Abstract
BackgroundDifferences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.MethodsTo this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.ResultsThe pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.ConclusionsCollectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0428-x) contains supplementary material, which is available to authorized users.
Highlights
Natural Killer (NK) cells were originally regarded as a component of first-line innate immune defences against invading pathogens and tumors [1]
We studied phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with hepatitis C virus (HCV) genotype-1 virus who were subsequently treated with PEG-IFNα/RBV showing divergent clinical response to the treatment with either NR or sustained virologic response (SVR)
Molecular organization of NK cells during HCV infection is associated with treatment outcome Purified NK cells from prospectively collected cryopreserved PBMCs on a set of 9 sequential HCV patients starting treatment with PEG-IFNα/RBV for 48 weeks were evaluated first
Summary
Natural Killer (NK) cells were originally regarded as a component of first-line innate immune defences against invading pathogens and tumors [1]. Ascierto et al Journal of Translational Medicine (2015) 13:77 surface density directly associates to changes in NK cell function including cytotoxic activity [7], crosstalk with other cells of the immune system [11,12,13], cytokines production in recall-like responses [14,15,16], and control of pathogens replication through direct interaction with infected cells [17,18,19,20,21,22] In line with these observations, in vivo differences in activating receptor density on peripheral NK cells are associated with diverging clinical courses upon acute viral infection with hepatitis C virus (HCV) [19,21] and during chronic HIV-1 infection [23,24,25]. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV
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