Displaying publications 81 - 100 of 155 in total

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  1. 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.
  2. Rosli NA, Al-Maleki AR, Loke MF, Tay ST, Rofiee MS, Teh LK, et al.
    PLoS One, 2024;19(3):e0298434.
    PMID: 38446753 DOI: 10.1371/journal.pone.0298434
    In H. pylori infection, antibiotic-resistance is one of the most common causes of treatment failure. Bacterial metabolic activities, such as energy production, bacterial growth, cell wall construction, and cell-cell communication, all play important roles in antimicrobial resistance mechanisms. Identification of microbial metabolites may result in the discovery of novel antimicrobial therapeutic targets and treatments. The purpose of this work is to assess H. pylori metabolomic reprogramming in order to reveal the underlying mechanisms associated with the development of clarithromycin resistance. Previously, four H. pylori isolates were induced to become resistant to clarithromycin in vitro by incrementally increasing the concentrations of clarithromycin. Bacterial metabolites were extracted using the Bligh and Dyer technique and analyzed using metabolomic fingerprinting based on Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-Q-ToF-MS). The data was processed and analyzed using the MassHunter Qualitative Analysis and Mass Profiler Professional software. In parental sensitivity (S), breakpoint isolates (B), and induced resistance isolates (R) H. pylori isolates, 982 metabolites were found. Furthermore, based on accurate mass, isotope ratios, abundances, and spacing, 292 metabolites matched the metabolites in the Agilent METLIN precise Mass-Personal Metabolite Database and Library (AM-PCDL). Several metabolites associated with bacterial virulence, pathogenicity, survival, and proliferation (L-leucine, Pyridoxone [Vitamine B6], D-Mannitol, Sphingolipids, Indoleacrylic acid, Dulcitol, and D-Proline) were found to be elevated in generated resistant H. pylori isolates when compared to parental sensitive isolates. The elevated metabolites could be part of antibiotics resistance mechanisms. Understanding the fundamental metabolome changes in the course of progressing from clarithromycin-sensitive to breakpoint to resistant in H. pylori clinical isolates may be a promising strategy for discovering novel alternatives therapeutic targets.
  3. Choh LC, Ong GH, Vellasamy KM, Kalaiselvam K, Kang WT, Al-Maleki AR, et al.
    PMID: 23386999 DOI: 10.3389/fcimb.2013.00005
    The genus Burkholderia consists of diverse species which includes both "friends" and "foes." Some of the "friendly" Burkholderia spp. are extensively used in the biotechnological and agricultural industry for bioremediation and biocontrol. However, several members of the genus including B. pseudomallei, B. mallei, and B. cepacia, are known to cause fatal disease in both humans and animals. B. pseudomallei and B. mallei are the causative agents of melioidosis and glanders, respectively, while B. cepacia infection is lethal to cystic fibrosis (CF) patients. Due to the high rate of infectivity and intrinsic resistance to many commonly used antibiotics, together with high mortality rate, B. mallei and B. pseudomallei are considered to be potential biological warfare agents. Treatments of the infections caused by these bacteria are often unsuccessful with frequent relapse of the infection. Thus, we are at a crucial stage of the need for Burkholderia vaccines. Although the search for a prophylactic therapy candidate continues, to date development of vaccines has not advanced beyond research to human clinical trials. In this article, we review the current research on development of safe vaccines with high efficacy against B. pseudomallei, B. mallei, and B. cepacia. It can be concluded that further research will enable elucidation of the potential benefits and risks of Burkholderia vaccines.
  4. Sim JH, Abdul Aziz YF, Mansor A, Vijayananthan A, Foong CC, Vadivelu J
    Med Educ Online, 2015;20:26185.
    PMID: 25697602 DOI: 10.3402/meo.v20.26185
    INTRODUCTION: The purpose of this study was to compare students' performance in the different clinical skills (CSs) assessed in the objective structured clinical examination.

    METHODS: Data for this study were obtained from final year medical students' exit examination (n=185). Retrospective analysis of data was conducted using SPSS. Means for the six CSs assessed across the 16 stations were computed and compared.

    RESULTS: Means for history taking, physical examination, communication skills, clinical reasoning skills (CRSs), procedural skills (PSs), and professionalism were 6.25±1.29, 6.39±1.36, 6.34±0.98, 5.86±0.99, 6.59±1.08, and 6.28±1.02, respectively. Repeated measures ANOVA showed there was a significant difference in the means of the six CSs assessed [F(2.980, 548.332)=20.253, p<0.001]. Pairwise multiple comparisons revealed significant differences between the means of the eight pairs of CSs assessed, at p<0.05.

    CONCLUSIONS: CRSs appeared to be the weakest while PSs were the strongest, among the six CSs assessed. Students' unsatisfactory performance in CRS needs to be addressed as CRS is one of the core competencies in medical education and a critical skill to be acquired by medical students before entering the workplace. Despite its challenges, students must learn the skills of clinical reasoning, while clinical teachers should facilitate the clinical reasoning process and guide students' clinical reasoning development.

  5. Foong CC, Bashir Ghouse NL, Lye AJ, Pallath V, Hong WH, Vadivelu J
    Ann Med, 2022 Dec;54(1):195-210.
    PMID: 35019800 DOI: 10.1080/07853890.2021.1967440
    BACKGROUND: Poor academic performance and failure can cause undesired effects for students, schools, and society. Understanding why some students fail while their peers succeed is important to enhance student performance. Therefore, this study explores the differences in the learning process between high- and low-achieving pre-clinical medical students from a theory of action perspective.

    METHODS: This study employed a qualitative instrumental case study design intended to compare two groups of students-high-achieving students (n = 14) and low-achieving students (n = 5), enrolled in pre-clinical medical studies at the Universiti Malaya, Malaysia. Data were collected through reflective journals and semi-structured interviews. Regarding journaling, participants were required to recall their learning experiences of the previous academic year. Two analysts coded the data and then compared the codes of high- and low-achieving students. The third analyst reviewed the codes. Themes were identified iteratively, working towards comparing the learning processes of high- and low-achieving students.

    RESULTS: Data analysis revealed four themes-motivation and expectation, study methods, self-management, and flexibility of mindset. First, high-achieving students were more motivated and had higher academic expectations than low-achieving students. Second, high-achieving students adopted study planning and deep learning approaches, whereas low-achieving students adopted superficial learning approaches. Third, in contrast to low-achieving students, high-achieving students exhibited better time management and studied consistently. Finally, high-achieving students proactively sought external support and made changes to overcome challenges. In contrast, low-achieving students were less resilient and tended to avoid challenges.

    CONCLUSION: Based on the theory of action, high-achieving students utilize positive governing variables, whereas low-achieving students are driven by negative governing variables. Hence, governing variable-based remediation is needed to help low-achieving students interrogate the motives behind their actions and realign positive governing variables, actions, and intended outcomes.Key MessagesThis study found four themes describing the differences between high- and low-achieving pre-clinical medical students: motivation and expectation, study methods, self-management, and flexibility of mindset.Based on the theory of action approach, high-achieving pre-clinical medical students are fundamentally different from their low-achieving peers in terms of their governing variables, with the positive governing variables likely to have guided them to act in a manner beneficial to and facilitating desirable academic performance.Governing variable-based remediation may help students interrogate the motives of their actions.

  6. Mariappan V, Vellasamy KM, Mohamad NA, Subramaniam S, Vadivelu J
    Front Microbiol, 2021;12:718774.
    PMID: 34759896 DOI: 10.3389/fmicb.2021.718774
    On a global scale, antimicrobial resistance (AMR) is recognized as a One Health challenge due to the continual and increased development and distribution of resistant microbes and genes among humans, animals, and the environment. These sectors contribute to the increase in AMR, as antibiotics are widely used in healthcare to treat or prevent bacterial infection; as growth enhancers, therapeutics and metaphylactics in animal husbandry; and transmitted in the environment through irrigation using wastewater or inappropriate disposal and treatment of human and agricultural waste. However, there is a major drawback in terms of the lack of research assessing the coexistence of AMR in these sectors. Extensive research highlighted food-animal manufacture structures that are likely to harbor reservoirs or promote transmission of AMR, in addition to increasing human colonization with AMR commensal bacteria. Numerous antibiotic stewardship policies have been designed and implemented in medical practices and animal husbandry in high- and middle-income countries. However, research concentrating on high-income settings, attitudes, emotions, and beliefs on the utilization of antimicrobials remain underexplored in lower- and middle-income countries such as Malaysia. Microbiological, epidemiological, and social science exploration are required at community and farming across the One Health range to fill huge gaps in information and knowledge of AMR. Manipulating human activities and character associated with antibiotics is a multifaceted progression that includes elements like knowledge, social behavior, attitudes, approaches, social standards, socioeconomic settings, peer pressure, experiences, and biophysical environment. Therefore, understanding these aspects in the utilization of antimicrobial drugs among the different sectors is essential to develop and implement policies to curb AMR development and transmission that overarch all sectors within the One Health consortium in Malaysia.
  7. Zulkefli NJ, Mariappan V, Vellasamy KM, Chong CW, Thong KL, Ponnampalavanar S, et al.
    PeerJ, 2016;4:e1802.
    PMID: 26998408 DOI: 10.7717/peerj.1802
    Background. Central intermediary metabolism (CIM) in bacteria is defined as a set of metabolic biochemical reactions within a cell, which is essential for the cell to survive in response to environmental perturbations. The genes associated with CIM are commonly found in both pathogenic and non-pathogenic strains. As these genes are involved in vital metabolic processes of bacteria, we explored the efficiency of the genes in genotypic characterization of Burkholderia pseudomallei isolates, compared with the established pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) schemes. Methods. Nine previously sequenced B. pseudomallei isolates from Malaysia were characterized by PFGE, MLST and CIM genes. The isolates were later compared to the other 39 B. pseudomallei strains, retrieved from GenBank using both MLST and sequence analysis of CIM genes. UniFrac and hierachical clustering analyses were performed using the results generated by both MLST and sequence analysis of CIM genes. Results. Genetic relatedness of nine Malaysian B. pseudomallei isolates and the other 39 strains was investigated. The nine Malaysian isolates were subtyped into six PFGE profiles, four MLST profiles and five sequence types based on CIM genes alignment. All methods demonstrated the clonality of OB and CB as well as CMS and THE. However, PFGE showed less than 70% similarity between a pair of morphology variants, OS and OB. In contrast, OS was identical to the soil isolate, MARAN. To have a better understanding of the genetic diversity of B. pseudomallei worldwide, we further aligned the sequences of genes used in MLST and genes associated with CIM for the nine Malaysian isolates and 39 B. pseudomallei strains from NCBI database. Overall, based on the CIM genes, the strains were subtyped into 33 profiles where majority of the strains from Asian countries were clustered together. On the other hand, MLST resolved the isolates into 31 profiles which formed three clusters. Hierarchical clustering using UniFrac distance suggested that the isolates from Australia were genetically distinct from the Asian isolates. Nevertheless, statistical significant differences were detected between isolates from Malaysia, Thailand and Australia. Discussion. Overall, PFGE showed higher discriminative power in clustering the nine Malaysian B. pseudomallei isolates and indicated its suitability for localized epidemiological study. Compared to MLST, CIM genes showed higher resolution in distinguishing those non-related strains and better clustering of strains from different geographical regions. A closer genetic relatedness of Malaysian isolates with all Asian strains in comparison to Australian strains was observed. This finding was supported by UniFrac analysis which resulted in geographical segregation between Australia and the Asian countries.
  8. Munusamy K, Loke MF, Vadivelu J, Tay ST
    Microb Pathog, 2021 Mar;152:104614.
    PMID: 33202254 DOI: 10.1016/j.micpath.2020.104614
    Candidiasis is the most common fungal infection associated with high morbidity and mortality among immunocompromised patients. The ability to form biofilm is essential for Candida albicans pathogenesis and drug resistance. In this study, the planktonic cell and biofilm proteomes of C. albicans SC5314 strain analyzed using Liquid Chromatography-Mass Spectrometry (LC-MS) were compared. In total, 280 and 449 proteins are annotated from the planktonic cell and biofilm proteomes, respectively. The biofilm proteome demonstrated significantly higher proportion of proteins associated with the endomembrane system, mitochondrion and cytoplasm than planktonic proteome. Among proteins detected, 143 and 207 biological processes are annotated, of which, 38 and 102 are specific to the planktonic cell and biofilm proteomes, respectively, while 105 are common biological processes. The specific biological processes of C. albicans planktonic cell proteome are associated with cell polarity, energy metabolism and nucleotide (purine) metabolism, oxido-reduction coenzyme metabolic process, monosaccharide and amino acid (methionine) biosynthesis, regulation of anatomical structure morphogenesis and cell cycling, and single organism reproduction. Meanwhile, regulation of cellular macromolecule biosynthesis and metabolism, transcription and gene expression are major biological processes specifically associated with C. albicans biofilm proteome. Biosynthesis of leucine, isoleucine, and thiocysteine are highlighted as planktonic-related pathways, whereas folate metabolism, fatty acid metabolism and biosynthesis of amino acids (lysine, serine and glycine) are highlighted as biofilm-related pathways. In summary, LC-MS-based proteomic analysis reveals different adaptative strategies of C. albicans via specific biological and metabolic processes for planktonic cell and biofilm lifestyles. The mass spectrometry data are available via ProteomeXchange with identifiers PXD007830 (for biofilm proteome) and PXD007831 (for planktonic cell proteome).
  9. Munusamy K, Vadivelu J, Tay ST
    Rev Iberoam Micol, 2018 03 12;35(2):68-72.
    PMID: 29544734 DOI: 10.1016/j.riam.2017.07.001
    BACKGROUND: Biofilm is known to contribute to the antifungal resistance of Candida yeasts. Aureobasidin A (AbA), a cyclic depsipeptide targeting fungal sphingolipid biosynthesis, has been shown to be effective against several Candida species.

    AIMS: The aim of this study was to investigate Candida biofilm growth morphology, its biomass, metabolic activity, and to determine the effects of AbA on the biofilm growth.

    METHODS: The biofilm forming ability of several clinical isolates of different Candida species from our culture collection was determined using established methods (crystal violet and XTT assays). The determination of AbA planktonic and biofilm MICs was performed based on a micro-broth dilution method. The anti-biofilm effect of AbA on Candida albicans was examined using field emission scanning electron microscope (FESEM) analysis.

    RESULTS: A total of 35 (29.7%) of 118 Candida isolates were regarded as biofilm producers in this study. Candida parapsilosis was the largest producer, followed by Candida tropicalis and C. albicans. Two morphological variants of biofilms were identified in our isolates, with 48.6% of the isolates showing mainly yeast and pseudohyphae-like structures, while the remaining ones were predominantly filamentous forms. The biofilm producers were divided into two populations (low and high), based on the ability in producing biomass and their metabolic activity. Candida isolates with filamentous growth, higher biomass and metabolic activity showed lower AbA MIC50 (at least fourfold), compared to those exhibiting yeast morphology, and lower biomass and metabolic activity. The observation of filament detachment and the almost complete removal of biofilm from AbA-treated C. albicans biofilm in FESEM analysis suggests an anti-biofilm effect of AbA.

    CONCLUSIONS: The variability in the growth characteristics of Candida biofilm cultures affects susceptibility to AbA, with higher susceptibility noted in biofilm cultures exhibiting filamentous form and high biomass/metabolic activity.

  10. Wong KT, Vadivelu J, Puthucheary SD, Tan KL
    Pathology, 1996 May;28(2):188-91.
    PMID: 8743829
    In order to assess the usefulness of immunohistochemistry in the diagnosis of melioidosis, an infection by Burkholderia pseudomallei, polyclonal antibodies were applied to tissues from known cases of melioidosis and to other infected tissues. Formalin-fixed, paraffin-embedded tissues were stained by a modified immunoperoxidase technique. In autopsy tissues with inflammatory lesions of melioidosis, the cytoplasm of phagocytes and intact bacilli, both intra- and extracellular, were stained very strongly positive. Relatively more focal positive staining was observed in some but not all surgical biopsies from proven cases of melioidosis. In granulomas staining was mainly found in the central necrotic areas, with little staining of peripheral phagocytes. All control materials stained negative. Immunohistochemistry appears to be a useful diagnostic tool in melioidosis.
  11. Hong WH, Vadivelu J, Daniel EG, Sim JH
    Med Educ Online, 2015;20:27561.
    PMID: 26314338 DOI: 10.3402/meo.v20.27561
    Studies have shown the importance of metacognition in medical education. Metacognitive skills consist of two dimensions: knowledge of metacognition and regulation of metacognition.
  12. 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.
  13. See JX, Samudi C, Saeidi A, Menon N, Choh LC, Vadivelu J, et al.
    PLoS Negl Trop Dis, 2016 Mar;10(3):e0004503.
    PMID: 26974441 DOI: 10.1371/journal.pntd.0004503
    Burkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B. pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis.
  14. Menon N, Mariappan V, Vellasamy KM, Samudi C, See JX, Ganesh PS, et al.
    Access Microbiol, 2020;2(5):acmi000110.
    PMID: 32974575 DOI: 10.1099/acmi.0.000110
    Burkholderia pseudomallei is the causative agent for melioidosis. Because of its intracellular nature, the bacterium is capable of replicating within a plethora of eukaryotic cell lines. B. pseudomallei can remain dormant within host cells without symptoms for years, causing recrudescent infections. Here, we investigated the pathogenesis mechanism behind the suppression of T cell responses by B. pseudomallei . Peripheral blood mononuclear cells (1×106 cells/well) isolated by Ficoll Paque (Sigma-Aldrich) density gradient centrifugation were incubated with optimized concentrations of bacterial crude culture filtrate antigens (CFAs) (10 ug ml-1) and heat-killed bacteria [1 : 10 multiplicity of infection (m.o.i.)]. Following incubation, cells were investigated for surface expression of coinhibitory molecules by flow cytometry. We found that B. pseudomallei induced the upregulation of programmed death 1 (PD-1), a molecule responsible for T cell exhaustion, on T cells in vitro following exposure to crude CFAs of B. pseudomallei . This upregulation of PD-1 probably contributes to poor immune surveillance and disease pathogenesis.
  15. Venkatramanan M, Sankar Ganesh P, Senthil R, Akshay J, Veera Ravi A, Langeswaran K, et al.
    ACS Omega, 2020 Oct 13;5(40):25605-25616.
    PMID: 33073086 DOI: 10.1021/acsomega.0c02483
    Chromobacterium violaceum (C. violaceum) is a Gram-negative, rod-shaped facultatively anaerobic bacterium implicated with recalcitrant human infections. Here, we evaluated the anti-QS and antibiofilm activities of ethyl acetate extracts of Passiflora edulis (P. edulis) on the likely inactivation of acyl-homoserine lactone (AHL)-regulated molecules in C. violaceum both by in vitro and in silico analyses. Our investigations showed that the sub-MIC levels were 2, 1, and 0.5 mg/mL, and the concentrations showed a marked reduction in violacein pigment production by 75.8, 64.6, and 35.2%. AHL quantification showed 72.5, 52.2, and 35.9% inhibitions, inhibitions of EPS production (72.8, 36.5, and 25.9%), and reductions in biofilm formation (90.7, 69.4, and 51.8%) as compared to a control. Light microscopy and CLSM analysis revealed dramatic reduction in the treated biofilm group as compared to the control. GC-MS analysis showed 20 major peaks whose chemical structures were docked as the CviR ligand. The highest docking score was observed for hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester bonds in the active site of CviR with a binding energy of -8.825 kcal/mol. Together, we found that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester remarkably interacted with CviR to inhibit the QS system. Hence, we concluded that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester of P. edulis could likely be evaluated for treating C. violaceum infections.
  16. Yong YK, Saeidi A, Tan HY, Rosmawati M, Enström PF, Batran RA, et al.
    Front Immunol, 2018;9:472.
    PMID: 29616020 DOI: 10.3389/fimmu.2018.00472
    Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.
  17. Yong YK, Tan HY, Saeidi A, Rosmawati M, Atiya N, Ansari AW, et al.
    Innate Immun, 2017 07;23(5):459-467.
    PMID: 28606013 DOI: 10.1177/1753425917714854
    Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB) and IFN-γ in the exhaustion of innate-like TCR Vα7.2+CD4+T cells, in 15 individuals with chronic HBV (CHB) infection where six were HBV DNA+ and nine were HBV DNA-. The percentage of cytokine-producing T cells and MAIT cells were significantly perturbed in HBV patients relative to healthy controls (HCs). The intracellular expression of GrB and IFN-γ was significantly reduced in MAIT cells derived from HBV-infected patients as compared to HCs, and the levels correlated with the percentage and levels [mean fluorescence intensity (MFI)] of CD69 expression. The total expression of CD69 (iMFI) was lower in CHB patients as compared to HCs. The frequency of CD69+ cells correlated with the levels of cytokine expression (MFI), particularly in CHB patients as compared to HCs. In summary, the polyfunctionality of peripheral T cells was significantly reduced among CHB patients, especially in the TCR Vα7.2+CD4+T cells, and the levels of cytokine expression correlated with functional cytokine levels.
  18. 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.
  19. Ganesh PS, Vishnupriya S, Vadivelu J, Mariappan V, Vellasamy KM, Shankar EM
    Microbiol. Immunol., 2020 Feb;64(2):87-98.
    PMID: 31769530 DOI: 10.1111/1348-0421.12762
    Burkholderia cepacia complex (Bcc) are opportunistic pathogens implicated with nosocomial infections, and high rates of morbidity and mortality, especially in individuals with cystic fibrosis (CF). B. cepacia are naturally resistant to different classes of antibiotics, and can subvert the host innate immune responses by producing quorum sensing (QS) controlled virulence factors and biofilms. It still remains a conundrum as to how exactly the bacterium survives the intracellular environment within the host cells of CF patients and immunocompromised individuals although the bacterium can invade human lung epithelial cells, neutrophils, and murine macrophages. The mechanisms associated with intracellular survival in the airway epithelial cells and the role of QS and virulence factors in B. cepacia infections in cystic fibrosis remain largely unclear. The current review focuses on understanding the role of QS-controlled virulence factors and biofilms, and provides additional impetus to understanding the potentials of QS-inhibitory strategies against B. cepacia.
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