholar : PubMed/NCBI
24	Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, et al: Proteomics. Tissue-based map of the human proteome. Science. 347:1260419. 2015. View Article : Google Scholar : PubMed/NCBI
25	Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, et al: An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 489:391–399. 2012. View Article : Google Scholar : PubMed/NCBI
26	Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, Goldman M, Verstegen AMJ, Resch JM, McCarroll SA, et al: A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci. 20:484–496. 2017. View Article : Google Scholar : PubMed/NCBI
27	Ikemoto S: Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens - olfactory tubercle complex. Brain Res Brain Res Rev. 56:27–78. 2007. View Article : Google Scholar
28	Wesson DW and Wilson DA: Sniffing out the contributions of the olfactory tubercle to the sense of smell: Hedonics, sensory integration, and more? Neurosci Biobehav Rev. 35:655–668. 2011. View Article : Google Scholar : PubMed/NCBI
29	Arabi YM, Harthi A, Hussein J, Bouchama A, Johani S, Hajeer AH, Saeed BT, Wahbi A, Saedy A, Al Dabbagh T, et al: Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV). Infection. 43:495–501. 2015. View Article : Google Scholar : PubMed/NCBI
30	Hung ECW, Chim SSC, Chan PKS, Tong YK, Ng EKO, Chiu RWK, Leung C-B, Sung JJY, Tam JS and Lo YMD: Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome. Clin Chem. 49:2108–2109. 2003. View Article : Google Scholar : PubMed/NCBI
31	Lau KK, Yu WC, Chu CM, Lau ST, Sheng B and Yuen KY: Possible central nervous system infection by SARS coronavirus. Emerg Infect Dis. 10:342–344. 2004. View Article : Google Scholar : PubMed/NCBI
32	Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK and McCray PB Jr: Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 213:712–722. 2016. View Article : Google Scholar : PubMed/NCBI
33	Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, et al: Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 382:2268–2270. 2020. View Article : Google Scholar : PubMed/NCBI
34	Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, et al UCL Queen Square National Hospital for Neurology and Neurosurgery COVID-19 Study Group, : The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain. Jul 8–2020.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
35	von Weyhern CH, Kaufmann I, Neff F and Kremer M: Early evidence of pronounced brain involvement in fatal COVID-19 outcomes. Lancet. 395:e1092020. View Article : Google Scholar : PubMed/NCBI
36	Lu Y, Li X, Geng D, Mei N, Wu P-Y, Huang C-C, Jia T, Zhao Y, Wang D, Xiao A, et al: Cerebral micro-structural changes in COVID-19 patients - an MRI-based 3-month follow-up study. EClinicalMedicine. 25:1004842020. View Article : Google Scholar : PubMed/NCBI
37	Conde Cardona G, Quintana Pájaro LD, Quintero Marzola ID, Ramos Villegas Y and Moscote Salazar LR: Neurotropism of SARS-CoV 2: Mechanisms and manifestations. J Neurol Sci. 412:1168242020. View Article : Google Scholar : PubMed/NCBI
38	Wang HB, Zhang H, Zhang JP, Li Y, Zhao B, Feng GK, Du Y, Xiong D, Zhong Q, Liu WL, et al: Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun. 6:62402015. View Article : Google Scholar : PubMed/NCBI