Differential Pattern of Infection of Sylvatic Nymphs and Domiciliary Adults of Triatoma infestans with Trypanosoma cruzi Genotypes in Chile

Abstract. In Chile, the main vector of Chagas disease, Triatoma infestans, is under control after insecticide spraying. However, it has been found colonizing wild habitats. This study evaluated Trypanosoma cruzi infection of sylvatic and domiciliary T. infestans and identified their parasite genotypes. The sample studied was composed mainly of T. infestans sylvatic nymphs and domiciliary adults from a semi-urban area with human dwellings under vector control surveillance. Results showed prevalences of 57.7% in nymphs and 68.6% in adults. Hybridization tests showed a major T. cruzi lineage (TcI) circulating in sylvatic (93.3%) and domiciliary (100%) T. infestans. TcII, TcV, and TcVI were also detected, mainly in nymphs, suggesting differential adaptation of T. cruzi lineages among instars. We also discuss the origin of domiciliary individuals of T. infestans and the risk of human infection by triatomines of sylvatic foci that invade houses despite vector control programs.     

HIV-1 matrix protein p17 binds to the IL-8 receptor CXCR1 and shows IL-8-like chemokine activity on monocytes through Rho/ROCK activation

Exogenous HIV-1 matrix protein p17 was found to deregulate biologic activities of many different immune cells that are directly or indirectly involved in AIDS pathogenesis after binding to unknown cellular receptor(s). In particular, p17 was found to induce a functional program in monocytes related to activation and inflammation. In the present study, we demonstrate that CXCR1 is the receptor molecule responsible for p17 chemokine-like activity on monocytes. After CXCR1 binding, p17 was capable of triggering rapid adhesion and chemotaxis of monocytes through a pathway that involved Rho/ROCK. Moreover, CXCR1-silenced primary monocytes lost responsiveness to p17 chemoattraction, whereas CXCR1-transfected Jurkat cells acquired responsiveness. Surface plasmon resonance studies confirmed the capacity of p17 to bind CXCR1 and showed that the p17/CXCR1 interaction occurred with a low affinity compared with that measured for IL-8, the physiologic CXCR1 ligand. In all of its activities, p17 mimicked IL-8, the natural high-affinity ligand of CXCR1. Recent studies have highlighted the role of IL-8 and CXCR1 in HIV-1 replication and AIDS pathogenesis. Our findings herein call for an exploration of the therapeutic potential of blocking the p17/IL-8/CXCR1 axis in HIV-1 infection.     

Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis

Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterized. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either intraperitoneal injections of carbon tetrachloride (CCl(4) ) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for 1 year (mouse). Elastin synthesis, deposition, and degradation were investigated by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blotting, and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl(4) model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl(4) in MMP-12(-/-) mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared with WT. Conclusion: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies.     

Nonalcoholic fatty liver disease is associated with increased GHBP and reduced GH/IGF-I levels

Introduction Nonalcoholic fatty liver disease (NAFLD) has been described in adult GH deficiency syndrome. Furthermore, chronic liver disease can be associated with significant changes in levels of IGF‐I, GH‐binding protein (GHBP), IGF‐binding proteins (IGFBPs) and acid‐labile subunit (ALS). However, the effect of liver steatosis on the GHBP production has not been investigated yet. Aim of the study To explore whether GH secretion and/or levels of IGF‐I, IGFBP‐3, ALS and GHBP could be altered in obese patients in relation to the presence of liver steatosis. Materials and methods A total of 115 obese patients (BMI > 30) were enrolled in the protocol (65 patients with liver steatosis and 50 age‐ and BMI‐matched controls). In all patients, the following parameters were studied: serum levels of glucose, insulin, the HOMA index, IGF‐I, GHBP, IGFBP‐3, ALS and GH after GHRH and arginine stimulation test. Results As expected, patients with NAFLD had blood glucose, insulin, HOMA‐R significantly higher than controls, indicating a more severe insulin‐resistance state in NAFLD. Furthermore, patients with NAFLD had higher levels of GHBP and IGFBP‐3 and lower GH peak and IGF‐I levels as compared to controls. No difference was found in ALS levels between the groups. In a multivariate analysis, GHBP was positively associated with hepatic steatosis while IGF‐1 was negatively associated with hepatic steatosis. Conclusions This study demonstrates that in patients with NAFLD, the GHBP levels are increased, and that the GH/IGF‐I axis is significantly altered probably leading to reduced IGF‐I bioavailability at tissue level.     

Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome

Objective A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader–Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low‐Dose Tetracosactrin Stimulation Test (LDTST), 1 μg] or standard‐dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. Design Cross‐sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. Patients Eighty‐four children with PWS. Measurements Assessment of adrenal response by morning cortisol and ACTH dosage, and 1‐μg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm ; below this threshold, patients were submitted to a second test. Responses were correlated with the patients’ clinical and molecular characteristics to assess genotype–phenotype correlation. Results Pathological cortisol peak responses to the LDTST were registered in 12 patients (14·3%) who had reduced basal (169·4 ± 83·3 nm ) and stimulated (428·1 ± 69·6 nm ) cortisol levels compared to patients with normal responses (367·1 ± 170·6 and 775·9 ± 191·3 nm , P < 0·001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0·001), and the patients’ ages (P < 0·001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0·030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r² = 0·353, P < 0·001). Standard‐dose (250 μg) tetracosactrin test confirmed CAI in 4/12 patients (4·8% of the cohort). Conclusions Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.