NK cells: Natural born killers in the conflict between humans and HCV

Koziel, Margaret James

doi:10.1002/hep.21127

Cited by 11 publications

(8 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The main biological role of CXCL10 is the recruitment and activation of host antiviral immune effector cells to the site of infection. This chemokine preferentially targets T‐cells and NK‐cells, both pivotal in the control of HCV replication . In patients who spontaneously resolved the infection the baseline frequency of HCV‐specific IFNγ‐producing T‐cells was ∼6‐fold higher than in patients who developed chronicity ( P = 0.017) and remained markedly higher at week 1 ( P = 0.017) and week 2 ( P = 0.017) (Fig.…”

Section: Resultsmentioning

confidence: 96%

Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection

et al. 2014

View full text Add to dashboard Cite

The pathogenesis of hepatitis C virus (HCV) infection is strongly influenced by the nature of the host's antiviral immunity. Counterintuitively, elevated serum concentrations of C-X-C chemokine 10 (CXCL10), a potent chemoattractant for antiviral T-cells and NK-cells, are associated with poor treatment outcomes in patients with chronic HCV. It has been reported that an N-terminal truncated form of CXCL10, generated by the protease dipeptidylpeptidase 4 (DPP4), can act as chemokine antagonist. We sought to investigate CXCL10 antagonism in the clinical outcome and evolution of acute HCV infection. We collected serial blood samples from 16 patients, at the clinical onset of acute HCV infection and at 12 standardized follow-up timepoints over the first year. Intact and truncated CXCL10 and DPP4 activity were quantified in all longitudinal samples. In addition, NK-cell frequency/phenotype, and HCV-specific T-cell responses were assessed. Subjects developing chronicity (n 5 11) had higher concentrations of CXCL10 (P < 0.001), which was predominantly in a truncated form (P 5 0.036) compared to patients who spontaneously resolved infection (n 5 5). Truncated CXCL10 correlated with HCV-RNA (r 5 0.40, P < 0.001) and DPP4 activity (r 5 0.53, P < 0.001). Subjects who resolved infection had a higher frequency of HCV-specific interferongamma (IFNc)-producing T-cells (P 5 0.017) and predominance of cytotoxic NK-cells (P 5 0.005) compared to patients who became chronic. Patients who became persistently infected had higher proportions of cytokine-producing NK-cells, which were correlated with concentrations of truncated CXCL10 (r 5 0.92, P < 0.001). Conclusion: This study provides the first evidence of chemokine antagonism during acute HCV infection. We suggest that the DPP4-CXCL10 axis inhibits antiviral innate and adaptive host immunity and favors establishment of viral persistence. (HEPATOLOGY 2014;60:487-496) A pproximately 3-4 million people are newly infected with hepatitis C virus (HCV) annually, of whom more than 80% will develop chronic infection.1 It is well established that the host immune response plays a key role in defining the clinical outcome of HCV infection. [2][3][4][5] However, the precise mechanisms responsible for the high rates of viral persistence are not fully understood. This paucity of knowledge stems from the shortage of appropriate in vivo / in vitro models and the difficulty of collecting samples during the acute phase, as these subjects are usually asymptomatic or symptomatic for a short period only.1 This has impeded temporal investigations analyzing the relationship between host immunity and the clinical course of HCV infection.C-X-C chemokine 10 (CXCL10; also known as interferon-gamma [IFNc]-inducible-protein-10 or

show abstract

Section: Resultsmentioning

confidence: 96%

Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection

et al. 2014

View full text Add to dashboard Cite

show abstract

“…5D). Natural killer and natural killer T cells may also be expected to contribute to liver pathology [30][31][32][33] ; however, depletion of these cells in clodronate-treated mice with the PK136 monoclonal antibody did not prevent liver cell damage (Supporting Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

et al. 2010

View full text Add to dashboard Cite

The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. Conclusion: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication. (HEPATOLOGY 2010;52:25-32) P ersistent infection with hepatitis B or hepatitis C virus is one of the leading causes of lethal liver disease resulting from the development of liver cirrhosis and/or hepatocellular cancer.1 Because both viruses are poorly cytopathic, most of the ensuing liver destruction results from CD8 þ T cell responses directed against virus-infected hepatocytes. These cells prevent rapid dissemination of the virus and control viral replication by secreting interferon (IFN)-c and perforin. However, in the event of viral persistence, exaggerated and prolonged T cell activation results in severe liver pathology which can eventually be fatal. 2,3Thus CD8 þ T cells play a crucial role in both virus control and immunopathology. [4][5][6][7][8] Macrophages are resident in every organ of the body.9-11 With their potent phagocytic capacity, theyAbbreviations: ALT, alanine aminotransferase; IFN, interferon; IFNAR, IFN-a receptor; LCMV, lymphocytic choriomeningitis virus; LCMV-NP, lymphocytic choriomeningitis virus nucleoprotein.From the

show abstract

“…We investigated this at a functional level and found that IL28A inhibited IFN-γ production by NK cells. It has been shown by numerous studies that NK cells in patients with chronic HCV infection have normal or relatively higher cytotoxic activity (14,45,46), leading to the suggestion that functional or activated NK cells may contribute to the chronic persistence of infection in these patients. Indeed, a relative expansion of CD56 bright cells, known to produce IFN-γ, has previously been reported for the present cohort of patients (14), and high levels of IFN-γ expression have been reported in the livers of both humans and chimpanzees with chronic HCV infection (47,48).…”

Section: Discussionmentioning

confidence: 99%

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Dring

Morrison

McSharry

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

119

114

View full text Add to dashboard Cite

Hepatitis C is a common infection with significant morbidity and mortality, and only a minority of patients successfully clear the infection. Identification of factors that influence disease progression in HCV infection is difficult owing to the lack of well-defined patient cohorts. However, recent evidence supports a role for the innate immune system in virus clearance. In this study, we investigated innate immune genes for their contribution to disease progression in a unique cohort of well-controlled HCV-infected patients. The Irish cohort of HCV patients is uniquely homogenous; patients were infected with a single genotype of HCV from contaminated anti-D Ig. We genotyped 543 infected patients, including 247 patients who spontaneously resolved infection, for natural killer (NK) cellassociated killer cell Ig-like receptors (KIR) genes and the recently reported IL28B (IFNλ3) SNP. The NK cell gene KIR2DS3 was significantly increased in patients with chronic infection [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.25-2.90, P < 0.002]. The IL28B "T" allele was also significantly increased in chronically infected patients (OR 7.38, 95% CI 4.93-11.07, P < 10). The presence of both markers synergized to significantly increase the risk of chronic infection over either factor alone (OR 20.11, 95% CI 9.05-44.68, P < 10 −7). In functional experiments, we found that IL28A significantly inhibited IFN-γ production by NK cells. Thus, we demonstrate a functional link between NK cells and type 3 IFN. Our findings may contribute to the development of a prognostic test for HCV and identify therapeutic strategies for the clinical management of HCV-infected patients.

show abstract

NK cells: Natural born killers in the conflict between humans and HCV

Cited by 11 publications

References 27 publications

Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection

Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Contact Info

Product

Resources

About