title: Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes.
abstract: 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.
authors.affiliation: Tropical Infectious Disease Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.
authors.forename: Muttiah
authors.initials: M
authors.lastname: Barathan
authors.forename: Kaliappan
authors.initials: K
authors.lastname: Gopal
authors.forename: Rosmawati
authors.initials: R
authors.lastname: Mohamed
authors.forename: Rada
authors.initials: R
authors.lastname: Ellegård
authors.forename: Alireza
authors.initials: A
authors.lastname: Saeidi
authors.forename: Jamuna
authors.initials: J
authors.lastname: Vadivelu
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Ansari
authors.forename: Hussin A
authors.initials: HA
authors.lastname: Rothan
authors.forename: M
authors.initials: M
authors.lastname: Ravishankar Ram
authors.forename: Keivan
authors.initials: K
authors.lastname: Zandi
authors.forename: Li Y
authors.initials: LY
authors.lastname: Chang
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Vignesh
authors.forename: Karlhans F
authors.initials: KF
authors.lastname: Che
authors.forename: Adeeba
authors.initials: A
authors.lastname: Kamarulzaman
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.forename: Tunku
authors.initials: T
authors.lastname: Kamarul
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
mesh_terms: D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism; D008297:Male; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species