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Therapeutic Challenges in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Alaa A. A. Aljabali, Murtaza M. Tambuwala, Debmalya Barh, Kenneth Lundstrom
-B*15:27, -B*46:01, -C*01:02, an-C*07:29 alleles correlate with COVID-19 susceptibility, and HLA-A*02:02, -B*15:03, and -C*12:03 may have a protective role. Genetic polymorphisms that affect ACE2 and TMPRSS2 expression also increase the risk of infection, and variations in cytokine genes such as IL6, ILR, TNF etc. could be associated with cytokine storm affecting disease severity. In the GWAS (Genome-Wide Association Study), two loci are found associated with COVID-19 severity. These are 3p21.31 harboring genes such as FYCO1, SLC6A20, CCR9, LZTFL1, XCR1, and CXCR6, and 9q34.2, where the ABO genes are located [63]. It has also been reported that people with blood group A are more susceptible to SARS-CoV-2 infections [64]. Furthermore, inborn errors of type I IFN immunity are associated with very severe COVID-19 [65].
Genetic risks and association with severe COVID-19 among global populations
Published in Pathogens and Global Health, 2021
John Mauleekoonphairoj, Sompong Vongpunsawad, Apichai Khongphatthanayothin, Koonlawee Nademanee, Yong Poovorawan
Chromosomal locus 3p21.31 was highly correlated with disease severity in hospitalized Italian and Spanish COVID-19 patients (rs11385942; 95% confidence interval (CI), p = 1.15x10−10) [2], which was confirmed in the United Kingdom (rs13078854; 95% CI, p = 1.6x10−18) [3] and in a multi-ethnic study (rs73064425; 95% CI, p = 4.77x10−30) [4]. This gene-rich locus includes SLC6A20 (encoding sodium-imino acid transporter 1, which interacts with COVID-19 ACE2 receptor) and multiple chemokine receptors (CCR9, CXCR6, CCR1, and CCR2). Our analysis found that the frequency of the risk allele rs11385942 at this locus differs vastly among Southeast Asians, ranging from 0.21 in the Filipino population to 0.06 in the Thai population, but it was rare in Northeast Asians (Figure 1). Surprisingly, frequencies of risk alleles at 19p13.2 (rs74956615) and 19p13.3 (rs2109069) were also low among Northeast Asians relative to other populations. Collectively, these three loci encode inflammatory response genes (CCR2, TYK2, and DPP9) and are hypothesized to influence COVID-19 severity through hyper-inflammatory response and subsequent organ injury [3].
COVID-19 and human reproduction: A pandemic that packs a serious punch
Published in Systems Biology in Reproductive Medicine, 2021
George Anifandis, Helen G. Tempest, Rafael Oliva, Grace M. Swanson, Mara Simopoulou, Charles A. Easley, Michael Primig, Christina I. Messini, Paul J. Turek, Peter Sutovsky, Steve J. Ory, Stephen A. Krawetz
A radically different approach to identifying susceptibility genes has been through the application of genome wide association studies (Kachuri et al. 2020; Ellinghaus et al. 2020). Specifically, associations were detected at the 9q34.2 embedded in the ABO blood group locus and several other signals clustered at 3p21.31, which included genes for SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1 (Ellinghaus et al. 2020). A significant higher risk and a protective effect in A and O blood groups, respectively, was detected in patients with severe COVID-19 as compared with other blood groups. Locus 3p21.31, contains several genes with functions that are potentially relevant to COVID-19 susceptibility or prognosis. One of the candidates detected is SLC6A20, which encodes a transporter and functionally interacts with ACE2 (Ellinghaus et al. 2020). In addition, the locus also contains genes that encode chemokine receptors (CCR9; CXCR6) related to the immune response to airway pathogens (Wein et al. 2019). Using similar approaches, the HLA region was also confirmed to be important in the host response to viral infection (Kachuri et al. 2020). Overall the results from these genomic approaches are consistent with the maladaptive cytokine release in response to infection and other stimuli, known as ‘cytokine storm’. At both the local and systemic levels this causes substantial immune damage that has been reported as part of the pathogenesis in severe COVID-19 patients (Debnath et al. 2020; Ye et al. 2020).
The status surrounding chloroquine and other drugs as potential anti-infective agents for COVID-19
Published in Expert Review of Respiratory Medicine, 2020
Over the past two decades, we have successfully used old drugs such as the antibiotic and anticancer drug bleomycin to determine how cancer cells confer resistance to this agent. Using state-of-art drug screening approaches, we discovered that there is an uptake transporter called hCT2 (SLC22A16) that resides on the cell surface, which brings bleomycin into the cells [1]. Without the hCT2 transporter, cancer cells become extremely resistant to the cytotoxic and genotoxic effects of bleomycin [1]. Thus, a functional hCT2 is needed before administering the drug [2]. The same drug-screening program led to other findings including the observation that bleomycin has other properties whereby it can damage RNA, and not only DNA. We recently proposed that bleomycin can be repurposed and used as an antiviral agent [2]. Since many viruses such as SARS-CoV2, the cause of the COVID-19 pandemic, contain RNA as the genetic material it seems reasonable that bleomycin can be used to target the viral RNA for destruction. In the first place, our findings also raise a key question how the battery of drugs, including antivirals and antimalarials, that are being tested to potentially manage the treatment of COVID-19 enter the affected cells [3]. The focus of this report is to summarize the current state of the anti-malarial drugs chloroquine and hydroxychloroquine, as well as other agents, as potential treatment regimen for COVID-19. A central dogma on the in vivo actions of drug combinations must rely on efficient uptake of the molecules, and recent findings are pointing to the direction of transporters such as SLC6A20 [4]