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Barozi V, Tastan Bishop Ö. Impact of African-Specific ACE2 Polymorphisms on Omicron BA.4/5 RBD Binding and Allosteric Communication Within the ACE2-RBD Protein Complex. Int J Mol Sci 2025; 26:1367. [PMID: 39941135 PMCID: PMC11818624 DOI: 10.3390/ijms26031367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/27/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein's receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD-hACE2 interactions, potentially affecting viral infectivity across populations. This study identified the effects of six naturally occurring hACE2 polymorphisms with high allele frequency in the African population (S19P, K26R, M82I, K341R, N546D and D597Q) on the interaction with the S protein RBD of the BA.4/5 Omicron sub-lineage through post-molecular dynamics (MD), inter-protein interaction and dynamic residue network (DRN) analyses. Inter-protein interaction analysis suggested that the K26R variation, with the highest interactions, aligns with reports of enhanced RBD binding and increased SARS-CoV-2 susceptibility. Conversely, S19P, showing the fewest interactions and largest inter-protein distances, agrees with studies indicating it hinders RBD binding. The hACE2 M82I substitution destabilized RBD-hACE2 interactions, reducing contact frequency from 92 (WT) to 27. The K341R hACE2 variant, located distally, had allosteric effects that increased RBD-hACE2 contacts compared to WThACE2. This polymorphism has been linked to enhanced affinity for Alpha, Beta and Delta lineages. DRN analyses revealed that hACE2 polymorphisms may alter the interaction networks, especially in key residues involved in enzyme activity and RBD binding. Notably, S19P may weaken hACE2-RBD interactions, while M82I showed reduced centrality of zinc and chloride-coordinating residues, hinting at impaired communication pathways. Overall, our findings show that hACE2 polymorphisms affect S BA.4/5 RBD stability and modulate spike RBD-hACE2 interactions, potentially influencing SARS-CoV-2 infectivity-key insights for vaccine and therapeutic development.
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Affiliation(s)
- Victor Barozi
- Research Unit in Bioinformatics (RUBi), Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda 6139, South Africa;
| | - Özlem Tastan Bishop
- Research Unit in Bioinformatics (RUBi), Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda 6139, South Africa;
- National Institute for Theoretical and Computational Sciences (NITheCS), Matieland 7602, South Africa
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Shum MHH, Lee Y, Tam L, Xia H, Chung OLW, Guo Z, Lam TTY. Binding affinity between coronavirus spike protein and human ACE2 receptor. Comput Struct Biotechnol J 2024; 23:759-770. [PMID: 38304547 PMCID: PMC10831124 DOI: 10.1016/j.csbj.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 01/14/2024] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
Coronaviruses (CoVs) pose a major risk to global public health due to their ability to infect diverse animal species and potential for emergence in humans. The CoV spike protein mediates viral entry into the cell and plays a crucial role in determining the binding affinity to host cell receptors. With particular emphasis on α- and β-coronaviruses that infect humans and domestic animals, current research on CoV receptor use suggests that the exploitation of the angiotensin-converting enzyme 2 (ACE2) receptor poses a significant threat for viral emergence with pandemic potential. This review summarizes the approaches used to study binding interactions between CoV spike proteins and the human ACE2 (hACE2) receptor. Solid-phase enzyme immunoassays and cell binding assays allow qualitative assessment of binding but lack quantitative evaluation of affinity. Surface plasmon resonance, Bio-layer interferometry, and Microscale Thermophoresis on the other hand, provide accurate affinity measurement through equilibrium dissociation constants (KD). In silico modeling predicts affinity through binding structure modeling, protein-protein docking simulations, and binding energy calculations but reveals inconsistent results due to the lack of a standardized approach. Machine learning and deep learning models utilize simulated and experimental protein-protein interaction data to elucidate the critical residues associated with CoV binding affinity to hACE2. Further optimization and standardization of existing approaches for studying binding affinity could aid pandemic preparedness. Specifically, prioritizing surveillance of CoVs that can bind to human receptors stands to mitigate the risk of zoonotic spillover.
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Affiliation(s)
- Marcus Ho-Hin Shum
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- School of Public Health, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, China
| | - Yang Lee
- School of Public Health, The University of Hong Kong, Hong Kong, China
- Centre for Immunology and Infection (C2i), Hong Kong Science Park, Hong Kong, China
| | - Leighton Tam
- School of Public Health, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, China
| | - Hui Xia
- Department of Chemistry, South University of Science and Technology of China, China
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Oscar Lung-Wa Chung
- Department of Chemistry, South University of Science and Technology of China, China
| | - Zhihong Guo
- Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Tommy Tsan-Yuk Lam
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- School of Public Health, The University of Hong Kong, Hong Kong, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, China
- Centre for Immunology and Infection (C2i), Hong Kong Science Park, Hong Kong, China
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Salum GM, Abd El Meguid M, Fotouh BE, Dawood RM. Impacts of host factors on susceptibility to SARS-CoV-2 infection and COVID-19 progression. J Immunoassay Immunochem 2024; 45:493-517. [PMID: 39552098 DOI: 10.1080/15321819.2024.2429538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
SARS-CoV-2, identified in Wuhan, China, in December 2019, is the third coronavirus responsible for a global epidemic, following SARS-CoV (2002) and MERS-CoV (2012). Given the recent emergence of COVID-19, comprehensive immunological data are still limited. The susceptibility and severity of SARS-CoV-2 infection are influenced by various host factors, including hormonal changes, genetic variations, inflammatory biomarkers, and behavioral attitudes. Identifying genetic factors contributing to infection severity may accelerate therapeutic development, including drug repurposing, natural extracts, and post-vaccine interventions (Initiative and Covid, 2021). This review discusses the human protein machinery involved in (a) SARS-CoV-2 host receptors, (b) the human immune response, and (c) the impact of demographic and genetic differences on individual risk for COVID-19. This review aims to clarify host factors implicated in SARS-CoV-2 susceptibility and progression, highlighting potential therapeutic targets and supportive treatment strategies.
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Affiliation(s)
- Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Giza, Egypt
| | - Mai Abd El Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Giza, Egypt
| | - Basma E Fotouh
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Giza, Egypt
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Anwer F, Navid A, Faiz F, Haider U, Nasir S, Farooq M, Zahra M, Bano A, Bashir HH, Ahmad M, Abbas SA, Room SE, Saeed MT, Ali A. AbAMPdb: a database of Acinetobacter baumannii specific antimicrobial peptides. Database (Oxford) 2024; 2024:baae096. [PMID: 39395188 PMCID: PMC11470754 DOI: 10.1093/database/baae096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 10/14/2024]
Abstract
Acinetobacter baumannii has emerged as a prominent nosocomial pathogen, exhibiting a progressive rise in resistance to therapeutic interventions. This rise in resistance calls for alternative strategies. Here, we propose an alternative yet specialized resource on antimicrobial peptides (AMPs) against A. baumannii. Database 'AbAMPdb' is the manually curated collection of 300 entries containing the 250 experimental AMP sequences and 50 corresponding synthetic or mutated AMP sequences. The mutated sequences were modified with reported amino acid substitutions intended for decreasing the toxicity and increasing the antimicrobial potency. AbAMPdb also provides 3D models of all 300 AMPs, comprising 250 natural and 50 synthetic or mutated AMPs. Moreover, the database offers docked complexes comprising 5000 AMPs and their corresponding A. baumannii target proteins. These complexes, accessible in Protein Data Bank format, enable the 2D visualization of the interacting amino acid residues. We are confident that this comprehensive resource furnishes vital information concerning AMPs, encompassing their docking interactions with virulence factors and antibiotic resistance proteins of A. baumannii. To enhance clinical relevance, the characterized AMPs could undergo further investigation both in vitro and in vivo. Database URL: https://abampdb.mgbio.tech/.
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Affiliation(s)
- Farha Anwer
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Ahmad Navid
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Fiza Faiz
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Uzair Haider
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Samavi Nasir
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Muhammad Farooq
- Department of Medical Lab Technology, BIC, University of Harīpur, Haripur, Khyber Pakhtunkhwa 22620, Pakistan
| | - Maryam Zahra
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Anosh Bano
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Hafiza Hira Bashir
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Madiha Ahmad
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Syeda Aleena Abbas
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Shah E Room
- Xylexa Inc, National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Muhammad Tariq Saeed
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
| | - Amjad Ali
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan
- MGBIO (SMC-PRIVATE) Limited, C4 H Building 1, National Science and Technology Park, NUST, H-12, Islamabad 44000, Pakistan
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Elemam NM, Bouzid A, Alsafar H, Ahmed SBM, Hafezi S, Venkatachalam T, Eldohaji L, Al Hamidi T, Gerges PH, Halabi N, Hadj-Kacem H, Talaat IM, Taneera J, Sulaiman N, Maghazachi AA, Hamid Q, Hamoudi R, Saber-Ayad M. Association of specific ACE2 and TMPRSS2 variants with circulatory cytokines of COVID-19 Emirati patients. Front Immunol 2024; 15:1348229. [PMID: 38855114 PMCID: PMC11157456 DOI: 10.3389/fimmu.2024.1348229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 05/06/2024] [Indexed: 06/11/2024] Open
Abstract
INTRODUCTION The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. METHODS We compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. RESULTS Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1β, IL-2, IL-15, and IL-17A in COVID-19 patients. CONCLUSION Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.
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Affiliation(s)
- Noha M. Elemam
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Amal Bouzid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Habiba Alsafar
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Department of Biomedical Engineering, College of Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Emirates Bio-Research Centre, Ministry of Interior, Abu Dhabi, United Arab Emirates
| | - Samrein BM Ahmed
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Health, Wellbeing and Life Sciences, Department of Biosciences and Chemistry, Sheffield Hallam University, Sheffield, United Kingdom
| | - Shirin Hafezi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Thenmozhi Venkatachalam
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Physiology and Immunology College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Leen Eldohaji
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Tasneem Al Hamidi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Peter Habib Gerges
- School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Nour Halabi
- Al Jalila Genomics Center of Excellence, Al Jalila Children’s Specialty Hospital, Dubai, United Arab Emirates
| | - Hassen Hadj-Kacem
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Iman M. Talaat
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Jalal Taneera
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Nabil Sulaiman
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Family Medicine, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
| | - Rifat Hamoudi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Maha Saber-Ayad
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, Cairo University, Giza, Egypt
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Zhang Y, Chen S, Tian Y, Fu X. Host factors of SARS-CoV-2 in infection, pathogenesis, and long-term effects. Front Cell Infect Microbiol 2024; 14:1407261. [PMID: 38846354 PMCID: PMC11155306 DOI: 10.3389/fcimb.2024.1407261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/08/2024] [Indexed: 06/09/2024] Open
Abstract
SARS-CoV-2 is the causative virus of the devastating COVID-19 pandemic that results in an unparalleled global health and economic crisis. Despite unprecedented scientific efforts and therapeutic interventions, the fight against COVID-19 continues as the rapid emergence of different SARS-CoV-2 variants of concern and the increasing challenge of long COVID-19, raising a vast demand to understand the pathomechanisms of COVID-19 and its long-term sequelae and develop therapeutic strategies beyond the virus per se. Notably, in addition to the virus itself, the replication cycle of SARS-CoV-2 and clinical severity of COVID-19 is also governed by host factors. In this review, we therefore comprehensively overview the replication cycle and pathogenesis of SARS-CoV-2 from the perspective of host factors and host-virus interactions. We sequentially outline the pathological implications of molecular interactions between host factors and SARS-CoV-2 in multi-organ and multi-system long COVID-19, and summarize current therapeutic strategies and agents targeting host factors for treating these diseases. This knowledge would be key for the identification of new pathophysiological aspects and mechanisms, and the development of actionable therapeutic targets and strategies for tackling COVID-19 and its sequelae.
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Affiliation(s)
| | | | - Yan Tian
- Department of Endocrinology and Metabolism, Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Medical School, West China Hospital and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, Chengdu, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Medical School, West China Hospital and Cancer Center, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, Chengdu, China
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Yadav V, Ravichandran S. Significance of understanding the genomics of host-pathogen interaction in limiting antibiotic resistance development: lessons from COVID-19 pandemic. Brief Funct Genomics 2024; 23:69-74. [PMID: 36722037 DOI: 10.1093/bfgp/elad001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 12/15/2022] [Accepted: 01/09/2023] [Indexed: 02/02/2023] Open
Abstract
The entire world is facing the stiff challenge of COVID-19 pandemic. To overcome the spread of this highly infectious disease, several short-sighted strategies were adopted such as the use of broad-spectrum antibiotics and antifungals. However, the misuse and/or overuse of antibiotics have accentuated the emergence of the next pandemic: antimicrobial resistance (AMR). It is believed that pathogens while transferring between humans and the environment carry virulence and antibiotic-resistant factors from varied species. It is presumed that all such genetic factors are quantifiable and predictable, a better understanding of which could be a limiting step for the progression of AMR. Herein, we have reviewed how genomics-based understanding of host-pathogen interactions during COVID-19 could reduce the non-judicial use of antibiotics and prevent the eruption of an AMR-based pandemic in future.
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Affiliation(s)
- Vikas Yadav
- Department of Translational Medicine, Clinical Research Centre, Skaone University Hospital, Lund University, Malmo SE-20213, Sweden
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Longsompurana P, Rungrotmongkol T, Plongthongkum N, Wangkanont K, Wolschann P, Poo-arporn RP. Computational design of novel nanobodies targeting the receptor binding domain of variants of concern of SARS-CoV-2. PLoS One 2023; 18:e0293263. [PMID: 37874836 PMCID: PMC10597523 DOI: 10.1371/journal.pone.0293263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 10/09/2023] [Indexed: 10/26/2023] Open
Abstract
The COVID-19 pandemic has created an urgent need for effective therapeutic and diagnostic strategies to manage the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the emergence of numerous variants of concern (VOCs) has made it challenging to develop targeted therapies that are broadly specific in neutralizing the virus. In this study, we aimed to develop neutralizing nanobodies (Nbs) using computational techniques that can effectively neutralize the receptor-binding domain (RBD) of SARS-CoV-2 VOCs. We evaluated the performance of different protein-protein docking programs and identified HDOCK as the most suitable program for Nb/RBD docking with high accuracy. Using this approach, we designed 14 novel Nbs with high binding affinity to the VOC RBDs. The Nbs were engineered with mutated amino acids that interacted with key amino acids of the RBDs, resulting in higher binding affinity than human angiotensin-converting enzyme 2 (ACE2) and other viral RBDs or haemagglutinins (HAs). The successful development of these Nbs demonstrates the potential of molecular modeling as a low-cost and time-efficient method for engineering effective Nbs against SARS-CoV-2. The engineered Nbs have the potential to be employed in RBD-neutralizing assays, facilitating the identification of novel treatment, prevention, and diagnostic strategies against SARS-CoV-2.
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Affiliation(s)
- Phoomintara Longsompurana
- Biological Engineering Program, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
| | - Thanyada Rungrotmongkol
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Nongluk Plongthongkum
- Biological Engineering Program, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
| | - Kittikhun Wangkanont
- Center of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Molecular Crop, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Peter Wolschann
- Institute of Theoretical Chemistry, University of Vienna, Vienna, Austria
| | - Rungtiva P. Poo-arporn
- Biological Engineering Program, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
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Sahranavard-Pirbazari P, Khoshghiafeh A, Kamali MJ, Esfandiar H, Bakhtiari M, Ahmadifard M. A comprehensive review of ACE2, ACE1, TMPRSS2 and IFITM3 gene polymorphisms and their effect on the severity of COVID-19. Adv Med Sci 2023; 68:450-463. [PMID: 37926001 DOI: 10.1016/j.advms.2023.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/01/2023] [Accepted: 10/24/2023] [Indexed: 11/07/2023]
Abstract
Recent events have raised concerns about the outbreak of a pandemic by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An infection caused by a virus can provoke an inflammatory reaction, which can result in severe lung damage, failure of several organs, and death. The unique genetic makeup of each individual may be a component in the development of each of these responses. In this context, genetic variants of the genes linked to the invasion of the virus into the host's body can be analyzed. Various elements have a function in viral entry. ACE2 is used by SARS-CoV-2 as a receptor to enter the cell. TMPRSS2 is then responsible for cutting the virus into its components. In addition, lung damage occurs when there is an imbalance between ACE1 and ACE2. Another component that plays a significant role in virus penetration is called IFITM3, which is created as a reaction to interferon. This protein prevents viruses in the Coronaviridae family from entering cells. This study aimed to analyze DNA polymorphisms in the ACE2, ACE1, TMPRSS2, and IFITM3 genes. Findings showed certain polymorphisms appear to be associated with the severity of the disease, including respiratory, coronary, and neurological disorders. The results also indicated that certain polymorphisms were protective against this virus. Varying populations have a different frequency of high-risk polymorphisms, so different treatment and preventative techniques must be implemented. Additional population studies should be conducted in this region to reduce the incidence of COVID-19-related morbidity and mortality.
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Affiliation(s)
| | - Azin Khoshghiafeh
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Javad Kamali
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Hanieh Esfandiar
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Marzieh Bakhtiari
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohamadreza Ahmadifard
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Haycroft ER, Davis SK, Ramanathan P, Lopez E, Purcell RA, Tan LL, Pymm P, Wines BD, Hogarth PM, Wheatley AK, Juno JA, Redmond SJ, Gherardin NA, Godfrey DI, Tham WH, Selva KJ, Kent SJ, Chung AW. Antibody Fc-binding profiles and ACE2 affinity to SARS-CoV-2 RBD variants. Med Microbiol Immunol 2023:10.1007/s00430-023-00773-w. [PMID: 37477828 PMCID: PMC10372118 DOI: 10.1007/s00430-023-00773-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 06/26/2023] [Indexed: 07/22/2023]
Abstract
Emerging SARS-CoV-2 variants, notably Omicron, continue to remain a formidable challenge to worldwide public health. The SARS-CoV-2 receptor-binding domain (RBD) is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. Here, we comprehensively investigated the impact of RBD mutations, including 5 variants of concern (VOC) or interest-including Omicron (BA.2)-and 33 common point mutations, both on IgG recognition and ACE2-binding inhibition, as well as FcγRIIa- and FcγRIIIa-binding antibodies, in plasma from two-dose BNT162b2-vaccine recipients and mild-COVID-19 convalescent subjects obtained during the first wave using a custom-designed bead-based 39-plex array. IgG-recognition and FcγR-binding antibodies were decreased against the RBD of Beta and Omicron, as well as point mutation G446S, found in several Omicron sub-variants as compared to wild type. Notably, while there was a profound decrease in ACE2 inhibition against Omicron, FcγR-binding antibodies were less affected, suggesting that Fc functional antibody responses may be better retained against the RBD of Omicron in comparison to neutralization. Furthermore, while measurement of RBD-ACE2-binding affinity via biolayer interferometry showed that all VOC RBDs have enhanced affinity to human ACE2, we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695) has reduced affinity to VOCs, while K26R (rs4646116) and S19P (rs73635825) have increased binding kinetics to the RBD of VOCs, potentially affecting virus-host interaction and, thereby, host susceptibility. Collectively, our findings provide in-depth coverage of the impact of RBD mutations on key facets of host-virus interactions.
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Affiliation(s)
- Ebene R Haycroft
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Samantha K Davis
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Pradhipa Ramanathan
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Ester Lopez
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Ruth A Purcell
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Li Lynn Tan
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia
| | - Phillip Pymm
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Bruce D Wines
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - P Mark Hogarth
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Adam K Wheatley
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Jennifer A Juno
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Samuel J Redmond
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Nicholas A Gherardin
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Dale I Godfrey
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Wai-Hong Tham
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Kevin John Selva
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia.
| | - Stephen J Kent
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia.
- Melbourne Sexual Health Centre, Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.
| | - Amy W Chung
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia.
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11
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Devaux CA, Fantini J. ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus. Front Microbiol 2023; 14:1199561. [PMID: 37520374 PMCID: PMC10373931 DOI: 10.3389/fmicb.2023.1199561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/23/2023] [Indexed: 08/01/2023] Open
Abstract
Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus's affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare E329G allele of ACE2 with higher allele frequencies in European populations exhibit a improved affinity for the SARS-CoV-2 spike N501Y variant of the virus. This may suggest that this viral N501Y variant emerged in the human population after SARS-CoV-2 had infected a human carrying the rare E329G allele of ACE2. In addition, this viral evolution could impact viral replication as well as the ability of the adaptive humoral response to control infection with RBD-specific neutralizing antibodies. In a shifting landscape, this ACE2-driven genetic drift of SARS-CoV-2 which we have named the 'boomerang effect', could complicate the challenge of preventing COVID with a SARS-CoV-2 spike-derived vaccine.
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Affiliation(s)
- Christian A. Devaux
- Laboratory Microbes Evolution Phylogeny and Infection (MEPHI), Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Centre National de la Recherche Scientifique (CNRS-SNC5039), Marseille, France
| | - Jacques Fantini
- INSERM UMR_S1072, Marseille, France, Aix-Marseille Université, Marseille, France
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12
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Tekcan A, Cihangiroglu M, Capraz M, Capraz A, Yigit S, Nursal AF, Menekse E, Durmaz ZH, Dortok Demir H, Ozcelik B. Association of ACE ID, MTHFR C677T, and MIF-173GC variants with the clinical course of COVID-19 patients. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 42:782-796. [PMID: 36973934 DOI: 10.1080/15257770.2023.2194341] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/15/2023] [Accepted: 03/15/2023] [Indexed: 03/29/2023]
Abstract
The course of coronavirus disease-2019 (COVID-19) differs from person to person. The relationship between the genetic variations of the host and the course of COVID-19 has been a matter of interest. In this study, we investigated whether Angiotensin-Converting Enzyme (ACE) ID, Methylenetetrahydrofolate Reductase (MTHFR) C677T, and Macrophage Migration Inhibitory Factor (MIF)-173GC variants are risk factors for the clinical course of COVID-19 disease in Turkish patients. One hundred COVID-19 patients were included in the study. The diagnosis of COVID-19 was made using Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Chest Computed Tomography (CT). The patients were evaluated in 3 groups: intensive care, service, and outpatient treatment. ACE ID, MTHFR C677T, and MIF-173GC variants were genotyped by PCR-Restriction Fragment Length Polymorphism (RFLP) methods. When the genotype distribution between the groups was examined, it was found that the frequency of the ACE DD genotype and the D allele was higher in the intensive care group compared to the hospitalized and outpatient groups. MTHFR C677T CT genotype T allele and MIF-173GC, CC genotype C allele were more prevalent in the intensive care group compared to other groups. Patients with PCR-positive results had a higher MTHFR C677T C/C genotype and C allele. In CT-positive patients, the MTHFR C677T CT genotype and the MIF-173GC, G allele were more common. It is predicted that genetic predisposition may contribute to COVID-19 morbidity and mortality. Our results show that ACE ID, MTHFR C677T, and MIF-173GC variants affect the course of COVID-19 disease in the Turkish population.
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Affiliation(s)
- Akın Tekcan
- Faculty of Medicine, Department of Medical Biology, Amasya University, Amasya, Turkey
| | - Mustafa Cihangiroglu
- Faculty of Medicine, Department of Infectious Diseases, Amasya University, Amasya, Turkey
| | - Mustafa Capraz
- Faculty of Medicine, Department of Internal Medicine, Amasya University, Amasya, Turkey
| | - Aylin Capraz
- Faculty of Medicine, Department of Chest Diseases, Amasya University, Amasya, Turkey
| | - Serbülent Yigit
- Faculty of Veterinary Medicine, Department of Veterinary Genetics, Ondokuz Mayıs University, Samsun, Turkey
| | - Ayse Feyda Nursal
- Faculty of Medicine, Department of Medical Genetics, Hitit University, Corum, Turkey
| | - Elif Menekse
- Sabuncuoglu Serefeddin Education and Research Hospital, Biochemistry Clinic, Amasya, Turkey
| | - Zeynep Hülya Durmaz
- Sabuncuoglu Serefeddin Education and Research Hospital, Biochemistry Clinic, Amasya, Turkey
| | - Hatice Dortok Demir
- Faculty of Medicine, Department of Biochemistry, Amasya University, Amasya, Turkey
| | - Burak Ozcelik
- Sabuncuoglu Serefeddin Education and Research Hospital, Amasya, Turkey
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13
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Muhammad N, Naeemi H, Azeem A, Sadaqat R, Shehzad U, Siddique K, Hassan U, Raza A, Rashid MU. Genetic analysis of ACE2 peptidase domain in SARS-CoV-2-positive and SARS-CoV-2-negative individuals from Pakistan. Mol Biol Rep 2023; 50:4309-4316. [PMID: 36920597 PMCID: PMC10016156 DOI: 10.1007/s11033-023-08315-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/31/2023] [Indexed: 03/16/2023]
Abstract
BACKGROUND The outbreak of coronavirus disease 2019 (COVID-19) has emerged as a serious public health emergency of global concern. Angiotensin converting enzyme 2 (ACE2) peptidase domain is important for the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Germline variants in ACE2 peptidase domain may influence the susceptibility for SARS-CoV-2 infection and disease severity in the host population. ACE2 genetic analysis among Caucasians showed inconclusive results. This is the first Asian study investigating the contribution of ACE2 germline variants to SARS-CoV-2 infection in Pakistani population. METHODS In total, 442 individuals, including SARS-CoV-2-positive (n = 225) and SARS-CoV-2-negative (n = 217) were screened for germline variants in ACE2 peptidase domain (exons 2, 3, 9, and 10) using high resolution melting and denaturing high-performance liquid chromatography analyses followed by DNA sequencing of variant fragments. The identified variant was analyzed by in silico tools for potential effect on ACE2 protein. RESULTS A missense variant, p.Lys26Arg, was identified in one SARS-CoV-2-positive (1/225; 0.4%) and three SARS-CoV-2-negative (3/217; 1.4%) individuals. No significant difference in the minor allele frequency of this variant was found among SARS-CoV-2-positive and SARS-CoV-2-negative individuals (1/313; 0.3% versus 3/328; 0.9%; P = 0.624), respectively. The SARS-CoV-2-positive patient carrying p.Lys26Arg showed mild COVID-19 disease symptoms. It was predicted as benign variant by in silico tool. No variant was detected in ACE2 residues important for binding of SARS-CoV-2 spike protein. CONCLUSION The p.Lys26Arg variant may have no association with SARS-CoV-2 susceptibility in Pakistani population. Whole ACE2 gene screening is warranted to clarify its role in SARS-CoV-2 infection.
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Affiliation(s)
- Noor Muhammad
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan
| | - Humaira Naeemi
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan
| | - Ayesha Azeem
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan
| | - Rida Sadaqat
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan
| | - Umara Shehzad
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan
| | | | - Usman Hassan
- Department of Pathology, SKMCH&RC, Lahore, Pakistan
| | - Aun Raza
- Department of Internal Medicine, SKMCH&RC, Lahore, Pakistan
| | - Muhammad Usman Rashid
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), 7-A, Block R-3, Johar Town, Lahore, Pakistan.
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14
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Giotis ES, Cil E, Brooke GN. Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients. Viruses 2022; 14:2728. [PMID: 36560732 PMCID: PMC9788624 DOI: 10.3390/v14122728] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence, as well as immune and vaccine escape capabilities, highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to become infected by the virus, more likely to develop severe disease and exhibit a higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and, in particular, androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2, as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection, and antiandrogens could be used as a preventative measure at the pre- or early hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.
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Affiliation(s)
- Efstathios S. Giotis
- Department of Infectious Diseases, Imperial College London, London W2 1PG, UK
- School of Life Sciences, University of Essex, Colchester CO4 3SQ, UK
| | - Emine Cil
- School of Life Sciences, University of Essex, Colchester CO4 3SQ, UK
| | - Greg N. Brooke
- School of Life Sciences, University of Essex, Colchester CO4 3SQ, UK
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15
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Devaux CA, Camoin-Jau L. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection. Front Microbiol 2022; 13:1042200. [PMID: 36519165 PMCID: PMC9742611 DOI: 10.3389/fmicb.2022.1042200] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/07/2022] [Indexed: 08/01/2023] Open
Abstract
It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled "ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome"), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients' therapy.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Center National de la Recherche Scientifique, Marseille, France
| | - Laurence Camoin-Jau
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Laboratoire d’Hématologie, Hôpital de La Timone, APHM, Boulevard Jean-Moulin, Marseille, France
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16
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Nhung VP, Ton ND, Ngoc TTB, Thuong MTH, Hai NTT, Oanh KTP, Hien LTT, Thach PN, Hai NV, Ha NH. Host Genetic Risk Factors Associated with COVID-19 Susceptibility and Severity in Vietnamese. Genes (Basel) 2022; 13:1884. [PMID: 36292769 PMCID: PMC9601961 DOI: 10.3390/genes13101884] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Since the emergence and rapid transmission of SARS-CoV-2, numerous scientific reports have searched for the association of host genetic variants with COVID-19, but the data are mostly acquired from Europe. In the current work, we explored the link between host genes (SARS-CoV-2 entry and immune system related to COVID-19 sensitivity/severity) and ABO blood types with COVID-19 from whole-exome data of 200 COVID-19 patients and 100 controls in Vietnam. The O blood type was found to be a protective factor that weakens the worst outcomes of infected individuals. For SARS-CoV-2 susceptibility, rs2229207 (TC genotype, allele C) and rs17860118 (allele T) of IFNAR2 increased the risk of infection, but rs139940581 (CT genotype, allele T) of SLC6A20 reduced virus sensitivity. For COVID-19 progress, the frequencies of rs4622692 (TG genotype) and rs1048610 (TC genotype) of ADAM17 were significantly higher in the moderate group than in the severe/fatal group. The variant rs12329760 (AA genotype) of TMPRSS2 was significantly associated with asymptomatic/mild symptoms. Additionally, rs2304255 (CT genotype, allele T) of TYK2 and rs2277735 (AG genotype) of DPP9 were associated with severe/fatal outcomes. Studies on different populations will give better insights into the pathogenesis, which is ethnic-dependent, and thus decipher the genetic factor's contribution to mechanisms that predispose people to being more vulnerable to COVID-19.
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Affiliation(s)
- Vu Phuong Nhung
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Nguyen Dang Ton
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Tran Thi Bich Ngoc
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Ma Thi Huyen Thuong
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Nguyen Thi Thanh Hai
- National Hospital for Tropical Disease, Kim Chung, Dong Anh, Hanoi 100000, Vietnam
- Department of Biochemistry, Hanoi Medical University, 1 Ton That Tung, Dong Da, Hanoi 100000, Vietnam
| | - Kim Thi Phuong Oanh
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Le Thi Thu Hien
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Pham Ngoc Thach
- National Hospital for Tropical Disease, Kim Chung, Dong Anh, Hanoi 100000, Vietnam
| | - Nong Van Hai
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
| | - Nguyen Hai Ha
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
- Faculty of Biotechnology, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
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17
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Hattori T, Saito T, Okuya K, Takahashi Y, Miyamoto H, Kajihara M, Igarashi M, Takada A. Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells. Microbiol Spectr 2022; 10:e0087022. [PMID: 35862965 PMCID: PMC9430119 DOI: 10.1128/spectrum.00870-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/27/2022] [Indexed: 11/29/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 have a single envelope glycoprotein (S protein) that binds to human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. Previous mutational scanning studies have suggested that some substitutions corresponding to single nucleotide variants (SNVs) in human ACE2 affect the binding affinity to the receptor binding domain (RBD) of the SARS-CoV-2 S protein. However, the importance of these substitutions in actual virus infection is still unclear. In this study, we investigated the effects of the reported ACE2 SNV substitutions on the entry of SARS-CoV and SARS-CoV-2 into cells, using vesicular stomatitis Indiana virus (VSIV) pseudotyped with S proteins of these coronaviruses (CoVs). HEK293T cells transfected with plasmids expressing ACE2 having each SNV substitution were infected with the pseudotyped VSIVs and relative infectivities were determined compared to the cells expressing wild-type ACE2. We found that some of the SNV substitutions positively or negatively affected the infectivities of the pseudotyped viruses. Particularly, the H505R substitution significantly enhanced the infection with the pseudotyped VSIVs, including those having the substitutions found in the S protein RBD of SARS-CoV-2 variants of concern. Our findings suggest that human ACE2 SNVs may potentially affect cell susceptibilities to SARS-CoV and SARS-CoV-2. IMPORTANCE SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells. The interaction between the S protein and ACE2 is thought to be important for host susceptibility to these CoVs. Although previous studies suggested that some SNV substitutions in ACE2 might affect the binding to the S protein, it remains elusive whether these SNV substitutions actually alter the efficiency of the entry of SARS CoVs into cells. We analyzed the impact of the ACE2 SNVs on the cellular entry of SARS CoVs using pseudotyped VSIVs having the S protein on the viral surface. We found that some of the SNV substitutions positively or negatively affected the infectivities of the viruses. Our data support the notion that genetic polymorphisms of ACE2 may potentially influence cell susceptibilities to SARS CoVs.
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Affiliation(s)
- Takanari Hattori
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Takeshi Saito
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Kosuke Okuya
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Yuji Takahashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Masahiro Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Manabu Igarashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia
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18
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Ma Y, Li Q, Chen J, Liu S, Liu S, He X, Ling Y, Zheng J, Corpe C, Lu H, Wang J. Angiotensin-Converting Enzyme 2 SNPs as Common Genetic Loci and Optimal Early Identification Genetic Markers for COVID-19. Pathogens 2022; 11:947. [PMID: 36015068 PMCID: PMC9415427 DOI: 10.3390/pathogens11080947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/08/2022] [Accepted: 08/16/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Angiotensin-converting enzyme 2 (ACE2) is implicated as a host cell receptor that causes infection in the pathogenesis of coronavirus disease 2019 (COVID-19), and its genetic polymorphisms in the ACE2 gene may promote cardiovascular disease and systemic inflammatory injury in COVID-19 patients. Hence, the genetic background may potentially explain the broad interindividual variation in disease susceptibility and/or severity. Methods: Genetic susceptibility to COVID-19 was analyzed by examining single-nucleotide polymorphisms (SNPs) of ACE2 in 246 patients with COVID-19 and 210 normal controls using the TaqMan genotyping assay. Results: We demonstrated that the ACE2 SNPs rs4646142, rs6632677, and rs2074192 were associated with COVID-19 (for all, p < 0.05), and the differences in the ACE2 SNPs rs4646142 and rs6632677 were correlated with COVID-19-related systemic inflammatory injury and cardiovascular risk. Specifically, rs4646142 was associated with high-sensitivity C-reactive protein (hs-CRP), prealbumin (PAB), apolipoprotein A (APOA), high-density lipoprotein (HDL), and acid glycoprotein (AGP) levels. Rs6632677 was also associated with elevated CRP, acid glycoprotein (AGP), and haptoglobin (HPT). Conclusions: Our results suggest that the ACE2 SNPs rs4646142 and rs6632677 may be common genetic loci and optimal early identification genetic markers for COVID-19 with cardiovascular risk.
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Affiliation(s)
- Yan Ma
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Qiuyue Li
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Jun Chen
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Songmei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Shanshan Liu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Xiaomeng He
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yun Ling
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Jianghua Zheng
- Department of Laboratory Medicine, Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
| | - Christopher Corpe
- Nutritional Science Department, King’s College London, 150 Stamford Street, Waterloo, London SE1 9NH, UK
| | - Hongzhou Lu
- National Clinical Research Centre for Infectious Diseases, The Third People’s Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, China
| | - Jin Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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19
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Wang B, Gamazon ER. Modeling mutational effects on biochemical phenotypes using convolutional neural networks: application to SARS-CoV-2. iScience 2022; 25:104500. [PMID: 35669036 PMCID: PMC9159778 DOI: 10.1016/j.isci.2022.104500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 11/15/2021] [Accepted: 05/26/2022] [Indexed: 11/29/2022] Open
Abstract
Deep mutational scanning (DMS) experiments have been performed on SARS-CoV-2’s spike receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2) zinc-binding peptidase domain—both central players in viral infection and evolution and antibody evasion—quantifying how mutations impact biochemical phenotypes. We modeled biochemical phenotypes from massively parallel assays, using neural networks trained on protein sequence mutations in the virus and human host. Neural networks were significantly predictive of binding affinity, protein expression, and antibody escape, learning complex interactions and higher-order features that are difficult to capture with conventional methods from structural biology. Integrating the physicochemical properties of amino acids, such as hydrophobicity and long-range non-bonded energy per atom, significantly improved prediction (empirical p < 0.01). We observed concordance of the neural network predictions with molecular dynamics (multiple 500 ns or 1 μs all-atom) simulations of the spike protein-ACE2 interface, with critical implications for the use of deep learning to dissect molecular mechanisms.
Deep learning models of biochemical phenotypes from deep mutational scanning (DMS) data Prediction performance gain from using physicochemical properties of amino acids Concordance of neural network predictions with molecular dynamics simulations Improved causal inference properties for neural-network-defined phenotypes
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Affiliation(s)
- Bo Wang
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Eric R Gamazon
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.,Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.,Data Science Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.,Clare Hall, University of Cambridge, Cambridge CB3 9AL, UK
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20
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Gao K, Wang R, Chen J, Cheng L, Frishcosy J, Huzumi Y, Qiu Y, Schluckbier T, Wei X, Wei GW. Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2. Chem Rev 2022; 122:11287-11368. [PMID: 35594413 PMCID: PMC9159519 DOI: 10.1021/acs.chemrev.1c00965] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein-protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.
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Affiliation(s)
- Kaifu Gao
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Rui Wang
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Jiahui Chen
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Limei Cheng
- Clinical
Pharmacology and Pharmacometrics, Bristol
Myers Squibb, Princeton, New Jersey 08536, United States
| | - Jaclyn Frishcosy
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Yuta Huzumi
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Yuchi Qiu
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Tom Schluckbier
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Xiaoqi Wei
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
| | - Guo-Wei Wei
- Department
of Mathematics, Michigan State University, East Lansing, Michigan 48824, United States
- Department
of Electrical and Computer Engineering, Michigan State University, East Lansing, Michigan 48824, United States
- Department
of Biochemistry and Molecular Biology, Michigan
State University, East Lansing, Michigan 48824, United States
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21
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Comparative genomics, evolutionary epidemiology, and RBD-hACE2 receptor binding pattern in B.1.1.7 (Alpha) and B.1.617.2 (Delta) related to their pandemic response in UK and India. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 101:105282. [PMID: 35427787 PMCID: PMC9005225 DOI: 10.1016/j.meegid.2022.105282] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 04/04/2022] [Accepted: 04/08/2022] [Indexed: 02/07/2023]
Abstract
Background The massive increase in COVID-19 infection had generated a second wave in India during May–June 2021 with a critical pandemic situation. The Delta variant (B.1.617.2) was a significant factor during the second wave. Conversely, the UK had passed through the crucial phase of the pandemic from November to December 2020 due to B.1.1.7. The study tried to comprehend the pandemic response in the UK and India to the spread of the B.1.1.7 (Alpha, UK) variant and B.1.617.2 (Delta, India) variant. Methods This study was performed in three directions to understand the pandemic response of the two emerging variants. First, we served comparative genomics, such as genome sequence submission patterns, mutational landscapes, and structural landscapes of significant mutations (N501Y, D614G, L452R, E484Q, and P681R). Second, we performed evolutionary epidemiology using molecular phylogenetics, scatter plots of the cluster evaluation, country-wise transmission pattern, and frequency pattern. Third, the receptor binding pattern was analyzed using the Wuhan reference strain and the other two variants. Results The study analyzed the country-wise and region-wise genome sequences and their submission pattern, molecular phylogenetics, scatter plot of the cluster evaluation, country-wise geographical distribution and transmission pattern, frequency pattern, entropy diversity, and mutational landscape of the two variants. The structural pattern was analyzed in the N501Y, D614G L452R, E484Q, and P681R mutations. The study found increased molecular interactivity between hACE2-RBD binding of B.1.1.7 and B.1.617.2 compared to the Wuhan reference strain. Our receptor binding analysis showed a similar indication pattern for hACE2-RBD of these two variants. However, B.1.617.2 offers slightly better stability in the hACE2-RBD binding pattern through MD simulation than B.1.1.7. Conclusion The increased hACE2-RBD binding pattern of B.1.1.7 and B.1.617.2 might help to increase the infectivity compared to the Wuhan reference strain.
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22
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Muslim Dawood S, Khudhur Al Joofy I. Evaluation of IgM and IgG in COVID-19 Recovered Patients in Iraq. ARCHIVES OF RAZI INSTITUTE 2022; 77:1191-1197. [PMID: 36618307 PMCID: PMC9759244 DOI: 10.22092/ari.2022.357515.2054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023]
Abstract
Severe acute respiratory syndrome coronavirus-2 is a major threat to health care worldwide with high morbidity and mortality. Therefore, understanding the role of immune mechanisms and humoral response is vital in this disease. The present study aimed to investigate the relationship between Immunoglobulins (IgM, IgG) in COVID-19 recovered patients with age, gender, and severity of the disease. The duration of effect of antibody levels and protection against re-infection has also been evaluated in the patients. Three groups participated in this study; group 1: 0-14 days after recovery, group 2: 2 months after recovery, group 3: 3 months after recovery, group 4: 4-6 months after recovery, group 5: more than 6 months. The nasopharyngeal swab was used to confirm recovery by Real-Time Polymerase Chain Reaction (RT-PCR) technique. IgM and IgG antibody levels were evaluated using Enzyme-Linked Immuno Fluorescent Assay (ELIFA) technique. The results indicated that the IgM levels increased for one month during the seven days after infection and then decreased in most patients (P≤0.05). The mean of IgG in group 1 increased compared to those of other studied groups. A significant decrease was observed in group 2 compared to group 1, as well as in group 3 compared to groups 1, and 2. Also, a significant difference existed between group 4 compared to groups 1, 2, and 3. Finally, significant differences were noticed between group 5 compared to groups 1, 2, 3, and 4 (P≤0.05). No significant differences were observed in antibodies level between male, and female COVID-19 recovered patients in groups 1, 2, 3, 4, and 5 (P≤0.05). Finally, highly significant differences in IgG levels between mild, moderate, and severe subgroups in groups 1 and 2. The present study demonstrated that IgM and IgG against SARS-CoV-2 appeared in the early stages of the disease and decreased after 1 month and failed to maintain high levels during the 6-month observation.
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Affiliation(s)
- S Muslim Dawood
- Educational Laboratories, Unit of Clinical Immunology, Baghdad Medical City, Baghdad, Iraq
| | - I Khudhur Al Joofy
- Department of Biology, College of Science, Mustansiriyah University, Baghdad, Iraq
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23
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Hu P, Bauer VL, Sawyer SL, Diaz-Griffero F. Human ACE2 Polymorphisms from Different Human Populations Modulate SARS-CoV-2 Infection. Viruses 2022; 14:1451. [PMID: 35891433 PMCID: PMC9319759 DOI: 10.3390/v14071451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 6 million deaths worldwide. The high variability in COVID-19 symptoms remains one of the most interesting mysteries of the pandemic. Genetic and environmental factors are likely to be key determinants of COVID-19 symptomatology. Here, we explored ACE2 as a genetic determinant for SARS-CoV-2 infection and COVID-19 symptomatology. Each human genome encodes two alleles of ACE2, which encodes the cell entry receptor for SARS-CoV-2. Here, we determined whether naturally occurring human ACE2 (hACE2) polymorphisms in the human population affect SARS-CoV-2 infection and the severity of COVID-19 symptoms. ACE2 variants S19P, I21V, E23K, K26R, K31R, N33I, H34R, E35K, and T92I showed increased virus infection compared to wild-type ACE2; thus, these variants could increase the risk for COVID-19. In contrast, variants D38V, Y83H, I468V, and N638S showed reduced infection, indicating a potential protective effect. hACE2 variants K26R and T92I increased infection by three-fold without changing the levels of ACE2 on the surface of the cells, suggesting that these variants may increase the risk of severe COVID-19. On the contrary, hACE2 variants D38V and Y83H decreased SARS-CoV-2 infection by four- and ten-fold, respectively, without changing surface expression, suggesting that these variants may protect against severe COVID-19. Remarkably, all protective hACE2 Polymorphisms were found almost exclusively in Asian populations, which may provide a partial explanation for the low COVID-19 mortality rates in Asian countries. Thus, hACE2 polymorphisms may modulate susceptibility to SARS-CoV-2 in the host and partially account for the differences in severity of COVID-19 among different ethnic groups.
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Affiliation(s)
- Pan Hu
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Vanessa L. Bauer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80303, USA; (V.L.B.); (S.L.S.)
| | - Sara L. Sawyer
- BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80303, USA; (V.L.B.); (S.L.S.)
| | - Felipe Diaz-Griffero
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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24
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Wang Y, Wu M, Li Y, Yuen HH, He ML. The effects of SARS-CoV-2 infection on modulating innate immunity and strategies of combating inflammatory response for COVID-19 therapy. J Biomed Sci 2022; 29:27. [PMID: 35505345 PMCID: PMC9063252 DOI: 10.1186/s12929-022-00811-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/27/2022] [Indexed: 12/15/2022] Open
Abstract
The global pandemic of COVID-19 has caused huge causality and unquantifiable loss of social wealth. The innate immune response is the first line of defense against SARS-CoV-2 infection. However, strong inflammatory response associated with dysregulation of innate immunity causes severe acute respiratory syndrome (SARS) and death. In this review, we update the current knowledge on how SARS-CoV-2 modulates the host innate immune response for its evasion from host defense and its corresponding pathogenesis caused by cytokine storm. We emphasize Type I interferon response and the strategies of evading innate immune defense used by SARS-CoV-2. We also extensively discuss the cells and their function involved in the innate immune response and inflammatory response, as well as the promises and challenges of drugs targeting excessive inflammation for antiviral treatment. This review would help us to figure out the current challenge questions of SARS-CoV-2 infection on innate immunity and directions for future studies.
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Affiliation(s)
- Yiran Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Mandi Wu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Yichen Li
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Ho Him Yuen
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China. .,CityU Shenzhen Research Institute, Nanshan, Shenzhen, China.
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25
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Ghamdi FA, Naqvi S, Alabassi FA, Alhayyani S, Baig MR, Kumar V, Anwar F. Alterations in clinical characteristics of blood donors post COVID-19 recovery. Curr Pharm Des 2022; 28:981-992. [PMID: 35319357 DOI: 10.2174/1381612828666220322123225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/31/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Corona Virus Disease-19 (COVID-19), a current worldwide pandemic is a cuase of concern. Risk-adjusted differences in outcomes of the patients are not well characterized. Susceptibility to infection with respect to blood group, blood pressure, pulse rate, hemoglobin, age and BMI were analyzed. METHODS Blood donors, of all the ages and gender, who recovered from COVID-19 infection, were selected for the study Samples from Regional laboratory and the Central blood bank of Hafr al Batin, Saudi Arabia were collected. Out of 1508 healthy blood donor 134 had recovered from corona without any preexisting diseases. RESULTS Major donors were male (85.1%). 28% donors in age range of 26-35 years. O+(32.8%) were the highest donors. Systolic and diastolic blood pressure and pulse rate elevated significantly of age group 46-55 (p<0.05) and 56-65 (p<0.001). Systolic blood pressure in males (134.13 ± 9.57) was significantly higher (p<0.05) than those of females (129.35 ± 10.61). Donors with Rh+ significantly higher systolic (p<0.05) and pulse rate (p<0.05) as compared to Rh-. DISCUSSION O+ donors were highly susceptible. Blood pressure, pulse rate and Hb alter with age. Males exhibit higher variation in systolic blood pressure, with Rh+ factor playing a predominant role. Donors above 45-years of age and a high BMI have significantly elevated blood pressure and pulse. These results are challenging or contradictory from the results of Turkish and Chinese studies where blood group A+ was more predominantly affected by the SARS-CoV-2 with minimum infection rate on females and Rh- donors. CONCLUSION Factors like blood group V-2 treatment especially with the age group of 45 years and above.
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Affiliation(s)
- Fahad Al Ghamdi
- King Abdulaziz University, Department of Biochemistry, P.O. Box 80203 Jeddah 21589
| | - Salma Naqvi
- Gulf Medical University, Department of Biomedical Sciences, Ajman
| | - Fahad A Alabassi
- King Abdulaziz University, Department of Biochemistry, P.O. Box 80203 Jeddah 21589
| | - Sultan Alhayyani
- King Abdulaziz University, Department of Chemistry. College of Sciences & Arts, Rabigh
| | - Mirza Rafi Baig
- Dubai Pharmacy College, Department of Biochemistry; Sam Higginbottom Institute of Agriculture, Pharmaceutical sciences, Allahabad
| | - Vikas Kumar
- Dubai Pharmacy College, Department of Biochemistry; Sam Higginbottom Institute of Agriculture, Pharmaceutical sciences, Allahabad
| | - Firoz Anwar
- King Abdulaziz University, Department of Biochemistry, P.O. Box 80203 Jeddah 21589
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26
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Alimoradi N, Sharqi M, Firouzabadi D, Sadeghi MM, Moezzi MI, Firouzabadi N. SNPs of ACE1 (rs4343) and ACE2 (rs2285666) genes are linked to SARS-CoV-2 infection but not with the severity of disease. Virol J 2022; 19:48. [PMID: 35305693 PMCID: PMC8934128 DOI: 10.1186/s12985-022-01782-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/10/2022] [Indexed: 01/08/2023] Open
Abstract
COVID-19 and the renin-angiotensin system (RAS) are linked by angiotensin-converting enzyme 2 (ACE2), a key enzyme in RAS that has been validated as a SARS-CoV-2 receptor. Functional ACE1/ACE2 gene polymorphisms may lead to the imbalance between ACE/ACE2 ratio and thus generating RAS imbalance that is associated with higher degrees of lung damage in ARDS that may contribute to the COVID-19 infection outcome. Herein, we investigated the role of RAS gene polymorphisms, ACE1 (A2350G) and ACE2 (G8790A) as risk predictors for susceptibility and severity of COVID-19 infection. A total of 129 included: negative controls without a history of COVID-19 infection (n = 50), positive controls with a history of COVID-19 infection who were not hospitalized (n = 35), and patients with severe COVID-19 infection who were hospitalized in the intensive care unit (n = 44). rs4343 of ACE and rs2285666 of ACE2 were genotyped using PCR-RFLP method. Our results indicated that susceptibility to COVID-19 infection was associated with age, GG genotype of A2350G (Pa = 0.01; OR 4.7; 95% CI 1.4-15.1 and Pc = 0.040; OR 2.5; 95% CI 1.05-6.3) and GG genotype of G8790A (Pa = 0.044; OR 6.17; 95% CI 1.05-35.71 and Pc = 0.0001; OR 5.5; 95% CI 2.4-12.4). The G allele of A2350G (Pa = 0.21; OR 1.74; 95% CI 0.73-4.17 and Pc = 0.007; OR 2.1; 95% CI 1.2-3.5) and G allele of G8790A (Pa = 0.002; OR 4.26; 95% CI 1.7-10.65 and Pc = 0.0001; OR 4.7; 95% CI 2.4-9.2) were more frequent in ICU-admitted patients and positive control group. Also lung involvement due to COVID-19 infection was associated with age and the comorbidities such as diabetes. In conclusion, our findings support the association between the wild genotype (GG) of ACE2 and homozygote genotype (GG) of ACE1 and sensitivity to COVID-19 infection, but not its severity. However, confirmation of this hypothesis requires further studies with more participants.
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Affiliation(s)
- Nahid Alimoradi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Moein Sharqi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Dena Firouzabadi
- Shahid Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
- Clinical Pharmacy Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Moein Sadeghi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Iman Moezzi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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27
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Jang KK, Kaczmarek ME, Dallari S, Chen YH, Tada T, Axelrad J, Landau NR, Stapleford KA, Cadwell K. Variable susceptibility of intestinal organoid-derived monolayers to SARS-CoV-2 infection. PLoS Biol 2022; 20:e3001592. [PMID: 35358182 PMCID: PMC9004766 DOI: 10.1371/journal.pbio.3001592] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 04/12/2022] [Accepted: 03/04/2022] [Indexed: 01/08/2023] Open
Abstract
Gastrointestinal effects associated with Coronavirus Disease 2019 (COVID-19) are highly variable for reasons that are not understood. In this study, we used intestinal organoid-derived cultures differentiated from primary human specimens as a model to examine interindividual variability. Infection of intestinal organoids derived from different donors with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in orders of magnitude differences in virus replication in small intestinal and colonic organoid-derived monolayers. Susceptibility to infection correlated with angiotensin I converting enzyme 2 (ACE2) expression level and was independent of donor demographic or clinical features. ACE2 transcript levels in cell culture matched the amount of ACE2 in primary tissue, indicating that this feature of the intestinal epithelium is retained in the organoids. Longitudinal transcriptomics of organoid-derived monolayers identified a delayed yet robust interferon signature, the magnitude of which corresponded to the degree of SARS-CoV-2 infection. Interestingly, virus with the Omicron variant spike (S) protein infected the organoids with the highest infectivity, suggesting increased tropism of the virus for intestinal tissue. These results suggest that heterogeneity in SARS-CoV-2 replication in intestinal tissues results from differences in ACE2 levels, which may underlie variable patient outcomes.
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Affiliation(s)
- Kyung Ku Jang
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Maria E. Kaczmarek
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Simone Dallari
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Ying-Han Chen
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Takuya Tada
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Jordan Axelrad
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Nathaniel R. Landau
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Kenneth A. Stapleford
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States of America
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Acharjee A, Stephen Kingsly J, Kamat M, Kurlawala V, Chakraborty A, Vyas P, Vaishnav R, Srivastava S. Rise of the SARS-CoV-2 Variants: can proteomics be the silver bullet? Expert Rev Proteomics 2022; 19:197-212. [PMID: 35655386 DOI: 10.1080/14789450.2022.2085564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION The challenges posed by emergent strains of SARS-CoV-2 need to be tackled by contemporary scientific approaches, with proteomics playing a significant role. AREAS COVERED In this review, we provide a brief synthesis of the impact of proteomics technologies in elucidating disease pathogenesis and classifiers for the prognosis of COVID-19 and propose proteomics methodologies that could play a crucial role in understanding emerging variants and their altered disease pathology. From aiding the design of novel drug candidates to facilitating the identification of T cell vaccine targets, we have discussed the impact of proteomics methods in COVID-19 research. Techniques varied as mass spectrometry, single-cell proteomics, multiplexed ELISA arrays, high-density proteome arrays, surface plasmon resonance, immunopeptidomics, and in silico docking studies that have helped augment the fight against existing diseases were useful in preparing us to tackle SARS-CoV-2 variants. We also propose an action plan for a pipeline to combat emerging pandemics using proteomics technology by adopting uniform standard operating procedures and unified data analysis paradigms. EXPERT OPINION The knowledge about the use of diverse proteomics approaches for COVID-19 investigation will provide a framework for future basic research, better infectious disease prevention strategies, improved diagnostics, and targeted therapeutics.
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Affiliation(s)
- Arup Acharjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | | | - Madhura Kamat
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed-to-be University), Mumbai, India
| | - Vishakha Kurlawala
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed-to-be University), Mumbai, India
| | | | - Priyanka Vyas
- Department of Biotechnology and Botany, Mahila PG Mahavidyalaya, J. N. V University, Jodhpur, India
| | - Radhika Vaishnav
- Department of Life Sciences, Ivy Tech Community College, Indianapolis, Indiana, USA
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
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da Silva Torres MK, Bichara CDA, de Almeida MDNDS, Vallinoto MC, Queiroz MAF, Vallinoto IMVC, dos Santos EJM, de Carvalho CAM, Vallinoto ACR. The Complexity of SARS-CoV-2 Infection and the COVID-19 Pandemic. Front Microbiol 2022; 13:789882. [PMID: 35222327 PMCID: PMC8870622 DOI: 10.3389/fmicb.2022.789882] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the death of millions of people worldwide and thousands more infected individuals developed sequelae due to the disease of the new coronavirus of 2019 (COVID-19). The development of several studies has contributed to the knowledge about the evolution of SARS-CoV2 infection and the disease to more severe forms. Despite this information being debated in the scientific literature, many mechanisms still need to be better understood in order to control the spread of the virus and treat clinical cases of COVID-19. In this article, we carried out an extensive literature review in order to bring together, in a single article, the biological, social, genetic, diagnostic, therapeutic, immunization, and even socioeconomic aspects that impact the SAR-CoV-2 pandemic. This information gathered in this article will enable a broad and consistent reading of the main aspects related to the current pandemic.
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Affiliation(s)
- Maria Karoliny da Silva Torres
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
| | - Carlos David Araújo Bichara
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
| | - Maria de Nazaré do Socorro de Almeida
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
- Laboratory of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Mariana Cayres Vallinoto
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
- University Center of the State of Pará, Belém, Brazil
| | - Maria Alice Freitas Queiroz
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
| | | | - Eduardo José Melo dos Santos
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
- Laboratory of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | | | - Antonio Carlos R. Vallinoto
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém, Brazil
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Lashgari NA, Momeni Roudsari N, Momtaz S, Abdolghaffari AH. Transmembrane serine protease 2 and angiotensin-converting enzyme 2 anti-inflammatory receptors for COVID-19/inflammatory bowel diseases treatment. World J Gastroenterol 2021; 27:7943-7955. [PMID: 35046622 PMCID: PMC8678820 DOI: 10.3748/wjg.v27.i46.7943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/12/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) refer to a subgroup of chronic, progressive, long-term, and relapsing inflammatory disorders. IBD may spontaneously grow in the colon, and in severe cases may result in tumor lesions such as invasive carcinoma in inflamed regions of the intestine. Recent epidemiological reports indicate that old age and underlying diseases such as IBD contribute to severity and mortality in patients with coronavirus disease 2019 (COVID-19). Currently, the ongoing COVID-19 pandemic caused serious morbidity and mortality worldwide. It has also been shown that the transmembrane serine protease 2 is an essential factor for viral activation and viral engulfment. Generally, viral entry causes a 'cytokine storm' that induces excessive generation of proinflammatory cytokines/chemokines including interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor-α, and interferon-γ. Future research could concentrate on developing inflammatory immunological responses that are efficient to encounter COVID-19. Current analysis elucidates the role of inflammation and immune responses during IBD infection with COVID-19 and provides a list of possible targets for IBD-regulated therapies in particular. Data from clinical, in vitro, and in vivo studies were collected in English from PubMed, Google Scholar, Scopus, and the Cochrane library until May 2021.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj 141554364, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran 1941933111, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj 141554364, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1941933111, Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran 1941933111, Iran
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Paniri A, Hosseini MM, Akhavan-Niaki H. Impact of new UK (B.1.1.7) SARS-Cov-2 variant on interacting with ACE2 and host immune response. GENE REPORTS 2021; 25:101342. [PMID: 34493993 PMCID: PMC8414842 DOI: 10.1016/j.genrep.2021.101342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 11/25/2022]
Affiliation(s)
- Alireza Paniri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Haleh Akhavan-Niaki
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
- Zoonoses Research Center, Pasteur Institute of Iran, Amol, Iran
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Calcagnile M, Verri T, Tredici MS, Forgez P, Alifano M, Alifano P. Codon usage, phylogeny and binding energy estimation predict the evolution of SARS-CoV-2. One Health 2021; 13:100352. [PMID: 34841034 PMCID: PMC8610831 DOI: 10.1016/j.onehlt.2021.100352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/04/2022] Open
Abstract
In the frames of a One Health strategy, i.e. a strategy should be able to predict susceptibility to infection in both humans and animals, developing a SARS-CoV-2 mutation tracking system is a goal. We observed that the phylogenetic proximity of vertebrate ACE2 receptors does not affect the binding energy for the viral spike protein. However, all viral variants seem to bind ACE2 better in many animals than in humans. Moreover, two observations highlight that the evolution of the virus started at the beginning of 2020 and culminated with the appearance of the variants. First, codon usage analysis shows that the B.1.1.7 (alpha), B.1.351 (beta) and B.1.617.2 (delta) variants, similar in the use of codons, are also similar to a virus sampled in January 2020. Second, the host-specific D614G mutation becomes prevalent starting from March 2020. Overall, we show that SARS-CoV-2 undergoes a process of molecular evolution that begins with the optimization of codons followed by the functional optimization of the spike protein.
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Affiliation(s)
- Matteo Calcagnile
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy
| | - Tiziano Verri
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy
| | - Maurizio Salvatore Tredici
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy
| | - Patricia Forgez
- INSERM UMR-S 1124 T3S, Eq 5 Cellular Homeostasis, Cancer and Therapy, University of Paris, Campus Saint Germain, Paris, France
| | - Marco Alifano
- Thoracic Surgery Department, Cochin Hospital, APHP Centre, University of Paris, France
- INSERM U1138 Team «Cancer, Immune Control, and Escape», Cordeliers Research Center, University of Paris, France
| | - Pietro Alifano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy
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Icard P, Simula L, Rei J, Fournel L, De Pauw V, Alifano M. On the footsteps of Hippocrates, Sanctorius and Harvey to better understand the influence of cold on the occurrence of COVID-19 in European countries in 2020. Biochimie 2021; 191:164-171. [PMID: 34555456 PMCID: PMC8458079 DOI: 10.1016/j.biochi.2021.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 11/30/2022]
Abstract
COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential.
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Affiliation(s)
- Philippe Icard
- Université Caen Normandie, Medical School, CHU de Caen, Caen, F-14000, France; INSERM U1086, Interdisciplinary Research Unit for Cancer Prevention and Treatment, CLCC François Baclesse, Caen University, France; Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France.
| | - Luca Simula
- INSERM U1016, CNRS UMR8104, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris University, Paris, 75014, France
| | - Joana Rei
- Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France
| | - Ludovic Fournel
- Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France; INSERM U1124, Cellular Homeostasis and Cancer, Paris University, Paris, France
| | - Vincent De Pauw
- Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France
| | - Marco Alifano
- Service de Chirurgie Thoracique, Hôpital Cochin, Paris University Hospitals, APHP, France; INSERM U1138, Integrative Cancer Immunology, Paris, France
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Role of multiple factors likely contributing to severity-mortality of COVID-19. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 96:105101. [PMID: 34624542 PMCID: PMC8491954 DOI: 10.1016/j.meegid.2021.105101] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 02/08/2023]
Abstract
COVID-19 stalled the world in 2020 and continues to be the greatest health crisis of this generation. While the apparent case fatality rates across fluctuates around ~2% globally, associated mortality/death rate (deaths per million population) varies distinctly across regions from the global average of ~600 per million population. Heterogeneous factors have been linked with COVID-19 associated mortalities and these include age, share of geriatric population, comorbidities, trained immunity and climatic conditions. Apart from direct or indirect role of endemic diseases, dietary factors and host immunity in regulating COVID-19 severity, human behaviour will inevitably control outcome of this pandemic. Comprehensive understanding of these factors will have a bearing on management of future health crises.
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Li R, Qin C. Expression pattern and function of SARS-CoV-2 receptor ACE2. BIOSAFETY AND HEALTH 2021; 3:312-318. [PMID: 34466800 PMCID: PMC8393493 DOI: 10.1016/j.bsheal.2021.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/12/2021] [Accepted: 08/25/2021] [Indexed: 02/05/2023] Open
Abstract
Since the outbreak at the end of 2019, SARS-CoV-2 has been spreading around the world for more than one year. Scientists have been intensely conducting research on this newly emerged coronavirus and the disease caused by it. Angiotensin-converting enzyme 2 (ACE2), as a receptor mediating the cellular entry of SARS-CoV-2, has become a hot spot for researchers. Here, we summarized the recent progresses on the function, expression and distribution characteristics of ACE2 in human body and among populations. We further discussed the interaction mechanism of ACE2 and SARS-CoV-2 S protein, focusing on key residues that effect interaction and binding ability of SARS-CoV-2 variants. This will facilitate researchers to better understand SARS-CoV-2 infection and transmission route, adaptation mechanism, and designing treatment strategies.
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Affiliation(s)
| | - Chengfeng Qin
- Corresponding author: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
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Figueroa-Pizano MD, Campa-Mada AC, Carvajal-Millan E, Martinez-Robinson KG, Chu AR. The underlying mechanisms for severe COVID-19 progression in people with diabetes mellitus: a critical review. AIMS Public Health 2021; 8:720-742. [PMID: 34786431 PMCID: PMC8568590 DOI: 10.3934/publichealth.2021057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/20/2021] [Indexed: 01/08/2023] Open
Abstract
Diabetes mellitus (DM) has a high incidence of comorbidities among patients with severe coronavirus disease 2019 (COVID-19). The elevated prevalence of DM in the world population makes it a significant risk factor because diabetic individuals appear to be prone to clinical complications and have increased mortality rates. Here, we review the possible underlying mechanisms involved in DM that led to worse outcomes in COVID-19. The impacts of hyperglycemia side effects, secondary comorbidities, weakened innate and adaptive immunity, chronic inflammation, and poor nutritional status, commonly present in DM, are discussed. The role of the SARS-CoV-2 receptor and its polymorphic variations on higher binding affinity to facilitate viral uptake in people with DM were also considered. Clinical differences between individuals with type 1 DM and type 2 DM affected by COVID-19 and the potential diabetogenic effect of SARS-CoV-2 infection were addressed.
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Affiliation(s)
- María D Figueroa-Pizano
- Research Center for Food and Development, CIAD, AC, Carretera Gustavo Enrique Astiazarán Rosas No. 46, C.P. 83304, Hermosillo, Sonora, México
| | - Alma C Campa-Mada
- Research Center for Food and Development, CIAD, AC, Carretera Gustavo Enrique Astiazarán Rosas No. 46, C.P. 83304, Hermosillo, Sonora, México
| | - Elizabeth Carvajal-Millan
- Research Center for Food and Development, CIAD, AC, Carretera Gustavo Enrique Astiazarán Rosas No. 46, C.P. 83304, Hermosillo, Sonora, México
| | - Karla G Martinez-Robinson
- Research Center for Food and Development, CIAD, AC, Carretera Gustavo Enrique Astiazarán Rosas No. 46, C.P. 83304, Hermosillo, Sonora, México
| | - Agustin Rascon Chu
- Research Center for Food and Development, CIAD, AC, Carretera Gustavo Enrique Astiazarán Rosas No. 46, C.P. 83304, Hermosillo, Sonora, México
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Feng F, Chen J, Zhao J, Li Y, Li M, Sun C. Killing Two Birds with One Stone by Administration of Soluble ACE2: A Promising Strategy to Treat Both Cardiovascular Diseases and SARS-CoV-2 Infection. Viruses 2021; 13:2243. [PMID: 34835049 PMCID: PMC8622942 DOI: 10.3390/v13112243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells mainly by the angiotensin converting enzyme 2 (ACE2) receptor, which can recognize the spike (S) protein by its extracellular domain. Previously, recombinant soluble ACE2 (sACE2) has been clinically used as a therapeutic treatment for cardiovascular diseases. Recent data demonstrated that sACE2 can also be exploited as a decoy to effectively inhibit the cell entry of SARS-CoV-2, through blocking SARS-CoV-2 binding to membrane-anchored ACE2. In this study, we summarized the current findings on the optimized sACE2-based strategies as a therapeutic agent, including Fc fusion to prolong the half-life of sACE2, deep mutagenesis to create high-affinity decoys for SARS-CoV-2, or designing the truncated functional fragments to enhance its safety, among others. Considering that COVID-19 patients are often accompanied by manifestations of cardiovascular complications, we think that administration of sACE2 in COVID-19 patients may be a promising therapeutic strategy to simultaneously treat both cardiovascular diseases and SARS-CoV-2 infection. This review would provide insights for the development of novel therapeutic agents against the COVID-19 pandemic.
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Affiliation(s)
- Fengling Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jiaoshan Chen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jin Zhao
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Yanjun Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Minchao Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
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Möhlendick B, Schönfelder K, Breuckmann K, Elsner C, Babel N, Balfanz P, Dahl E, Dreher M, Fistera D, Herbstreit F, Hölzer B, Koch M, Kohnle M, Marx N, Risse J, Schmidt K, Skrzypczyk S, Sutharsan S, Taube C, Westhoff TH, Jöckel KH, Dittmer U, Siffert W, Kribben A. ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19. Pharmacogenet Genomics 2021; 31:165-171. [PMID: 34001841 PMCID: PMC8415730 DOI: 10.1097/fpc.0000000000000436] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/16/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19. PATIENTS AND METHODS We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19. RESULTS SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease. CONCLUSIONS In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.
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Affiliation(s)
| | | | | | - Carina Elsner
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen
| | - Nina Babel
- Center for Translational Medicine, Ruhr University Bochum, Herne
| | - Paul Balfanz
- Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital Aachen
| | - Edgar Dahl
- RWTH Centralized Biomaterial Bank (RWTH cBMB), Medical Faculty
| | - Michael Dreher
- Department of Pneumology and Intensive Care Medicine, University Hospital Aachen, RWTH Aachen University, Aachen
| | | | - Frank Herbstreit
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University of Duisburg-Essen, Essen
| | - Bodo Hölzer
- Department of Nephrology, Ruhr University Bochum, Herne
| | | | | | - Nikolaus Marx
- Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital Aachen
| | | | - Karsten Schmidt
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University of Duisburg-Essen, Essen
| | - Sarah Skrzypczyk
- Center for Translational Medicine, Ruhr University Bochum, Herne
| | | | - Christian Taube
- Department of Pulmonary Medicine, Ruhrlandklinik, University Hospital Essen
| | | | - Karl-Heinz Jöckel
- Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen
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Deng H, Yan X, Yuan L. Human genetic basis of coronavirus disease 2019. Signal Transduct Target Ther 2021; 6:344. [PMID: 34545062 PMCID: PMC8450706 DOI: 10.1038/s41392-021-00736-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 07/28/2021] [Accepted: 08/08/2021] [Indexed: 02/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in considerable morbidity and mortality worldwide. COVID-19 incidence, severity, and mortality rates differ greatly between populations, genders, ABO blood groups, human leukocyte antigen (HLA) genotypes, ethnic groups, and geographic backgrounds. This highly heterogeneous SARS-CoV-2 infection is multifactorial. Host genetic factors such as variants in the angiotensin-converting enzyme gene (ACE), the angiotensin-converting enzyme 2 gene (ACE2), the transmembrane protease serine 2 gene (TMPRSS2), along with HLA genotype, and ABO blood group help to explain individual susceptibility, severity, and outcomes of COVID-19. This review is focused on COVID-19 clinical and viral characteristics, pathogenesis, and genetic findings, with particular attention on genetic diversity and variants. The human genetic basis could provide scientific bases for disease prediction and targeted therapy to address the COVID-19 scourge.
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Affiliation(s)
- Hao Deng
- Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China.
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
- Disease Genome Research Center, Central South University, Changsha, China.
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China.
| | - Xue Yan
- Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
- Disease Genome Research Center, Central South University, Changsha, China
| | - Lamei Yuan
- Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
- Disease Genome Research Center, Central South University, Changsha, China
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
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Serpeloni JM, Lima Neto QA, Lucio LC, Ramão A, Carvalho de Oliveira J, Gradia DF, Malheiros D, Ferrasa A, Marchi R, Figueiredo DLA, Silva WA, Ribeiro EMSF, Cólus IMS, Cavalli LR. Genome interaction of the virus and the host genes and non-coding RNAs in SARS-CoV-2 infection. Immunobiology 2021; 226:152130. [PMID: 34425415 PMCID: PMC8378551 DOI: 10.1016/j.imbio.2021.152130] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/22/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
In this review, we highlight the interaction of SARS-CoV-2 virus and host genomes, reporting the current studies on the sequence analysis of SARS-CoV-2 isolates and host genomes from diverse world populations. The main genetic variants that are present in both the virus and host genomes were particularly focused on the ACE2 and TMPRSS2 genes, and their impact on the patients' susceptibility to the virus infection and severity of the disease. Finally, the interaction of the virus and host non-coding RNAs is described in relation to their regulatory roles in target genes and/or signaling pathways critically associated with SARS-CoV-2 infection. Altogether, these studies provide a significant contribution to the knowledge of SARS-CoV-2 mechanisms of infection and COVID-19 pathogenesis. The described genetic variants and molecular factors involved in host/virus genome interactions have significantly contributed to defining patient risk groups, beyond those based on patients' age and comorbidities, and they are promising candidates to be potentially targeted in treatment strategies for COVID-19 and other viral infectious diseases.
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Affiliation(s)
- Juliana M Serpeloni
- Departamento de Biologia Geral, CCB, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Quirino Alves Lima Neto
- Departamento de Ciências Básicas da Saúde, CCS, Universidade Estadual de Maringá, Maringá, PR, Brazil
| | - Léia Carolina Lucio
- Programa de Pós-graduação em Ciências Aplicadas à Saúde, CCS, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, PR, Brazil
| | - Anelisa Ramão
- Departamento de Ciências Biológicas, Universidade Estadual do Centro-Oeste, Guarapuava, PR, Brazil
| | | | | | - Danielle Malheiros
- Departamento de Genética, SCB, Universidade Federal do Paraná, PR, Brazil
| | - Adriano Ferrasa
- Departamento de Informática, SECATE, Universidade Estadual de Ponta Grossa, Ponta Grossa, PR, Brazil
| | - Rafael Marchi
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - David L A Figueiredo
- Departamento de Medicina, Universidade Estadual do Centro-Oeste, UNICENTRO e Instituto de Pesquisa para o Câncer, IPEC, Guarapuava, PR, Brazil
| | - Wilson A Silva
- Departamento de Genética, Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, SP, e Instituto de Pesquisa para o Câncer, IPEC, Guarapuava, PR, Brazil
| | | | - Ilce M S Cólus
- Departamento de Biologia Geral, CCB, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Luciane R Cavalli
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil.
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Ogedjo M, Onoka I, Sahini M, Shadrack DM. Accommodating receptor flexibility and free energy calculation to reduce false positive binders in the discovery of natural products blockers of SARS-COV-2 spike RBD-ACE2 interface. Biochem Biophys Rep 2021; 27:101024. [PMID: 34056140 PMCID: PMC8148615 DOI: 10.1016/j.bbrep.2021.101024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 11/28/2022] Open
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which causes coronavirus disease-19 (COVID-19) has caused more than 2 million deaths around the globe. The high transmissibility rate of the disease is related to the strong interaction between the virus spike receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) as documented in several reports. In this study, using state-of-the-art computational methods, natural products were screened and their molecular mechanism to disrupt spike RBD-ACE2 recognition was evaluated. There is the sensitivity of results to receptor ensemble docking calculations. Binding free energy and MD simulation are important tools to evaluate the thermodynamics of binding stability and the capacity of top hits to disrupt RBD-ACE2 recognition. The free energy profiles provide a slight decrease in binding affinity of the virus-receptor interaction. Three flavonoids parvisoflavone B (3), alpinumisoflavone (5) and norisojamicin (2) were effective in blocking the viral entry by binding strongly at the spike RBD-ACE2 interface with the inhibition constant of 0.56, 0.78 and 0.93 μM, respectively. The same compounds demonstrated similar effect on free ACE2 protein. Compound (2), also demonstrated ability to bind strongly on free spike RBD. Well-tempered metadynamics established that parvisoflavone B (3) works by binding to three sites namely interface α, β and loop thereby inhibiting viral cell entry. Owing to their desirable pharmacokinetic properties, the presented top hit natural products are suggested for further SARS-COV-2 molecular targets and subsequent in vitro and in vivo evaluations.
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Affiliation(s)
- Marcelina Ogedjo
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma, P.O.Box 338, Dodoma, Tanzania
| | - Isaac Onoka
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma, P.O.Box 338, Dodoma, Tanzania
| | - Mtabazi Sahini
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma, P.O.Box 338, Dodoma, Tanzania
| | - Daniel M. Shadrack
- Department of Chemistry, Faculty of Natural and Applied Sciences, St. John's University of Tanzania, P.O.Box 47, Dodoma, Tanzania
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Abstract
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). There is growing evidence that host genetics play an important role in COVID-19 severity. Based on current knowledge about the human protein machinery for SARS-CoV-2 entry, the host innate immune response, and virus-host interactions, the potential effects of human genetic polymorphisms, which may contribute to clinical differences in SARS-CoV-2 pathogenesis, may help to determine the individual risk for COVID-19 infection and outcome.
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Affiliation(s)
- Joris R Delanghe
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium; Research Foundation-Flanders (FWO), Brussels, Belgium
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43
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Shadrack DM, Vuai SAH, Sahini MG, Onoka I. In silico study of the inhibition of SARS-COV-2 viral cell entry by neem tree extracts. RSC Adv 2021; 11:26524-26533. [PMID: 35480004 PMCID: PMC9037307 DOI: 10.1039/d1ra04197e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/03/2021] [Indexed: 12/13/2022] Open
Abstract
The outbreak of COVID-19, caused by SARS-COV-2, is responsible for higher mortality and morbidity rates across the globe. Until now, there is no specific treatment of the disease and hospitalized patients are treated according to the symptoms they develop. Efforts to identify drugs and/or vaccines are ongoing processes. Natural products have shown great promise in the treatment of many viral related diseases. In this work, using in silico methods, bioactive compounds from the neem tree were investigated for their ability to block viral cell entry as spike RBD-ACE2 inhibitors. Azadirachtin H, quentin and margocin were identified as potential compounds that demonstrated viral cell entry inhibition properties. The structural re-orientation of azadirachtin H was observed as the mechanism for viral cell entry inhibition. These compounds possessed good pharmacodynamic properties. The proposed molecules can serve as a starting point towards developing effective anti-SARS-COV-2 drugs targeting the inhibition of viral cell entry upon further in vitro and in vivo validation.
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Affiliation(s)
- Daniel M Shadrack
- Department of Chemistry, Faculty of Natural and Applied Sciences, St John's University of Tanzania Dodoma P. O. Box 47 +255 713 696 089
| | - Said A H Vuai
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma Dodoma P. O. Box 338 Tanzania
| | - Mtabazi G Sahini
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma Dodoma P. O. Box 338 Tanzania
| | - Isaac Onoka
- Department of Chemistry, College of Natural and Mathematical Sciences, University of Dodoma Dodoma P. O. Box 338 Tanzania
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Hashemi SMA, Thijssen M, Hosseini SY, Tabarraei A, Pourkarim MR, Sarvari J. Human gene polymorphisms and their possible impact on the clinical outcome of SARS-CoV-2 infection. Arch Virol 2021; 166:2089-2108. [PMID: 33934196 PMCID: PMC8088757 DOI: 10.1007/s00705-021-05070-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/23/2021] [Indexed: 12/13/2022]
Abstract
The SARS-CoV-2 pandemic has become one of the most serious health concerns globally. Although multiple vaccines have recently been approved for the prevention of coronavirus disease 2019 (COVID-19), an effective treatment is still lacking. Our knowledge of the pathogenicity of this virus is still incomplete. Studies have revealed that viral factors such as the viral load, duration of exposure to the virus, and viral mutations are important variables in COVID-19 outcome. Furthermore, host factors, including age, health condition, co-morbidities, and genetic background, might also be involved in clinical manifestations and infection outcome. This review focuses on the importance of variations in the host genetic background and pathogenesis of SARS-CoV-2. We will discuss the significance of polymorphisms in the ACE-2, TMPRSS2, vitamin D receptor, vitamin D binding protein, CD147, glucose-regulated protein 78 kDa, dipeptidyl peptidase-4 (DPP4), neuropilin-1, heme oxygenase, apolipoprotein L1, vitamin K epoxide reductase complex 1 (VKORC1), and immune system genes for the clinical outcome of COVID-19.
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Affiliation(s)
- Seyed Mohammad Ali Hashemi
- Department of Bacteriology and Virology, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Marijn Thijssen
- Laboratory for Clinical and Epidemiological Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, 3000 Leuven, Belgium
| | - Seyed Younes Hosseini
- Department of Bacteriology and Virology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alijan Tabarraei
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mahmoud Reza Pourkarim
- Laboratory for Clinical and Epidemiological Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, 3000 Leuven, Belgium
- Health Policy Research Centre, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamal Sarvari
- Department of Bacteriology and Virology, Shiraz University of Medical Sciences, Shiraz, Iran
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Bakhshandeh B, Sorboni SG, Javanmard AR, Mottaghi SS, Mehrabi MR, Sorouri F, Abbasi A, Jahanafrooz Z. Variants in ACE2; potential influences on virus infection and COVID-19 severity. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 90:104773. [PMID: 33607284 PMCID: PMC7886638 DOI: 10.1016/j.meegid.2021.104773] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/08/2021] [Accepted: 02/12/2021] [Indexed: 02/07/2023]
Abstract
The third pandemic of coronavirus infection, called COVID-19 disease, was first detected in November 2019th. Various determinants of disease progression such as age, sex, virus mutations, comorbidity, lifestyle, host immune response, and genetic background variation have caused clinical variability of COVID-19. The causative agent of COVID-19 is an enveloped coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that invades host cells using an endocytic pathway. The SARS-CoV-2 spike protein is the main viral protein that contributes to the fusion of the virus particle to the host cell through angiotensin-converting enzyme 2 (ACE2). The highly conserved expression of ACE2 is found in various animals, which indicates its pivotal physiological function. The ACE2 has a crucial role in vascular, renal, and myocardial physiology. Genetic factors contributing to the outcome of SARS-CoV-2 infection are unknown; however, variants in the specific sites of ACE2 gene could be regarded as a main genetic risk factor for COVID-19. Given that ACE2 is the main site for virus landing on host cells, the effect of amino acid sequences of ACE2 on host susceptibility to COVID-19 seems reasonable. It would likely have a substantial role in the occurrence of a wide range of clinical symptoms. Several ACE2 variants can affect the protein stability, influencing the interaction between spike protein and ACE2 through imposing conformational changes while some other variants are known to cause a decrease or an increase in the ligand-receptor affinity. The other variations are located at the proteolytic cleavage site, which can influence virus infection; because soluble ACE2 can act as a decoy receptor for virus and decrease virus intake by cell surface ACE2. Notably, polymorphisms of regulatory and non-coding regions such as promoter in ACE2, can play crucial role in different expression levels of ACE2 among different individuals. Many studies should be performed to investigate the involvement of ACE2 polymorphism with susceptibility to COVID-19. Herein, we discuss some reported associations between variants of ACE2 and COVID-19 in details. In addition, the mode of action of ACE2 and its role in SARS-CoV-2 infection are highlighted which is followed by addressing the effects of several ACE2 variants on its protein stability, viral tropism or ligand-receptor affinity, secondary and tertiary structure or protein conformation, proteolytic cleavage site, and finally inter-individual clinical variability in COVID-19. The polymorphisms of regulatory regions of ACE2 and their effect on expression levels of ACE2 are also provided in this review. Such studies can improve the prediction of the affinity of mutant ACE2 variations with spike protein, and help the biopharmaceutical industry to design effective approaches for recombinant hACE2 therapy and vaccination of COVID-19 disease.
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Affiliation(s)
- Behnaz Bakhshandeh
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran; Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | | | - Amir-Reza Javanmard
- Molecular Genetics Department, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Saeed Mottaghi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Mohammad-Reza Mehrabi
- Department of Microbial Biotechnology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farzaneh Sorouri
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zohreh Jahanafrooz
- Department of Biology, Faculty of Sciences, University of Maragheh, Maragheh, Iran
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46
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Ma S, Li H, Yang J, Yu K. Molecular simulation studies of the interactions between the human/pangolin/cat/bat ACE2 and the receptor binding domain of the SARS-CoV-2 spike protein. Biochimie 2021; 187:1-13. [PMID: 33984400 PMCID: PMC8110333 DOI: 10.1016/j.biochi.2021.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 11/15/2022]
Abstract
The recent outbreak of SARS-CoV-2 has had a profound effect on the world. Similar to that in SARS-CoV, the entry receptor of SARS-CoV-2 is ACE2. The binding of SARS-CoV-2 spike protein to ACE2 is the critical to the virus infection. Recently multiple species (human, Chinese chrysanthemum, Malay pangolin and cat) have been reported to be susceptible to the virus infection. However, the binding capacity and the detailed binding mechanism of SARS-CoV-2 spike protein to ACE2 of these species remains unexplored. Herein free energy calculations with MM-GBSA and Potential of Mean Forces together reveal that the Human-SARS-CoV-2 has a higher stability tendency than Human-SARS-CoV. Meanwhile, we uncover that SARS-CoV-2 has an enhanced ability to bind with the ACE2 in humans, pangolins and cats compared to that in bats. Analysis of key residues with energy decomposition and residue contact maps reveal several important consensus sites in ACE2s among the studied species, and determined the more favorable specified residues among the different types of amino acids. These results provide important implications for understanding SARS-CoV-2 host range which will make it possible to control the spread of the virus and use of animal models, targeted drug screening and vaccine candidates against SARS-CoV-2.
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Affiliation(s)
- Shaojie Ma
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430074, PR China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, PR China
| | - Hui Li
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Shanghai Institute for Advanced Immunochemical Studies, And School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Jun Yang
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430074, PR China; National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, PR China.
| | - Kunqian Yu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Shanghai Institute for Advanced Immunochemical Studies, And School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
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47
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Sepahvandi A, Ghaffari M, Bahmanpour AH, Moztarzadeh F, Zarrintaj P, Uludağ H, Mozafari M. COVID-19: insights into virus-receptor interactions. MOLECULAR BIOMEDICINE 2021; 2:10. [PMID: 34766003 PMCID: PMC8035060 DOI: 10.1186/s43556-021-00033-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 03/03/2021] [Indexed: 01/03/2023] Open
Abstract
The recent outbreak of Coronavirus Disease 2019 (COVID-19) calls for rapid mobilization of scientists to probe and explore solutions to this deadly disease. A limited understanding of the high transmissibility of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) relative to other coronavirus strains guides a deeper investigation into the virus/receptor interactions. The cutting-edge studies in thermodynamic and kinetic properties of interactions such as protein-protein interplays have been reviewed in many modeling and analysis studies. Highlighting the thermodynamic assessments of biological interactions and emphasizing the boosted transmissibility of SARS-CoV-2 despite its high similarity in structure and sequence with other coronavirus strains is an important and highly valuable investigation that can lead scientists to discover analytical and fundamental approaches in studying virus's interactions. Accordingly, we have attempted to describe the crucial factors such as conformational changes and hydrophobicity particularities that influence on thermodynamic potentials in the SARS-COV-2 S-protein adsorption process. Discussing the thermodynamic potentials and the kinetics of the SARS-CoV-2 S-protein in its interaction with the ACE2 receptors of the host cell is a fundamental approach that would be extremely valuable in designing candidate pharmaceutical agents or exploring alternative treatments.
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Affiliation(s)
- Azadeh Sepahvandi
- Department of Mechanical Engineering College of Engineering and Computing, University of South Carolina, 301 Main St, Columbia, SC 29208 USA
| | - Maryam Ghaffari
- Biomaterial Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, Tehran, Iran
| | - Amir Hossein Bahmanpour
- Biomaterial Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, Tehran, Iran
| | - Fathollah Moztarzadeh
- Biomaterial Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, Tehran, Iran
| | - Payam Zarrintaj
- School of Chemical Engineering, Oklahoma State University, 420 Engineering North, Stillwater, OK 74078 USA
| | - Hasan Uludağ
- Department of Chemical and Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2V4 Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1 Canada
- Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3 Canada
| | - Masoud Mozafari
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Currently at: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON Canada
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48
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Modeling mutational effects on biochemical phenotypes using convolutional neural networks: application to SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 33532766 PMCID: PMC7852230 DOI: 10.1101/2021.01.28.428521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biochemical phenotypes are major indexes for protein structure and function characterization. They are determined, at least in part, by the intrinsic physicochemical properties of amino acids and may be reflected in the protein three-dimensional structure. Modeling mutational effects on biochemical phenotypes is a critical step for understanding protein function and disease mechanism as well as enabling drug discovery. Deep Mutational Scanning (DMS) experiments have been performed on SARS-CoV-2’s spike receptor binding domain and the human ACE2 zinc-binding peptidase domain - both central players in viral infection and evolution and antibody evasion - quantifying how mutations impact binding affinity and protein expression. Here, we modeled biochemical phenotypes from massively parallel assays, using convolutional neural networks trained on protein sequence mutations in the virus and human host. We found that neural networks are significantly predictive of binding affinity, protein expression, and antibody escape, learning complex interactions and higher-order features that are difficult to capture with conventional methods from structural biology. Integrating the intrinsic physicochemical properties of amino acids, including hydrophobicity, solvent-accessible surface area, and long-range non-bonded energy per atom, significantly improved prediction (empirical p<0.01) though there was such a strong dependence on the sequence data alone to yield reasonably good prediction. We observed concordance of the DMS data and our neural network predictions with an independent study on intermolecular interactions from molecular dynamics (multiple 500 ns or 1 μs all-atom) simulations of the spike protein-ACE2 interface, with critical implications for the use of deep learning to dissect molecular mechanisms. The mutation- or genetically-determined component of a biochemical phenotype estimated from the neural networks has improved causal inference properties relative to the original phenotype and can facilitate crucial insights into disease pathophysiology and therapeutic design.
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49
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Villoutreix BO, Calvez V, Marcelin AG, Khatib AM. In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2-Spike RBD Interface. Int J Mol Sci 2021; 22:1695. [PMID: 33567580 PMCID: PMC7915722 DOI: 10.3390/ijms22041695] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 12/24/2022] Open
Abstract
SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike-ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure-function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.
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Affiliation(s)
- Bruno O. Villoutreix
- Integrative Computational Pharmacology and Data Mining, INSERM UMR 1141, NeuroDiderot, Robert-Debré Hospital, 75019 Paris, France
| | - Vincent Calvez
- Sorbonne Université, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Laboratoire de Virologie, F75013 Paris, France; (V.C.); (A.-G.M.)
| | - Anne-Geneviève Marcelin
- Sorbonne Université, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Laboratoire de Virologie, F75013 Paris, France; (V.C.); (A.-G.M.)
| | - Abdel-Majid Khatib
- Université de Bordeaux, INSERM, LAMC, U1029, F-33600 Pessac, France
- Institut Bergonié, 33000 Bordeaux, France
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IgM and IgG Profiles Reveal Peculiar Features of Humoral Immunity Response to SARS-CoV-2 Infection. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18031318. [PMID: 33535692 PMCID: PMC7908175 DOI: 10.3390/ijerph18031318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/28/2021] [Accepted: 01/28/2021] [Indexed: 12/23/2022]
Abstract
The emergence of coronavirus disease 2019 (COVID-19) is globally a major healthcare threat. There is little information regarding the mechanisms and roles of the humoral response in SARS-CoV-2 infection. The aim of this study was to analyze the antibody levels (IgM and IgG) by chemiluminescence immunoassay in 54 subjects positive to SARS-CoV-2 swab test in relation to their clinical status (whether asymptomatic, pauci-symptomatic or with mild, sever or critical symptoms), the time from the symptom onset, sex, age, and comorbidities. Overall, the presence of comorbidities and the age of subjects were associated with their clinical status. The IgG concentrations were significantly higher in patients who developed critical and severe symptoms and seemed to be independent from age, sex and comorbidities. IgG titers peaked around day 60, and then began gradually to drop, decreasing by approximately 50% on the 180th day, while the IgM titers progressively decreased as early as the tenth day, but they could be detected even at later time points. Despite the small number of individuals, some peculiar characteristics of the humoral response in COVID-19 emerged. We observed a high inter-individual variability, an ephemeral IgG half-life in several patients, and a persistence of IgM in others.
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