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  1. From Fever to Action: Diagnosis, Treatment, and Prevention of Acute Undifferentiated Febrile Illnesses
    Barathan M
    Pathog Dis, 2024 Apr 13.
    PMID: 38614961 DOI: 10.1093/femspd/ftae006
    Acute Undifferentiated Febrile Illness (AUFI) presents a clinical challenge, often characterized by sudden fever, non-specific symptoms, and potential life-threatening implications. This review highlights the global prevalence, types, challenges, and implications of AUFI, especially in tropical and subtropical regions where infectious diseases thrive. It delves into the difficulties in diagnosis, prevalence rates, regional variations, and potential causes, ranging from bacterial and viral infections to zoonotic diseases. Furthermore, it explores treatment strategies, preventive measures, and the critical role of the One Health approach in addressing AUFI. The paper also addresses the emerging zoonotic risks and ongoing outbreaks, including COVID-19, Rickettsia spp., and other novel pathogens, emphasizing their impact on AUFI diagnosis and management. Challenges in resource-limited settings are analyzed, highlighting the need for bolstered healthcare infrastructure, enhanced diagnostics, and collaborative One Health strategies. Amidst the complexity of emerging zoonotic threats, this review underscores the urgency for a multifaceted approach to mitigate the growing burden of AUFI, ensuring early diagnosis, appropriate treatment, and effective prevention strategies.
  2. Naturally Occurring Phytochemicals to Target Breast Cancer Cell Signaling
    Barathan M, Vellasamy KM, Mariappan V, Venkatraman G, Vadivelu J
    Appl Biochem Biotechnol, 2023 Sep 29.
    PMID: 37773580 DOI: 10.1007/s12010-023-04734-0
    Almost 70% of clinically used antineoplastic drugs are originated from natural products such as plants, marine organism, and microorganisms and some of them are also structurally modified natural products. The naturally occurring drugs may specifically act as inducers of selective cytotoxicity, anti-metastatic, anti-mutagenic, anti-angiogenesis, antioxidant accelerators, apoptosis inducers, autophagy inducers, and cell cycle inhibitors in cancer therapy. Precisely, several reports have demonstrated the involvement of naturally occurring anti-breast cancer drugs in regulating the expression of oncogenic and tumor suppressors associated with carcinogen metabolism and signaling pathways. Anticancer therapies based on nanotechnology have the potential to improve patient outcomes through targeted therapy, improved drug delivery, and combination therapies. This paper has reviewed the current treatment for breast cancer and the potential disadvantages of those therapies, besides the various mechanism used by naturally occurring phytochemicals to induce apoptosis in different types of breast cancer. Along with this, the contribution of nanotechnology in improving the effectiveness of anticancer drugs was also reviewed. With the development of sciences and technologies, phytochemicals derived from natural products are continuously discovered; however, the search for novel natural products as chemoprevention drugs is still ongoing, especially for the advanced stage of breast cancer. Continued research and development in this field hold great promise for advancing cancer care and improving patient outcomes.
  3. Fulltext Unseen Weapons: Bacterial Extracellular Vesicles and the Spread of Antibiotic Resistance in Aquatic Environments
    Barathan M, Ng SL, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2024 Mar 07;25(6).
    PMID: 38542054 DOI: 10.3390/ijms25063080
    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.
  4. Fulltext The Profound Influence of Gut Microbiome and Extracellular Vesicles on Animal Health and Disease
    Barathan M, Ng SL, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2024 Apr 04;25(7).
    PMID: 38612834 DOI: 10.3390/ijms25074024
    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.
  5. Fulltext Hypericin-photodynamic therapy leads to interleukin-6 secretion by HepG2 cells and their apoptosis via recruitment of BH3 interacting-domain death agonist and caspases
    Barathan M, Mariappan V, Shankar EM, Abdullah BJ, Goh KL, Vadivelu J
    Cell Death Dis, 2013;4:e697.
    PMID: 23807226 DOI: 10.1038/cddis.2013.219
    Photodynamic therapy (PDT) has emerged as a capable therapeutic modality for the treatment of cancer. PDT is a targeted cancer therapy that reportedly leads to tumor cell apoptosis and/or necrosis by facilitating the secretion of certain pro-inflammatory cytokines and expression of multiple apoptotic mediators in the tumor microenvironment. In addition, PDT also triggers oxidative stress that directs tumor cell killing and activation of inflammatory responses. However, the cellular and molecular mechanisms underlying the role of PDT in facilitating tumor cell apoptosis remain ambiguous. Here, we investigated the ability of PDT in association with hypericin (HY) to induce tumor cell apoptosis by facilitating the induction of reactive oxygen species (ROS) and secretion of Th1/Th2/Th17 cytokines in human hepatocellular liver carcinoma cell line (HepG2) cells. To discover if any apoptotic mediators were implicated in the enhancement of cell death of HY-PDT-treated tumor cells, selected gene profiling in response to HY-PDT treatment was implemented. Experimental results showed that interleukin (IL)-6 was significantly increased in all HY-PDT-treated cells, especially in 1 μg/ml HY-PDT, resulting in cell death. In addition, quantitative real-time PCR analysis revealed that the expression of apoptotic genes, such as BH3-interacting-domain death agonist (BID), cytochrome complex (CYT-C) and caspases (CASP3, 6, 7, 8 and 9) was remarkably higher in HY-PDT-treated HepG2 cells than the untreated HepG2 cells, entailing that tumor destruction of immune-mediated cell death occurs only in PDT-treated tumor cells. Hence, we showed that HY-PDT treatment induces apoptosis in HepG2 cells by facilitating cytotoxic ROS, and potentially recruits IL-6 and apoptosis mediators, providing additional hints for the existence of alternative mechanisms of anti-tumor immunity in hepatocellular carcinoma, which contribute to long-term suppression of tumor growth following PDT.
  6. Fulltext Cytotoxic Activity of Isoniazid Derivative in Human Breast Cancer Cells
    Barathan M, Zulpa AK, Vellasamy KM, Mariappan V, Shivashekaregowda NKH, Ibrahim ZA, et al.
    In Vivo, 2021 8 20;35(5):2675-2685.
    PMID: 34410956 DOI: 10.21873/invivo.12551
    BACKGROUND/AIM: Isoniazid is an antibiotic used for the treatment of tuberculosis. Previously, we found that the isoniazid derivative (E)-N'-(2,3,4-trihydroxybenzylidene) isonicotinohydrazide (ITHB4) could be developed as novel antimycobacterial agent by lead optimization. We further explored the ability of this compound compared to zerumbone in inhibiting the growth of MCF-7 breast cancer cells.

    MATERIALS AND METHODS: Cytotoxicity was measured by the MTT assay and further confirmed via apoptosis, ROS, cell cycle, DNA fragmentation and cytokine assays.

    RESULTS: ITHB4 demonstrated a lower IC50 compared to zerumbone in inhibiting the proliferation of MCF-7 cells. ITHB4 showed no toxicity against normal breast and human immune cells. Apoptosis assay revealed that ITHB4, at a concentration equal to the IC50, induces apoptosis of MCF-7 cells and cell cycle arrest at the sub-G1 and G2/M phases. ITHB4 triggered accumulation of intracellular ROS and nuclear DNA fragmentation. Secretion of pro-inflammatory cytokines induced inflammation and potentially immunogenic cell death.

    CONCLUSION: ITHB4 has almost similar chemotherapeutic properties as zerumbone in inhibiting MCF-7 growth, and hence provide the basis for further experiments in animal models.

  7. Fulltext Hijacking of the Host's Immune Surveillance Radars by Burkholderia pseudomallei
    Mariappan V, Vellasamy KM, Barathan M, Girija ASS, Shankar EM, Vadivelu J
    Front Immunol, 2021;12:718719.
    PMID: 34456925 DOI: 10.3389/fimmu.2021.718719
    Burkholderia pseudomallei (B. pseudomallei) causes melioidosis, a potentially fatal disease for which no licensed vaccine is available thus far. The host-pathogen interactions in B. pseudomallei infection largely remain the tip of the iceberg. The pathological manifestations are protean ranging from acute to chronic involving one or more visceral organs leading to septic shock, especially in individuals with underlying conditions similar to COVID-19. Pathogenesis is attributed to the intracellular ability of the bacterium to 'step into' the host cell's cytoplasm from the endocytotic vacuole, where it appears to polymerize actin filaments to spread across cells in the closer vicinity. B. pseudomallei effectively evades the host's surveillance armory to remain latent for prolonged duration also causing relapses despite antimicrobial therapy. Therefore, eradication of intracellular B. pseudomallei is highly dependent on robust cellular immune responses. However, it remains ambiguous why certain individuals in endemic areas experience asymptomatic seroconversion, whereas others succumb to sepsis-associated sequelae. Here, we propose key insights on how the host's surveillance radars get commandeered by B. pseudomallei.
  8. Release of pro-inflammatory cytokines TNF-α, IFN-γ and IL-6 by Burkholderia pseudomallei- stimulated peripheral blood mononucleocytes of acute myeloid leukemia patients
    Zulpa AK, Barathan M, Iyadorai T, Chandramathi S, Vellasamy KM, Vadivelu J, et al.
    Trop Biomed, 2021 Jun 01;38(2):180-185.
    PMID: 34172708 DOI: 10.47665/tb.38.2.055
    Acute myeloid leukemia (AML) is a malignant disease progressed from abnormal production of immature myeloid cells, which is often associated with concurrent infections after diagnosis. It was widely established that infections are the major contributors to mortality in this group due to the prevalency of neutropenia. Gram-negative Burkholderia pseudomallei is the causative agent of melioidosis. This disease had been reported in several neutropenic cancer patients undergoing chemotherapy resulting in severe clinical presentations and high mortalities which is in need of critical attention. Studies show that cytokines are important mediators of melioidosis progression and low neutrophil counts are associated with progression of its severity. However, to date, there are no reports on cytokine production in neutropenic cancer patients who are prone to melioidosis. Hence, here we assessed the cytokine production in neutropenic AML patients by introducing B. pseudomallei to their peripheral blood mononuclear cell (PBMC) culture in vitro. We observed that inflammatory response related cytokines namely TNF-α, IFN-γ IL-6 and IL-10 were highly circulated in infected PBMCs suggesting that these cytokines may play important roles in the progression of severity in melioidosis infected neutropenic patients.
  9. Fulltext Online health information seeking among people with diabetes mellitus and its association with self-management
    Leelavathi M, Teh Rohaila J, Thenmolle A, Mohamad Salehuddin MS, Barathan M, Natasha PJ, et al.
    Medicine & Health, 2018;13(2):72-82.
    MyJurnal
    Diabetes requires dedicated self-management to be able to achieve good control and outcome as this is a lifelong condition. The internet offers an amazing wealth of health information which may influence diabetes self-management. The aim of this study was to determine the prevalence of online health information seeking among people with diabetes and its associated factors. About 380 participants answered the online health information seeking questionnaire developed from literature search and expert panel review. Diabetes Self-Management was assessed using the Diabetes Self-Management Questionnaire (DSMQ). The prevalence of online health information seeking among people with diabetes was 38.4%. Common information sought included diabetes treatment (82.9%) lifestyle modification (77.4%) and diabetes prevention (67.3%). A large majority (93.1%) felt that the online information on diabetes was useful. Doctors and printed reading materials were the most common sources of information for diabetes (94.2% & 65.3%). Lower median age (59 years, IQR = 11), having a family member with diabetes, (COR = 1.188) tertiary education (COR = 6.037) and those who are employed (COR = 3.880) have higher odds of seeking online diabetes related health information. However, there was no significant association between online health information seeking and diabetes self-management. Prevalence of online health information seeking among people with diabetes was at an acceptable level. However, it was not associated with optimal diabetic self-management. Doctors and printed information remain as popular sources of information and hence should be maintained.
    Study site: Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia

  10. Selective pks+ Escherichia coli strains induce cell cycle arrest and apoptosis in colon cancer cell line
    Zulpa AK, Barathan M, Iyadorai T, Mariappan V, Vadivelu J, Teh CSJ, et al.
    World J Microbiol Biotechnol, 2023 Oct 06;39(12):333.
    PMID: 37801157 DOI: 10.1007/s11274-023-03767-1
    pks+ Escherichia coli (E. coli) triggers genomic instability in normal colon cells which leads to colorectal cancer (CRC) tumorigenesis. Previously, we reported a significant presentation of pks+ E. coli strains in CRC patients' biopsies as compared to healthy cohorts. In this work, using an in vitro infection model, we further explored the ability of these strains in modulating cell cycle arrest and activation of apoptotic mediators in both primary colon epithelial cells (PCE) and CRC cells (HCT-116). Sixteen strains, of which eight tumours and the matching non-malignant tissues, respectively, from eight pks+ E. coli CRC patients were subjected to BrDU staining and cell cycle analysis via flow cytometry, while a subset of these strains underwent analysis of apoptotic mediators including caspase proteins, cellular reactive oxygen species (cROS) and mitochondrial membrane potential (MMP) via spectrophotometry as well as proinflammatory cytokines via flow cytometry. Data revealed that all strains exerted S-phase cell cycle blockade in both cells and G2/M phase in PCE cells only. Moreover, more significant upregulation of Caspase 9, cROS, proinflammatory cytokines and prominent downregulation of MMP were detected in HCT-116 cells indicating the potential role of pks related bacterial toxin as anticancer agent as compared to PCE cells which undergo cellular senescence leading to cell death without apparent upregulation of apoptotic mediators. These findings suggest the existence of discrepancies underlying the mechanism of action of pks+ E. coli on both cancer and normal cell lines. This work propounds the rationale to further understand the mechanism underlying pks+ E. coli-mediated CRC tumorigenesis and cancer killing.
  11. Anticancer effect of aromatic isoniazid derivatives in human gastric adenocarcinoma cells
    Barathan M, Shivashekaregowda NKH, Hoong SM, Vellasamy KM, Vadivelu J
    Toxicol Appl Pharmacol, 2023 Dec 15;481:116767.
    PMID: 38007073 DOI: 10.1016/j.taap.2023.116767
    Current treatments for stomach cancer are often effective in curing cancer. However, these treatments can also have significant side effects, and they may not be effective in all cases. Hence synthetic compounds exhibit promise as potential agents for cancer treatment. In a previous study, we identified (E)-N'- (2,3,4-trihydroxybenzylidene) isonicotinohydrazide (ITHB4) as a novel antimycobacterial derivative of isoniazid with cytotoxic effects on the MCF-7 breast cancer cell line. This led us to investigate the potential anti-cancer properties of ITHB4 against adenocarcinoma gastric (AGS) cell line. The cytotoxic effect of ITHB4 has been determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and further confirmed for anticancer properties by means of apoptosis, reactive oxygen species (ROS), nuclear fragmentation, lactate dehydrogenase (LDH), caspases, cytokines and morphological including phenotypic changes of cells assay. The ITHB4 demonstrated a lower IC50 in inhibiting growth of AGS cells at 24 h compared to 48 and 72 h. ITHB4 has also shown no toxicity human immune cells. Treatment of ITHB4 against AGS for 24 h eventually lead to formation of early apoptotic AGS cells, reduced mitochondrial membrane potential, nuclear condensation, and nuclear fragmentation lastly increased in ROS levels together with the release of LDH, and secretion of caspases. The altered cytokine profile in ITHB4 treated AGS hints at the possibility that ITHB4 may possess anti-tumor and anti-inflammatory properties. Our results in this study demonstrate that ITHB4 has almost similar chemotherapeutic properties against gastric adenocarcinoma cells compared to breast cancer cell. This is suggesting that the anticancer capabilities of this compound should be in vivo and clinically assessed.
  12. Comparative expression of pro-inflammatory and apoptotic biosignatures in chronic HBV-infected patients with and without liver cirrhosis
    Barathan M, Riazalhosseini B, Iyadorai T, Vellasamy KM, Vadivelu J, Chang LY, et al.
    Microb Pathog, 2021 Dec;161(Pt A):105231.
    PMID: 34619310 DOI: 10.1016/j.micpath.2021.105231
    The interplay of immune mediators is paramount to optimal host anti-viral immune responses, especially against chronic hepatitis B virus (HBV) infection. Here, we investigated the dynamic changes in host immune responses in chronic HBV-infected individuals with and without liver cirrhosis by examining the signatures of apoptosis and plasma levels of pro-inflammatory cytokines, chemokines, and cytotoxic proteins. A total of 40 chronic HBV patients with and without liver cirrhosis were studied for plasma levels of immune mediators, and signatures of apoptosis in peripheral blood mononuclear cells (PBMCs). The intracellular concentrations of reactive oxygen species (ROS) in patients with chronic HBV with liver cirrhosis was relatively higher as compared to chronic HBV patients. The onset of apoptosis was sustained due to ongoing liver inflammation in concert with plasma TNF-α and IL-6 levels. Plasma VEGF was upregulated among chronic HBV patients with liver cirrhosis, whereas CCL2, CCL5 and granzyme B levels were down-regulated. High levels of ROS, IL-6 and TNF-α correlated with ongoing inflammation among chronic HBV patients with liver cirrhosis, which likely attributed to the expression of biosignatures of apoptosis and activation in immune cells.
  13. Peripheral loss of CD8(+) CD161(++) TCRVα7·2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients
    Barathan M, Mohamed R, Vadivelu J, Chang LY, Saeidi A, Yong YK, et al.
    Eur J Clin Invest, 2016 Feb;46(2):170-80.
    PMID: 26681320 DOI: 10.1111/eci.12581
    Mucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear.
  14. Fulltext HIV-Mycobacterium tuberculosis co-infection: a 'danger-couple model' of disease pathogenesis
    Shankar EM, Vignesh R, Ellegård R, Barathan M, Chong YK, Bador MK, et al.
    Pathog Dis, 2014 Mar;70(2):110-8.
    PMID: 24214523 DOI: 10.1111/2049-632X.12108
    Tuberculosis (TB) and human immunodeficiency virus (HIV) infection interfere and impact the pathogenesis phenomena of each other. Owing to atypical clinical presentations and diagnostic complications, HIV/TB co-infection continues to be a menace for healthcare providers. Although the increased access to highly active antiretroviral therapy (HAART) has led to a reduction in HIV-associated opportunistic infections and mortality, the concurrent management of HIV/TB co-infection remains a challenge owing to adverse effects, complex drug interactions, overlapping toxicities and tuberculosis -associated immune reconstitution inflammatory syndrome. Several hypotheses have been put forward for the exacerbation of tuberculosis by HIV and vice versa supported by immunological studies. Discussion on the mechanisms produced by infectious cofactors with impact on disease pathology could shed light on how to design potential interventions that could decelerate disease progression. With no vaccine for HIV and lack of an effective vaccine for tuberculosis, it is essential to design strategies against HIV-TB co-infection.
  15. Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection
    Saeidi A, Chong YK, Yong YK, Tan HY, Barathan M, Rajarajeswaran J, et al.
    Cell Immunol, 2015 Sep;297(1):19-32.
    PMID: 26071876 DOI: 10.1016/j.cellimm.2015.05.005
    The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7Rα) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells.
  16. Chronic inflammation involves CCL11 and IL-13 to facilitate the development of liver cirrhosis and fibrosis in chronic hepatitis B virus infection
    Wong SW, Ting YW, Yong YK, Tan HY, Barathan M, Riazalhosseini B, et al.
    Scand J Clin Lab Invest, 2021 Apr;81(2):147-159.
    PMID: 33528280 DOI: 10.1080/00365513.2021.1876245
    The pathogenesis involving non-alcoholic fatty liver disease (NAFLD) in the context of chronic HBV (CHB) virus infection requires to be understood for developing improved modalities of diagnosis and treatment. We retrospectively investigated the association between NAFLD and CHB virus infection in the context of liver fibrosis. Among the 522 consecutive CHB patients who underwent transient elastography between years 2013 and 2016, we studied 455 subjects in the current investigation. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) scores were generally higher in patients with steatosis and fibrosis or cirrhosis. Antiviral treatment had significantly reduced the hepatitis B virus (HBV) viral load. Other liver function markers showed a significant positive correlation with both CAP and LSM scores. Plasma IL-13 was independently associated with increased CAP score where every increase of 1 unit of IL-13 was associated with an increase in CAP score by 0.98 unit. CCL11 was independently associated with LSM with every increase of CCL11 by a unit that, in turn, was associated with an increase of LSM score. We found that there was a high concurrence of NAFLD among patients with CHB virus infection. The presence of metabolic syndrome and chronic inflammation in CHB virus-infected patients were two independent factors that led to the progression of liver cirrhosis, with IL-13 playing the key role in linking the metabolic with the inflammatory components.
  17. CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides
    Barathan M, Mohamed R, Vadivelu J, Chang LY, Vignesh R, Krishnan J, et al.
    Cell Immunol, 2017 03;313:1-9.
    PMID: 28104239 DOI: 10.1016/j.cellimm.2016.12.002
    Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-β1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence.
  18. Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease
    Barathan M, Mohamed R, Saeidi A, Vadivelu J, Chang LY, Gopal K, et al.
    Eur J Clin Invest, 2015 May;45(5):466-74.
    PMID: 25721991 DOI: 10.1111/eci.12429
    Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses.
  19. Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
    Barathan M, Gopal K, Mohamed R, Ellegård R, Saeidi A, Vadivelu J, et al.
    Apoptosis, 2015 Apr;20(4):466-80.
    PMID: 25577277 DOI: 10.1007/s10495-014-1084-y
    Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(®) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.
  20. Fulltext Attrition of TCR Vα7.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated levels of PD-1 expression
    Saeidi A, Tien Tien VL, Al-Batran R, Al-Darraji HA, Tan HY, Yong YK, et al.
    PLoS One, 2015;10(4):e0124659.
    PMID: 25894562 DOI: 10.1371/journal.pone.0124659
    Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8(+) T cells co-expressing the semi-invariant TCR Vα7.2, 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 (HIV-1) 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-naïve HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naïve 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.
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