SARS-CoV-2 coronavirus uses for entry to human host cells a SARS-CoV receptor of the angiotensin-converting enzyme (ACE2) that catalyzes the conversion of angiotensin II into angiotensin (1-7). To understand the effect of ACE2 missense variants on protein structure, stability, and function, various bioinformatics tools were used including SIFT, PANTHER, PROVEAN, PolyPhen2.0, I. Mutant Suite, MUpro, SWISS-MODEL, Project HOPE, ModPred, QMEAN, ConSurf, and STRING. All twelve ACE2 nsSNPs were analyzed. Six ACE2 high-risk pathogenic nsSNPs (D427Y, R514G, R708W, R710C, R716C, and R768W) were found to be the most damaging by at least six software tools (cumulative score between 6 and 7) and exert deleterious effect on the ACE2 protein structure and likely function. Additionally, they revealed high conservation, less stability, and having a role in posttranslation modifications such a proteolytic cleavage or ADP-ribosylation. This in silico analysis provides information about functional nucleotide variants that have an impact on the ACE2 protein structure and function and therefore susceptibility to SARS-CoV-2.
The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.
Transmission of Human immunodeficiency virus type 1 (HIV-1) to permissive CD4+T cells requires the dissemination of virus from sites of infection to secondary lymphoid organs, where extensive viral replication occurs in CD4+T cells. Several studies demonstrated that DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) molecules located on the surface of Dendritic Cell subsets showed high-affinity binding to HIV-1 and Mycobacterium tuberculosis (Mtb). It is exploited by HIV-1 and Mtb as a part of their immune evasion strategy. In this study, we investigated the possible involvement of DC-SIGN encoding gene CD209 variants in the development of tuberculosis (TB) among HIV-1 infected patients as well as AIDS development and treatment response outcomes in a Moroccan population. Two single nucleotide polymorphisms in the CD209 promoter − 336A > G (rs4804803) and − 139G > A (rs2287886) were investigated. Two hundred eighteen Moroccan subjects living with HIV-1 were genotyped using direct DNA sequencing. Out of 218 patients, 90 were co-infected with Mtb. Stratification of patient was performed according to TB status: as HIV-1+/TB- and HIV-1+/TB+ patients and their AIDS status as: AIDS and Non-AIDS patients. Our results revealed that genotype and allele frequencies of the − 336A > G and − 139G > A polymorphisms were not significantly different between HIV-1+/TB- and HIV-1+/TB+ patients (p > 0.05). Likewise, the development of AIDS doesn’t appear to be affected by these two SNPs either (p > 0.05). Haplotype analysis showed that none of the 4 possible haplotypes is associated with HIV-1 and TB co-infection (p > 0.05). Interestingly, the analysis of the − 139 G > A genotype distribution according to the HIV-1 viral load showed an improvement in AG and GG patients, after ART, compared to AA patients (p = 0.0069 and p = 0.0476; respectively). Overall, -336A > G and − 139G > A polymorphisms don’t influence the susceptibility of HIV-1 infected individuals to develop TB and AIDS. However, -139G > A polymorphism may affect the response to treatment as measured by RNA viral load levels. Further investigations are needed for a better understanding of the role of DC-SIGN in HIV-1 infection to provide new therapeutic pathways.
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