Contributions of human ACE2 and TMPRSS2 in determining host-pathogen interaction in COVID-19

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is an emerging global public health crisis. Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contribute to the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Animal to human transmission of SARS-CoV-2 is considered as a rare event that necessarily required strong evolutionary adaptations. Till date no other human cellular receptors were identified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 by TMPRSS2 began the entire host-pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-protein binds to ACE2 with much higher affinity and stability than that of SARS-CoV’s. Molecular interactions between ACE2-S and TMMPRSS2-S are crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these three interacting proteins are key susceptibility factors for COVID-19. Specific protein-protein interactions (PPI) are being identified that explains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alter these PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs against ACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel lead phytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19 drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute in the future research on COVID-19.

A Study on the Impact of the COVID-19 Pandemic on the Aetiology of Paediatric Olfactory Dysfunction

“…It has been established that infection with SARS-CoV-2 mainly relies on two components, namely, angiotensinconverting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) [13]. ACE2 seems to play a more relevant role in viral transmission, as TMPRSS2 may be substituted for other proteases [14]. Additionally, there is a growing body of evidence for the involvement of support cells of the olfactory receptor neurons, such as sustentacular cells, in the pathogenesis of a SARS-CoV-2 infection [15,16].…”

Comparative assessment of the role of TMPRSS2 and ACE-2 receptors in the development of olfactory disorders in infection with coronavirus SARS-CoV-2

“…Фермент TMPRSS2 також сприяє проникненню вірусу в клітину шляхом розщеплення частини білка рецептора ACE2 [6]. Також відомо, що експресія рецепторів TMPRSS2 в легенях, передміхуровій залозі, шлунково-кишковому тракті, печінці, серці та рогівці вище, ніж в інших тканинах, з чим можна пов'язати розвиток критичних ускладнень коронавірусної хвороби саме в цих органах [9][10][11] Статистичний аналіз та графічна презентація результатів дослідження виконувалися з використанням пакету комп'ютерної програми Microsoft Exсel 2016 (Office16ProPlusVL_MAK edition №00339-21520-30133-AA867). Дані описової статистики наведені у форматі «середнє арифметичне ± стандартне відхилення» (М ± SD) або із зазначенням медіани та міжквартильного інтервалу (Me (Q1-Q3)) залежно від розподілу ознаки [12].…”

Targeting Viral ORF3a Protein: A New Approach to Mitigate COVID-19 Induced Immune Cell Apoptosis and Associated Respiratory Complications

“…28 It has been demonstrated in an in vitro study that SARS-CoV-2 is unable to infect ACE2 knockout Vero E6 and Hela cells, suggesting its importance in viral entry. 28,29 The cleavage of ACE2 and S-proteins for the entry of virus is mediated by TMPRSS2 enzyme, via membrane fusion, which is a major factor in the infection of COVID-19. In addition, other cell surface components also help Coronaviruses to enter the cells like DPP4 and furin, as in case of MERS-CoV.…”

“…In addition, other cell surface components also help Coronaviruses to enter the cells like DPP4 and furin, as in case of MERS-CoV. 28 A c c e p t e d M a n u s c r i p t ACE2 is the receptor for S-protein of SARS-CoV, placed on chromosome Xp22.2, encoding the protein that is belonging to the group of angiotensin-converting enzyme. The ACE2 receptor typically remains as a dimer with A and B forms, which is stabilised by the Sodiumdependent neutral amino acid transporter (B 0 AT1), also called SLC6A19.…”

“…32 Two S-protein trimers binds to a homodimer of ACE2, each through an ACE2 monomer. 28 Electrostatic, hydrogen bonding, and hydrophobic interactions of Lys314 and Glu54 of the ACE2 receptor with the S1 domain are reported in studies using molecular docking models. 33 Threedimensional electron microscopy reconstruction of the RDB-ACE2-B 0 AT1 complex assisted to identify the specific molecular interactions.…”