Role of Vitamin D, ACE2 and the Proteases as TMPRSS2 and Furin on SARS-CoV-2 Pathogenesis and COVID-19 Severity

Ortatatli, Mesut; Fatsa, Tugba; Mülazımoğlu, Deniz Doğan; Oren, Sema; Artuk, Cumhur; Hosbul, Tugrul; Kulahlioglu, Neslihan; Kenar, Levent

doi:10.1016/j.arcmed.2023.02.002

Cited by 3 publications

(3 citation statements)

References 38 publications

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“…Since the Lungs are the primary organ affected by COVID-19 infection, the high expression of Furin in the lungs highlights its importance in COVID19. A Recent study which aims to investigate the levels of mRNA expression of Furin in the peripheral blood of COVID-19 patients with different disease severity to understand if there is any correlation the disease severity reported a Statistically significant severe positive correlation in mRNA expression levels of Furin and, therefore, may affect COVID-19 susceptibility and severity 41 .…”

Section: Discussionmentioning

confidence: 99%

Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations

Pandey,

Srivastava,

Mishra

et al. 2024

Sci Rep

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SARS CoV-2, the causative agent for the ongoing COVID-19 pandemic, it enters the host cell by activating the ACE2 receptor with the help of two proteasesi.e., Furin and TMPRSS2. Therefore, variations in these genes may account for differential susceptibility and severity between populations. Previous studies have shown that the role of ACE2 and TMPRSS2 gene variants in understanding COVID-19 susceptibility among Indian populations. Nevertheless, a knowledge gap exists concerning the COVID-19 susceptibility of Furin gene variants among diverse South Asian ethnic groups. Investigating the role of Furin gene variants and their global phylogeographic structure is essential to comprehensively understanding COVID-19 susceptibility in these populations. We have used 450 samples from diverse Indian states and performed linear regression to analyse the Furin gene variant's with COVID-19 Case Fatality Rate (CFR) that could be epidemiologically associated with disease severity outcomes. Associated genetic variants were further evaluated for their expression and regulatory potential through various Insilco analyses. Additionally, we examined the Furin gene using next-generation sequencing (NGS) data from 393 diverse global samples, with a particular emphasis on South Asia, to investigate its Phylogeographic structure among diverse world populations. We found a significant positive association for the SNP rs1981458 with COVID-19 CFR (p < 0.05) among diverse Indian populations at different timelines of the first and second waves. Further, QTL and other regulatory analyses showed various significant associations for positive regulatory roles of rs1981458 and Furin gene, mainly in Immune cells and virus infection process, highlighting their role in host immunity and viral assembly and processing. The Furin protein–protein interaction suggested that COVID-19 may contribute to Pulmonary arterial hypertension via a typical inflammation mechanism. The phylogeographic architecture of the Furin gene demonstrated a closer genetic affinity of South Asia with West Eurasian populations. Therefore, it is worth proposing that for the Furin gene, the COVID-19 susceptibility of South Asians will be more similar to the West Eurasian population. Our previous studies on the ACE2 and TMPRSS2 genes showed genetic affinity of South Asian with East Eurasians and West Eurasians, respectively. Therefore, with the collective information from these three important genes (ACE2, TMPRSS2 and Furin) we modelled COVID-19 susceptibilityof South Asia in between these two major ancestries with an inclination towards West Eurasia. In conclusion, this study, for the first time, concluded the role of rs1981458 in COVID-19 severity among the Indian population and outlined its regulatory potential.This study also highlights that the genetic structure for COVID-19 susceptibilityof South Asia is distinct, however, inclined to the West Eurasian population. We believe this insight may be utilised as a genetic biomarker to identify vulnerable populations, which might be directly relevant for developing policies and allocating resources more effectively during an epidemic.

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Section: Discussionmentioning

confidence: 99%

Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations

Pandey,

Srivastava,

Mishra

et al. 2024

Sci Rep

View full text Add to dashboard Cite

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“…High mobility group box 1 protein (HMGB1), an evolutionarily conserved chromatin-binding protein that regulates ACE2 expression, is essential for the viral entry of both SARS-CoV-2 and SARS-CoV ( Wei et al., 2021 ). Interestingly, a negative correlation between ACE2 expression and COVID-19 severity has been proposed ( Mariappan and Balakrishna, 2020 ; Ortatatli et al., 2023 ). The large GTEx data revealed that ACE2 expression is high in Asian females and young people, those who are known to be less susceptible, and even less inflicted by severe or fatal outcome, while it is low in males, further decrease with age and type 2 diabetes mellitus (T2DM), those who are most susceptible to bad outcome ( Chen et al., 2020a ).…”

Section: Host Genetic Factors In Sars-cov-2 Susceptibility and Covid-...mentioning

confidence: 99%

Host factors of SARS-CoV-2 in infection, pathogenesis, and long-term effects

Zhang,

Chen,

Tian

et al. 2024

Front. Cell. Infect. Microbiol.

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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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“…In course of COVID-19, inadequate serum 25(OH)D 3 concentrations correlate with reduced ACE-2 levels and ACE-2 mRNA expression, and calcitriol supplementation seems to restore ACE-2 levels, re-establishing a physiological ratio of angiotensin 1-7/angiotensin II concentrations (shown Gotelli/Soldano/Hysa/Casabella/Cere/ Pizzorni/Paolino/Sulli/Smith/Cutolo in Fig. 2) [28]. Calcitriol and hydroxyderivatives of L 3 and T 3 can also bind to SARS-CoV-2 receptor-binding domain of ACE-2, hindering the interaction between the virus and the receptor [29].…”

Section: Vitamin D 3 and Sars-cov-2 Infectionmentioning

confidence: 99%

Understanding the Immune-Endocrine Effects of Vitamin D in SARS-CoV-2 Infection: A Role in Protecting against Neurodamage

Gotelli,

Soldano,

Hysa

et al. 2023

Neuroimmunomodulation

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Calcitriol and hydroxyderivatives of lumisterol and tachisterol are secosteroid hormones with immunomodulatory and anti-inflammatory properties. Since the beginning of the COVID-19 pandemic, several studies have correlated deficient serum concentrations of vitamin D3 (calcifediol) with increased severity of the course of SARS-CoV-2 infection. Among systemic complications, subjective (anosmia, ageusia, depression, dizziness) and objective (ischemic stroke, meningo-encephalitis, myelitis, seizures, Guillain-Barré syndrome) neurological symptoms have been reported in up to 80% of severe COVID-19 patients. In this narrative review we will resume the pathophysiology of SARS-CoV-2 infection and the mechanisms of acute and chronic neurological damage. SARS-CoV-2 can disrupt the integrity of the endothelial cells of the blood-brain barrier to enter the nervous central system. Invasion of pro-inflammatory cytokines and polarization of astrocytes and microglia cells always in a pro-inflammatory sense together with the pro-coagulative phenotype of cerebral endothelial vessels in response to both SARS-CoV-2 and immune cells invasion (immunothrombosis) are the major drivers of neuro-damage. Calcitriol and hydroxyderivatives of lumisterol and tachisterol could play an adjuvant role in neuroprotection, through mitigation of neuroinflammation and protection of endothelial integrity of the blood-brain barrier. Dedicated studies on this topic are currently lacking and are desirable to confirm the link between vitamin D3 and neuroprotection in COVID-19 patients.

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Role of Vitamin D, ACE2 and the Proteases as TMPRSS2 and Furin on SARS-CoV-2 Pathogenesis and COVID-19 Severity

Cited by 3 publications

References 38 publications

Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations

Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations

Host factors of SARS-CoV-2 in infection, pathogenesis, and long-term effects

Understanding the Immune-Endocrine Effects of Vitamin D in SARS-CoV-2 Infection: A Role in Protecting against Neurodamage

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