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Role of hemagglutinin esterase protein in neurological manifestation of COVID-19

Dear editor,

We read with interest an article by McQuaid et al. [1], in this article, the authors stated that “The lipid plasma membrane has structural proteins, namely the spike protein (SP), membrane protein, small membrane protein and hemagglutinin-esterase” [1]. For this claim, the authors cited a related study, but there is not any evidence on hemagglutinin-esterase gene in that cited reference [2]. However, according to the scientific evidence the genome of SARS-CoV-2 lacks the hemagglutinin-esterase (HE) gene and it has no HE glycoprotein [3,4,5,6], thus HE has no role in neurological manifestation of COVID-19.

From the emergence of SARS-CoV-2 in December 2019, a great amount of efforts and research have been made to characterize the virus and the clinical course of coronavirus disease 2019 (COVID-19) [7]. SARS-CoV-2 as an enveloped, positive-strand RNA virus is a member of Coronaviridae family in Nidovirales order [8]. According the genetic properties Coronaviridae family is subdivided to 4 genera including: alpha, beta, gamma and deltacoronavirus [9]. In addition, betacoronavirus genus has five subgenera: Embecovirus (lineage A), Sarbecovirus (lineage B), Merbecovirus (lineage C), Nobecovirus (lineage D) and Hibecovirus [10].

Between human coronaviruses, OC43-CoV and HKU1-CoV are considered as betacoronaviruses of linage A, however, both SARS-CoV and SARS-CoV-2 are betacoronaviruses of linage B and also MERS-CoV is a member of betacoronavirus of C lineage [11].

Between coronaviruses, betacoronaviruses lineage A including: bovine-CoV, OC43-CoV, HKU1-CoV, mouse hepatitis virus(MHV), harbor HE which acts functionally like spike (S) protein [12, 13]. The gene of HE is transmitted from influenza virus C/D to betacoronavirus lineage A progenitor via horizontal gene as 9-O-Ac-SA–specific hemagglutinin-esterase-fusion (HEF) [11]. The HE in betacoronaviruses lineage A does not show activity of membrane fusion unlike HEF in influenza virus C/D [11]. SARS-CoV-2 as a betacoronavirus of Sarbecovirus subgenus comprises four structural proteins spike (S), envelope (E), membrane protein (M), and nucleoprotein (N) and lacks HE [6].

In conclusion, HE gene is absent in betacoronaviruses such as SARS-CoV-2, MERS-CoV and SARS-CoV, thus HE has no role in neurological manifestation of COVID-19, however, some betacoronaviruses in subgenera Embecovirus have HE.

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COVID-19 :

Coronavirus Disease 2019


Severe acute respiratory syndrome-CoV

SARS-CoV-2 :

Severe acute respiratory syndrome-CoV-2


Middle East Respiratory Syndrome CoV


  1. McQuaid C, Brady M, Deane R. SARS-CoV-2 is there neuroinvasion? Fluids Barriers CNS. 2021;18(1):1–21.

    Article  Google Scholar 

  2. Das G, Mukherjee N, Ghosh S. Neurological insights of COVID-19 pandemic. ACS Chem Neurosci. 2020;11(9):1206–9.

    Article  CAS  Google Scholar 

  3. Kumar S, Nyodu R, Maurya VK, Saxena SK. Morphology, genome organization, replication, and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2019 (COVID-19). Coronavirus Dis. 2020;23:24.

    Google Scholar 

  4. Zandi M, Soltani S. Hemagglutinin-esterase cannot be considered as a candidate for designing drug against COVID-19. Mol Divers. 2021.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Devasena T. The Nanotechnology-COVID-19 interface. Gateway East: Springer; 2021. p. 31–58.

    Google Scholar 

  6. Zandi M, Soltani S, Feyzi K. SARS-CoV-2 as a betacoronavirus comprises five structural proteins? Infect Genet Evol. 2021.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Park SE. Epidemiology, virology, and clinical features of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Pediatr. 2020;63(4):119.

    Article  CAS  Google Scholar 

  8. Khailany RA, Safdar M, Ozaslan M. Genomic characterization of a novel SARS-CoV-2. Gene Rep. 2020;19:100682.

    Article  Google Scholar 

  9. El-Sayed A, Kamel M. Coronaviruses in humans and animals: the role of bats in viral evolution. Environ Sci Pollut Res. 2021.

    Article  Google Scholar 

  10. Li X, Luk HK, Lau SK, Woo PC. Human coronaviruses: general features. Ref Modul Biomed Sci. 2019.

    Article  Google Scholar 

  11. Kim C-H. SARS-CoV-2 evolutionary adaptation toward host entry and recognition of receptor O-Acetyl sialylation in virus–host interaction. Int J Mol Sci. 2020;21(12):4549.

    Article  CAS  Google Scholar 

  12. Lang Y, Li W, Li Z, Koerhuis D, Van Den Burg AC, Rozemuller E, et al. Coronavirus hemagglutinin-esterase and spike proteins coevolve for functional balance and optimal virion avidity. Proc Natl Acad Sci USA. 2020;117(41):25759–70.

    Article  CAS  Google Scholar 

  13. Soltani S. The hemagglutinin-esterase gene in human coronaviruses SARS-CoV-2, HKU1 and OC43. Eur Rev Med Pharmacol Sci. 2020;24(12):6484–5.

    CAS  PubMed  Google Scholar 

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MZ, Design, wrote; HK and SS involved in investigation. All authors have read and approved the final manuscript.

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Correspondence to Milad Zandi.

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Zandi, M., Karami, H. & Soltani, S. Role of hemagglutinin esterase protein in neurological manifestation of COVID-19. Fluids Barriers CNS 18, 39 (2021).

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