Monocytes inhibit hepatitis C virus-induced TRAIL expression on CD56bright NK cells.

BACKGROUND & AIMS: Natural killer (NK) cells play an important role in the pathogenesis of hepatitis C virus (HCV) infection. We have previously shown that culture-derived HCV (HCVcc) enhance tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) expression on healthy NK cells, but not on those from patients infected with HCV, which was likely dependent on accessory cells. Here we sought to elucidate the mechanisms involved in altered TRAIL upregulation in this setting. METHODS: Peripheral blood mononuclear cells (PBMC) from controls and patients infected with HCV were exposed to HCVcc. Cell depletions were performed to identify cells responsible for NK cell activation. Flow cytometry and ELISA were used to identify the cytokines involved in the NK activation process. RESULTS: In patients infected with HCV, soluble factors secreted by control PBMC restored the ability of NK cells to express TRAIL. Of note, CD14+ cell depletion had identical effects upon virus exposure and promoted increased degranulation. Moreover, increased concentrations of interleukin (IL)-18 binding protein a (IL-18BPa) and IL-36 receptor antagonist (IL-36RA) were observed after PBMC exposure to HCVcc in patients with HCV. HCVcc-induced NK cell TRAIL expression was inhibited by IL-18BPa and IL-36RA in control subjects. There were statistically significant correlations between IL-18BPa and indices of liver inflammation and fibrosis, supporting a role for this protein in the pathogenesis of chronic HCV infection. CONCLUSIONS: During chronic HCV infection, monocytes play a key role in negative regulation of NK cell activation, predominantly via secretion of inhibitors of IL-18 and IL-36. LAY SUMMARY: Coordination and collaboration between immune cells are essential to fight pathogens. Herein we show that during HCV infection monocytes secrete IL-18 and IL-36 inhibitory proteins, reducing NK cell activation, and consequently inhibiting their ability to express TRAIL and kill target cells.

Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity.

BACKGROUND & AIMS: The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation. METHODS: NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels. RESULTS: HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution. CONCLUSION: Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes. LAY SUMMARY: We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named metzincins, resulting in altered NK-mediated antibody-dependent killing (ADCC) of target cells. This mechanism may contribute to HCV persistence and may represent a general phenomenon whereby some viruses can escape host's immune responses.

Hepatitis C virus inhibits CD4 T cell function via binding to Toll-like receptor 7.

Toll-like receptor 7 (TLR7) is a ssRNA receptor that activates dendritic cells and macrophages upon ssRNA binding; however, little is known of its role in CD4+ T cells. We show here that hepatitis C virus (HCV) induces a dose dependent inhibition of cytokine production and expression of activation markers in CD4 T cells, which were restored by a TLR7-specific antagonist. These findings indicate that HCV induces CD4 T cell impairment via TLR7 which may contribute to failure of virus eradication, casting doubts on the use of TLR7 agonists to boost innate immunity in chronic RNA virus infections.

Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: data from the Brisighella Study.

Contrasting evidence shows a possible association between serum uric acid (SUA) and cognitive function in elderly subjects. We aimed at evaluating the impact of circulating SUA levels on cognitive function in a cohort of pharmacologically untreated young elderly subjects. For this study, we selected 288 healthy young elderly participants from the historical cohort of the Brisighella Heart Study (M: 108, F: 180; mean age: 69 ± 6 years old). Exclusion criteria were limitation of activities of daily living, depression, chronic pharmacological treatment, patients in secondary prevention for cardiovascular disease, known neurodegenerative disorders, confirmed diabetes or gout, and ultrasonic evaluated carotid atherosclerosis. Cognitive functions were assessed by scholarship-adjusted mini-mental state examination (MMSE). A stepwise multiple regression analysis was carried out including a large set of clinical and laboratory parameters, carotid intima-media thickness, and the Beck Depression scale score. The analysis was then repeated by gender. In the multiple regression analysis, the only factors associated with the MMSE score were: age (B = -0.058, 95% CI -0.108, -0.009, p = 0.022), LDL-C (B = -0.639, 95% CI -0.912, -0.411, p = 0.034) and SUA (B = -0.527, 95% CI -0.709, -0.344, p = 0.022). Repeating the analysis by low or high SUA level (based on the gender specific SUA distribution 50th percentile), it appears that in subjects with a low SUA, cognitive decline is only associated with age, while in those with high SUA it is associated with LDL-C (OR 1.18, 95% CI 1.07-1.33, p = 0.019) and SBP (OR 1.02, 95% CI 1.001-1.048, p = 0.039). Our data demonstrate a positive association between circulating levels of uric acid and cognitive dysfunction in a sample of pharmacologically untreated young elderly subjects.

Population health needs assessment and healthcare services use in a 3 years follow-up on administrative and clinical data: results from the Brisighella Heart Study.

INTRODUCTION: A large number of epidemiological trials clearly show the impact of the main cardiovascular disease risk factors in term of hospitalization and related cost, but relatively less frequently if this reflect the health needs of a given population. AIM: To develop a model for the health needs-assessment that will be applied to verify if and how the prevalence of some classical risk factors for cardiovascular disease predicts mortality and hospitalisation episodes at 3 years, and if it could express the health need of that population. The long-life clinical record of 1,704 subjects, recruited during the 2004 Brisighella Heart Study survey, has been monitored. We defined the health profile of these subjects at 2004 (based on clinical history, smoking and dietary habits, physical activity, drug use, anthropometric data, blood pressure, and hematological data) and then sampled data relative to their hospitalisations, mortality, and general medical assistance. RESULTS: Our results shows that age over 65 years (OR 4.08; 95 % CI 2.74-6.08), hypertension (OR 3.44; 95 % CI 2.36-5.01) and hypercholesterolemia (OR 1.33; 95 % CI 0.92-1.94) increase the probability to get hospitalised. Furthermore, the burden of care was defined and computed for our sample. Vascular and respiratory diseases [Burden of health care (Bc) = 24.5 and 36.5, respectively] are the most costly DRGs which means that the biggest part of our resources directed to cardiovascular patients were provided for these diagnoses. CONCLUSION: The application of the proposed model could help policy makers and researchers in directing resources and workforce in the treatment of cardiovascular diseases.