SARS-CoV-2 mechanisms of cell tropism in various organs considering host factors

Heliyon · 8 authors, 8 centres

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TL;DR

This comprehensive review details the molecular mechanisms of SARS-CoV-2 entry into host cells, highlighting that beyond the primary ACE2 receptor, alternative receptors (ASGR1, KREMEN1, AXL, CD147) and host proteases (TMPRSS2, Furin, Cathepsin L, ADAM) are critical for viral tropism in multiple organs. The paper discusses how polymorphisms in ACE2 and spike mutations drive variant emergence and impact pathogenicity, and it reviews potential therapeutic inhibitors targeting these host factors. The clinical significance lies in informing drug repurposing and development of host-directed therapies to combat COVID-19 and its variants.

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**Background:** The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in over 696 million cases and 6.9 million deaths globally. Understanding the molecular mechanisms of viral entry is crucial for drug design. While ACE2 is the primary receptor, the virus exhibits tropism in various organs, suggesting involvement of alternative receptors and host proteases. This review aims to comprehensively identify host molecular targets involved in SARS-CoV-2 entry, including receptors, co-receptors, and proteases, and to discuss their implications for therapeutic strategies.

**Methods:** Two independent investigators conducted a systematic search of PubMed, Scopus, Embase, and Web of Science from inception to February 28, 2023. The search used MeSH terms and keywords including "SARS-CoV-2" AND "Entry" OR "Route" OR "Mechanisms" OR "Receptor" OR "Interaction" OR "Attachment" OR "Binding." Manual reference checks and combination searches with different human body organs were also performed. Studies focusing on polymorphisms or mutations in the SARS-CoV-2 spike and human targets (ACE2, TMPRSS2, Furin, CD147) were selected. Records were managed using EndNote X7, and two authors independently screened titles/abstracts after duplicate removal.

**Key Results:** The review identifies ACE2 as the major receptor, expressed in approximately 72 human tissues, with primary expression in lung epithelial cells. Alternative receptors include ASGR1, KREMEN1, AXL, CD147, and integrins. Co-receptors such as DPP4 and ENPEP are also noted. Key host proteases facilitating viral entry are TMPRSS2, TMPRSS4, Furin, ADAM (especially ADAM-17), and Cathepsin L (CTSL). The spike protein contains a furin cleavage site (PRRA) not found in other SARS-like CoVs. Mutations in the spike RBD, such as N501Y, E484K, L452R, and T478K, are associated with variants including Alpha, Beta, Gamma, Delta, and Omicron. The Omicron variant has a transmission capacity 3–4 times higher than Delta. ACE2 polymorphisms (e.g., K26R, I21V, E23K) increase susceptibility, while others (e.g., K31R, E35K, N33I) are protective. TMPRSS2 genetic variants (e.g., rs112657409, rs2070788) may alter expression and susceptibility. The virus shows tropism in lung (alveolar epithelial cells), cardiovascular system (cardiomyocytes, pericytes), CNS (via neuropilin-1, olfactory nerve), gastrointestinal tract (enterocytes, pancreas), kidney (podocytes, tubular epithelial cells), liver, placenta, and stem cells. ACE2 expression increases with age, and males show higher susceptibility. Pre-existing conditions like heart failure and diabetes elevate ACE2 expression, increasing vulnerability. Potential therapeutic inhibitors include: ACE2 inhibitors (sphingosine, GB-2), TMPRSS2 inhibitors (nafamostat mesylate, camostat mesylate), Furin inhibitors (diminazene, naphthofluorescein, decanoyl-RVKR-CMK), ADAM modulators (irisin), CTSL inhibitors (K777, chlorpromazine, fluoxetine), and AXL inhibitor bemcentinib (phase II trials). Other drugs under clinical trial include DFV890, TD-0903, RBT-9, M5049, SNG001, and Paxlovid.

**Clinical Implications:** The detailed mapping of host factors involved in SARS-CoV-2 entry provides a foundation for developing host-directed therapies that may offer broad-spectrum efficacy against emerging variants. Targeting multiple entry pathways (e.g., combining TMPRSS2 and CTSL inhibitors) could be more effective. The identification of ACE2 polymorphisms and spike mutations explains variable clinical outcomes and informs vaccine updates. Repurposed drugs like camostat mesylate and nafamostat mesylate are viable options. Understanding organ-specific tropism helps explain multi-organ failure in severe COVID-19 and long COVID symptoms. The review emphasizes the need for personalized therapeutic approaches based on host genetic factors and variant characteristics.

STUDY TYPE

narrative_review

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

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100% · A

ORIGINAL PAPER

PMC10901034

SARS-CoV-2 mechanisms of cell tropism in various organs considering host factors

Heliyon

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ABSTRACT

A critical step in the drug design for SARS-CoV-2 is to discover its molecular targets. This study comprehensively reviewed the molecular mechanisms of SARS-CoV-2, exploring host cell tropism and interaction targets crucial for cell entry. The findings revealed that beyond ACE2 as the primary entry receptor, alternative receptors, co-receptors, and several proteases such as TMPRSS2, Furin, Cathepsin L, and ADAM play critical roles in virus entry and subsequent pathogenesis. Additionally, SARS-CoV-2 displays tropism in various human organs due to its diverse receptors. This review delves into the intricate details of receptors, host proteases, and the involvement of each organ. Polymorphisms in the ACE2 receptor and mutations in the spike or its RBD region contribute to the emergence of variants like Alpha, Beta, Gamma, Delta, and Omicron, impacting the pathogenicity of SARS-CoV-2. The challenge posed by mutations raises questions about the effectiveness of existing vaccines and drugs, necessitating consideration for updates in their formulations. In the urgency of these critical situations, repurposed drugs such as Camostat Mesylate and Nafamostat Mesylate emerge as viable pharmaceutical options. Numerous drugs are involved in inhibiting receptors and host factors crucial for SARS-CoV-2 entry, with most discussed in this review. In conclusion, this study may provide valuable insights to inform decisions in therapeutic approaches.

CITATION EXPORT

Emad Behboudi, Seyed Nooreddin Faraji, Gholamreza Daryabor et al.. SARS-CoV-2 mechanisms of cell tropism in various organs considering host factors. Heliyon. (2024). https://doi.org/10.1016/j.heliyon.2024.e26577

AUTHORS

8 · 8 CENTRES

Emad Behboudi, Seyed Nooreddin Faraji, Gholamreza Daryabor, Seyed Mohammad Ali Hashemi, Maryam Asadi, Fahime Edalat, Mohammad Javad Raee, Gholamreza Hatam

aDepartment of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
bDepartment of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
cAutoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
dDepartment of Bacteriology & Virology, Shiraz University of Medical Sciences, Shiraz, Iran
eDepartment of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran
fDepartment of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
gCenter for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
hBasic Sciences in Infectious Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran