Neurological complications of AIDS (NeuroAIDS) include primary HIV-associated neurocognitive disorder (HAND). OAS3 is an enzyme belonging to the 2', 5' oligoadenylate synthase family induced by type I interferons and involved in the degradation of both viral and endogenous RNA. Here, we used microarray datasets from NCBI of brain samples of non-demented HIV-negative controls (NDC), HIV, deceased patients with HAND and encephalitis (HIVE) (treated and untreated with antiretroviral therapy, ART), and with HAND without HIVE. The HAND/HIVE patients were stratified according to the OAS3 gene expression. The genes positively and negatively correlated to the OAS3 gene expression were used to perform a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to sixteen signatures. Expression analysis revealed significantly higher OAS3 expression in HAND/HIVE and HAND/HIVE/ART compared with NDC. OAS3 expressed an excellent diagnostic ability to discriminate NDC from HAND/HIVE, HAND from HAND/HIVE, HAND from HAND/HIVE/ART, and HIV from HAND/HIVE. Noteworthy, OAS3 expression levels in the brains of HAND/HIVE patients were positively correlated with viral load in both peripheral blood and cerebrospinal fluid (CSF). Furthermore, deconvolution analysis revealed that the genes positively correlated to OAS3 expression were associated with inflammatory signatures. Neuronal activation profiles were significantly activated by the genes negatively correlated to OAS3 expression levels. Moreover, gene ontology analysis performed on genes characterizing the microglia signature highlighted an immune response as a main biological process. According to our results, genes positively correlated to OAS3 gene expression in the brains of HAND/HIVE patients are associated with inflammatory transcriptomic signatures and likely worse cognitive impairment.

• MeSH
• 2',5'-oligoadenylátsynthetasa genetika   metabolismus   MeSH
• HIV infekce * komplikace   MeSH
• HIV * genetika   metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• neurokognitivní poruchy komplikace   metabolismus   MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2'-5'-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype 'gttg' carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

• MeSH
• 2',5'-oligoadenylátsynthetasa genetika   MeSH
• COVID-19 * genetika   epidemiologie   virologie   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• SARS-CoV-2 * genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Slovenská republika MeSH

The interferon signalling system elicits a robust cytokine response against a wide range of environmental pathogenic and internal pathological signals, leading to induction of a subset of interferon-induced proteins. We applied DSS (disuccinimidyl suberate) mediated cross-linking mass spectrometry (CLMS) to capture novel protein-protein interactions within the realm of interferon induced proteins. In addition to the expected interferon-induced proteins, we identified novel inter- and intra-molecular cross-linked adducts for the canonical interferon induced proteins, such as MX1, USP18, OAS3, and STAT1. We focused on orthogonal validation of a cohort of novel interferon-induced protein networks formed by the HLA-A protein (H2BFS-HLA-A-HMGA1) using co-immunoprecipitation assay, and further investigated them by molecular dynamics simulation. Conformational dynamics of the simulated protein complexes revealed several interaction sites that mirrored the interactions identified in the CLMS findings. Together, we showcase a proof-of-principle CLMS study to identify novel interferon-induced signaling complexes and anticipate broader use of CLMS to identify novel protein interaction dynamics within the tumour microenvironment.

• MeSH
• HLA antigeny MeSH
• HLA-A antigeny MeSH
• hmotnostní spektrometrie metody   MeSH
• interferony * MeSH
• lidé MeSH
• proteiny * chemie   MeSH
• reagencia zkříženě vázaná chemie   MeSH
• thiolesterasa ubikvitinu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide. The recombinant BCG strain expressing the genetically detoxified A subunit of the thermolabile toxin from Escherichia coli (LTAK63) adjuvant (rBCG-LTAK63) has previously been shown to confer superior protection and immunogenicity compared to BCG in a murine TB infection model. To further investigate the immunological mechanisms induced by rBCG-LTAK63, we evaluated the immune responses induced by rBCG-LTAK63, BCG, and Mycobacterium tuberculosis (Mtb) H37Rv strains in experimental infections of primary human M1 and M2 macrophages at the transcriptomic and cytokine secretion levels. The rBCG-LTAK63-infected M1 macrophages more profoundly upregulated interferon-inducible genes such as IFIT3, OAS3, and antimicrobial gene CXCL9 compared to BCG, and induced higher levels of inflammatory cytokines such as IL-12(p70), TNF-β, and IL-15. The rBCG-LTAK63-infected M2 macrophages more extensively upregulated transcripts of inflammation-related genes, TAP1, GBP1, SLAMF7, TNIP1, and IL6, and induced higher levels of cytokines related to inflammation and tissue repair, MCP-3 and EGF, as compared to BCG. Thus, our data revealed an important signature of immune responses induced in human macrophages by rBCG-LTAK63 associated with increased inflammation, activation, and tissue repair, which may be correlated with a protective immune response against TB.

• Publikační typ
• časopisecké články MeSH

Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.

• MeSH
• adaptorové proteiny signální transdukční fyziologie   MeSH
• aktivace transkripce MeSH
• chemorezistence genetika   fyziologie   MeSH
• dvouvláknová RNA MeSH
• interferonový regulační faktor 7 MeSH
• interferony metabolismus   fyziologie   MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• poškození DNA genetika   fyziologie   MeSH
• proteiny vázající RNA MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH