Результаты внедрения новой формы управляемой самостоятельной работы студентов в учебный процесс на кафедре патофизиологии

МЕДИЦИНСКИЕ ИНСТИТУТЫОБУЧЕНИ

Studies on immune impairment in chronic Hepatitis C virus infection / Barathan Muttiah

Hepatitis C virus (HCV) is a blood-borne pathogen that infects hepatocytes and causes widespread destruction to the host immune system. Estimates suggest that HCV has infected ~200 million people worldwide, and ~350,000-500,000 people die every year from HCV-associated hepatic and extra-hepatic complications. HCV has developed numerous mechanisms to evade host immune responses to establish persistence. Due to the lack of a preventive vaccine, the mainstay of current treatment is a combination therapy with interferon-α and ribavirin. The molecular mechanisms underlying the establishment of persistent HCV disease remain poorly understood. A better understanding of these mechanisms would aid design newer therapeutic targets and improve the quality of life of HCV-infected patients Here, we aimed to investigate the role of spontaneous apoptosis of immune cells, expansion of senescent and exhausted virus-specific T-cells, as well as potential depletion of circulating mucosal-associated invariant T (MAIT) cells, with immune impairment in chronic HCV (CHC) disease. We recruited 62 chronically-infected HCV patients and 62 healthy controls (HCs) to conduct a cross-sectional investigation. Peripheral blood mononuclear cells (PBMCs) were isolated, and co-cultured with HCV antigens and phytohaemagglutinin (PHA) individually prior to the investigations (except for apoptosis). Flow cytometry, quantitative real-time PCR (qRT-PCR), ELISA and QuantiGene Plex 2.0 analyses were employed to investigate apoptosis in immune cells. Multiparametric flow cytometry approaches were utilized to examine the phenotypes of immunosenescent T-cells and expression of co-inhibitory molecules on HCV-specific T cells, together with frequencies of circulating MAIT cells. Expression of molecules associated with T-cell inhibition was confirmed by qRT-PCR. iv The ability of HCV to induce apoptosis in immune cells correlated with the increase of apoptotic cells (Annexin V+PI+) and cellular reactive oxygen species (ROS). QuantiGene Plex 2.0 analysis showed differential regulation of apoptotic pathways involved in mitochondrial or activation of death receptors. Besides, the onset of immunosenescence was clearly evident from the up-regulation of HLA-DR, CD38, CD57 and CD127 on HCV-specific CD4+ and CD8+ T-cells of chronic HCV-infected patients. Furthermore, chronic HCV-infected patients displayed relatively significant increase of late-differentiated T-cells. Chronic HCV infection also resulted in significantly increased expressions of PD-1, CTLA-4, CD160 and TRAIL on HCV-specific CD4+ and CD8+ T cells suggestive of immune exhaustion. Increase in the levels of pro-inflammatory cytokines was also observed in PBMC cultures of chronic HCV-infected patients. MAIT cells of HCs expressed elevated levels of CCR5 and CCR6. Conversely, all these receptors were down-regulated on the circulating MAIT cells of chronic HCV-infected patients. Expression of PD-1 was also higher on MAIT cells of chronic HCV-infected patients relative to controls. In conclusion, our observation suggests the spontaneous onset of apoptosis signaling in chronic HCV disease, and increased frequency of late-senescent T-cells that lack the potential to survive, possibly contributing to viral persistence. These phenotypically defective HCV-specific T-cells may likely contribute to inadequate virus-specific T-cell responses. Decreased frequency of MAIT cells with elevated levels of PD-1 may result in diminished mucosal defense attributes, and could potentially contribute to HCV disease progression

Extracellular Vesicles in Breast Cancer: From Intercellular Communication to Therapeutic Opportunities

Breast cancer, a multifaceted and heterogeneous disease, poses significant challenges in terms of understanding its intricate resistance mechanisms and devising effective therapeutic strategies. This review provides a comprehensive overview of the intricate landscape of extracellular vesicles (EVs) in the context of breast cancer, highlighting their diverse subtypes, biogenesis, and roles in intercellular communication within the tumour microenvironment (TME). The discussion spans various aspects, from EVs and stromal cells in breast cancer to their influence on angiogenesis, immune response, and chemoresistance. The impact of EV production in different culture systems, including two dimensional (2D), three dimensional (3D), and organoid models, is explored. Furthermore, this review delves into the therapeutic potential of EVs in breast cancer, presenting emerging strategies such as engineered EVs for gene delivery, nanoplatforms for targeted chemotherapy, and disrupting tumour derived EVs as a treatment approach. Understanding these complex interactions of EV within the breast cancer milieu is crucial for identifying resistance mechanisms and developing new therapeutic targets

The Profound Influence of Gut Microbiome and Extracellular Vesicles on Animal Health and Disease

The animal gut microbiota, comprising a diverse array of microorganisms, plays a pivotal role in shaping host health and physiology. This review explores the intricate dynamics of the gut microbiome in animals, focusing on its composition, function, and impact on host–microbe interactions. The composition of the intestinal microbiota in animals is influenced by the host ecology, including factors such as temperature, pH, oxygen levels, and nutrient availability, as well as genetic makeup, diet, habitat, stressors, and husbandry practices. Dysbiosis can lead to various gastrointestinal and immune-related issues in animals, impacting overall health and productivity. Extracellular vesicles (EVs), particularly exosomes derived from gut microbiota, play a crucial role in intercellular communication, influencing host health by transporting bioactive molecules across barriers like the intestinal and brain barriers. Dysregulation of the gut–brain axis has implications for various disorders in animals, highlighting the potential role of microbiota-derived EVs in disease progression. Therapeutic approaches to modulate gut microbiota, such as probiotics, prebiotics, microbial transplants, and phage therapy, offer promising strategies for enhancing animal health and performance. Studies investigating the effects of phage therapy on gut microbiota composition have shown promising results, with potential implications for improving animal health and food safety in poultry production systems. Understanding the complex interactions between host ecology, gut microbiota, and EVs provides valuable insights into the mechanisms underlying host–microbe interactions and their impact on animal health and productivity. Further research in this field is essential for developing effective therapeutic interventions and management strategies to promote gut health and overall well-being in animals

Unseen Weapons: Bacterial Extracellular Vesicles and the Spread of Antibiotic Resistance in Aquatic Environments

This paper sheds light on the alarming issue of antibiotic resistance (ABR) in aquatic environments, exploring its detrimental effects on ecosystems and public health. It examines the multifaceted role of antibiotic use in aquaculture, agricultural runoff, and industrial waste in fostering the development and dissemination of resistant bacteria. The intricate interplay between various environmental factors, horizontal gene transfer, and bacterial extracellular vesicles (BEVs) in accelerating the spread of ABR is comprehensively discussed. Various BEVs carrying resistance genes like blaCTX-M, tetA, floR, and sul/I, as well as their contribution to the dominance of multidrug-resistant bacteria, are highlighted. The potential of BEVs as both a threat and a tool in combating ABR is explored, with promising strategies like targeted antimicrobial delivery systems and probiotic-derived EVs holding significant promise. This paper underscores the urgency of understanding the intricate interplay between BEVs and ABR in aquatic environments. By unraveling these unseen weapons, we pave the way for developing effective strategies to mitigate the spread of ABR, advocating for a multidisciplinary approach that includes stringent regulations, enhanced wastewater treatment, and the adoption of sustainable practices in aquaculture

Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion

Hepatitis C virus (HCV) represents a challenging global health threat to similar to 200 million infected individuals. Clinical data suggest that only similar to 10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.Funding Agencies|High Impact Research (HIR), University of Malaya [625/1/HIR/139]; University Malaya Fellowship Scheme [FG019-17AFR]; Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine (SvenskaLakaresallskapet)</p

Attrition of TCR Va7.2+CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8+ T cells co-expressing the semi-invariant TCR V alpha 7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161++ CD8+ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naive HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naive HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono-and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono-and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.Funding Agencies|High Impact Research [UM.C/625/1/HIR/MOHE/MED/014]; University of Malaya Research of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine</p

Percentage of CD8⁺ T cells expressing CD161⁺⁺ across different study groups.

<p><b>(A)</b> Scatter plots (gated on the CD3⁺ T-cell population) show co-staining with CD8 and CD161 on representative samples from 5 different clinical groups: CPTNs, CPTPs, HVTNs, HVTPs, and HCs. <b>(B)</b> CD161⁺⁺CD8⁺ T (MAIT cell) frequency in HCs showed significantly increased MAIT cell levels compared to other study groups. <b>(C)</b> CD161⁺CD8⁺ T cell frequency showed no difference across the different study groups. <b>(D-E)</b> CD161⁺⁺CD8⁺ MAIT cell frequency in subjects with HIV mono-infection and HIV/TB co-infection shows no significant correlation with either HIV plasma viral load (copies/mL) or CD4⁺ T-cell counts (cells/mm³). All graphs show median (red bars) and range (blue whiskers); <i>P</i> values are reported for two-sided Mann-Whitney tests with threshold for significance <i>P</i> = 0.025 after Bonferroni correction for 2 comparisons. Correlations between MAIT cell frequency and markers of HIV disease progression were assessed using two-tailed non-parametric Spearman’s rank. (Note: TN, treatment naïve; TP, treatment positive; HC, healthy control; CP, HIV/TB co-infection; HV, HIV mono-infection).</p