A protein coupling and molecular simulation analysis of the clinical mutants of androgen receptor revealed a higher binding for Leupaxin, to increase the prostate cancer invasion and motility.

Recently a novel coactivator, Leupaxin (LPXN), has been reported to interact with Androgen receptor (AR) and play a significant role in the invasion and progression of prostate cancer. The interaction between AR and LPXN occurs in a ligand-dependent manner and has been reported that the LIM domain in the Leupaxin interacts with the LDB (ligand-binding domain) domain AR. However, no detailed study is available on how the LPXN interacts with AR and increases the (prostate cancer) PCa progression. Considering the importance of the novel co-activator, LPXN, the current study also uses state-of-the-art methods to provide atomic-level insights into the binding of AR and LPXN and the impact of the most frequent clinical mutations H874Y, T877A, and T877S on the binding and function of LPXN. Protein coupling analysis revealed that the three mutants favour the robust binding of LPXN than the wild type by altering the hydrogen bonding network. Further understanding of the binding variations was explored through dissociation constant prediction which demonstrated similar reports as the docking results. A molecular simulation approaches further revealed the dynamic features which reported variations in the dynamics stability, protein packing, hydrogen bonding network, and residues flexibility index. Furthermore, we also assessed the protein motion and free energy landscape which also demonstrated variations in the internal dynamics. The binding free energy calculation revealed -32.95 ± 0.17 kcal/mol for the wild type, for H874Y the total binding energy (BFE) was -36.69 ± 0.11 kcal/mol, for T877A the BFE was calculated to be -38.78 ± 0.17 kcal/mol while for T877S the BFE -41.16 ± 0.12 kcal/mol. This shows that the binding of LPXN is increased by these mutations which consequently increase the PCa invasion and motility. In conclusion, the current study helps in understanding the protein networks and particular the coupling of AR-LPXN in prostate cancer and is of great interest in deciphering the molecular mechanism of disease and therapeutics developments.

SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues.

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.

ACE2, TMPRSS2, and L-SIGN Expression in Placentae From HIV-Positive Pregnancies Exposed to Antiretroviral Therapy-Implications for SARS-CoV-2 Placental Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding receptor ACE2 and the spike protein priming protease TMPRSS2 are coexpressed in human placentae. It is unknown whether their expression is altered in the context of HIV infection and antiretroviral therapy (ART). METHODS: We compared mRNA levels of SARS-CoV-2 cell-entry mediators ACE2, TMPRSS2, and L-SIGN by quantitative polymerase chain reaction in 105 placentae: 45 from pregnant women with HIV (WHIV) on protease inhibitor (PI)-based ART, 17 from WHIV on non-PI-based ART, and 43 from HIV-uninfected women. RESULTS: ACE2 levels were lower, while L-SIGN levels were higher, in placentae from WHIV on PI-based ART compared to those on non-PI-based ART and to HIV-uninfected women. TMPRSS2 levels were similar between groups. Black race was significantly associated with lower expression of ACE2 and higher expression of L-SIGN. ACE2 levels were significantly higher in placentae of female fetuses. CONCLUSIONS: We identified pregnant women of black race and WHIV on PI-based ART to have relatively lower expression of placental ACE2 than those of white race and HIV-uninfected women. This may potentially contribute to altered susceptibility to COVID-19 in these women, favorably by reduced viral entry or detrimentally by loss of ACE2 protection against hyperinflammation.

Expanding virus susceptibility spectrum of MDBK cells by expressing host receptors nectin 4 and TfR.

Cell-based vaccine manufacturing is a flexible and cost-effective approach for vaccine production which, however, requires cell adaptation to new vaccine strains. Generating one omnipotent or semi-omnipotent cell line feasible for the production of multiple viruses could help resolve this problem. We previously proposed virus Baltimore subtyping-based choice of receptors and a panel of minimally preferred receptors for the establishment of cells with a broad virus susceptibility spectrum. With the aim of establishing cells sensitive to viruses of livestocks including bovine, ovine and canine, we selected TfR and Nectin 4 from the minimally preferred receptor panel, and successfully sensitized the starting cell line MDBK to CPV and CDV infection. Our study is a preliminary validation of our previously identified associations between host receptor usage and virus Baltimore subtyping. Evidence from more viruses of the same Baltimore subtyping and more starting cell lines need to be used to consolidate our results.

An investigation into the molecular basis of cancer comorbidities in coronavirus infection.

Comorbidities in COVID-19 patients often worsen clinical conditions and may represent death predictors. Here, the expression of five genes, known to encode coronavirus receptors/interactors (ACE2, TMPRSS2, CLEC4M, DPP4 and TMPRSS11D), was investigated in normal and cancer tissues, and their molecular relationships with clinical comorbidities were investigated. Using expression data from GENT2 databases, we evaluated gene expression in all anatomical districts from 32 normal tissues in 3902 individuals. Functional relationships with body districts were analyzed by chilibot. We performed DisGeNet, genemania and DAVID analyses to identify human diseases associated with these genes. Transcriptomic expression levels were then analyzed in 31 cancer types and healthy controls from approximately 43 000 individuals, using GEPIA2 and GENT2 databases. By performing receiver operating characteristic analysis, the area under the curve (AUC) was used to discriminate healthy from cancer patients. Coronavirus receptors were found to be expressed in several body districts. Moreover, the five genes were found to associate with acute respiratory syndrome, diabetes, cardiovascular diseases and cancer (i.e. the most frequent COVID-19 comorbidities). Their expression levels were found to be significantly altered in cancer types, including colon, kidney, liver, testis, thyroid and skin cancers (P < 0.0001); AUC > 0.80 suggests that TMPRSS2, CLEC4M and DPP4 are relevant markers of kidney, liver, and thyroid cancer, respectively. The five coronavirus receptors are related to all main COVID-19 comorbidities and three show significantly different expression in cancer versus control tissues. Further investigation into their role may help in monitoring other comorbidities, as well as for follow-up of patients who have recovered from SARS-CoV-2 infection.