Biology subjects

Loboda, A.

Publications and source records attributed to Loboda, A..

6 recordsLinked to original sources

bioRxiv2023

Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease

The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabAs binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

immunology↗

bioRxiv2023

Understanding Complex Trait Susceptibilities and Ethnical Diversity in a Sample of 4,145 Russians Through Analysis of Clinical and Genetic Data

The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ethnicities. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of GWAS results for 465 unique phenotypes and allele frequencies.

genetics↗

bioRxiv2022

GCDPipe: risk gene, cell type, and drug ranking for complex traits

We introduce a user-friendly machine learning tool for risk gene, cell type, and drug ranking for complex traits - GCDPipe. It uses gene-level GWAS-derived data and publicly available expression data to train a model for prediction of disease risk genes and relevant cell types. Gene-ranking information is then coupled with known drug targets data to prioritize drugs based on their estimated functional effects associated with identified risk genes. The pipeline was tested in two case studies: inflammatory bowel disease (IBD) and schizophrenia, then it was applied to Alzheimers disease to investigate potential options for drug repurposing. The results show that GCDPipe is an effective tool to unify genetic risk factors with cellular context and known drug targets.

bioinformatics↗

bioRxiv2021

Antibodies to ILT3 abrogate myeloid immunosuppression and enable tumor killing

Tumor myeloid suppressor cells impede response to T cell checkpoint immunotherapy. Immunoglobulin-like transcript 3 (ILT3, gene name, LILRB4) expressed on dendritic cells (DCs) promotes antigen-specific tolerance. Circulating monocytic MDSCs that express ILT3 have been linked to clinical outcomes and a soluble form of ILT3 is elevated in certain cancers. We find that LILRB4 expression is correlated with Gene Expression Profile of T-cell inflamed tumor microenvironment shown to be significantly associated with response to the anti-PD1 antibody pembrolizumab across several tumor types. A potent and selective anti-ILT3 mAb effectively antagonized IL-10 polarization of DCs and enabled T cell priming. In an MLR assay anti-ILT3 combined with pembrolizumab afforded greater CD8+ T cell activation compared to either agent alone. Anti-ILT3 antibodies impaired the acquisition of a suppressive phenotype of monocytes co-cultured with SK-MEL-5 cancer cells, accompanied by a reduction in surface detection of peptidase inhibitor 16, a cis interaction candidate for ILT3. Growth of myeloid cell-abundant SK-MEL-5 tumors was abrogated by ILT3 blockade and remodeling of the immune tumor microenvironment was evident by CyTOF. These data support the testing of anti-ILT3 antibodies for the treatment of a wide range of solid tumors replete with myeloid cells.

cancer biology↗

bioRxiv2020

STUB1 is an intracellular checkpoint for interferon gamma sensing

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFN{gamma}) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFN{gamma} response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFN{gamma} sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.

cancer biology↗

bioRxiv2020

Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency

Current therapeutic interventions to eradicate latent HIV ("reservoir") and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, "INRs") and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-{beta} signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family - i.e. -ketobutyrate) were correlated with Treg frequencies in "Senescent-INRs" ex vivo, triggered the differentiation of TGF-{beta} producing Tregs and promoted HIV latency establishment in vitro. These cascades, downstream of PD-1/TGF-{beta}, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIV ex vivo. Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-{beta} specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

immunology↗