Toll like receptor 2 and CC chemokine receptor 5 cluster in the lipid raft enhances the susceptibility of Leishmania donovani infection in macrophages.

In experimental visceral leishmaniasis the causative obligate protozoan parasite, L. donovani invades and multiplies inside of macrophages, one of the sentries of the mammalian immune system. The initial host-parasite interaction between the Leishmania promastigote and the macrophage takes place at the plasma membrane interface. To trace any possible interaction between Toll-like receptor 2 (TLR2) and CC chemokine receptor 5 (CCR5) during early Leishmania-macrophage interactions, it was observed that the expression of both TLR2 and CCR5 were significantly increased, along with their recruitment to the lipid raft. TLR2 silencing attenuates CCR5 expression and restricts L. donovani infection, indicating a regulatory role of TLR2 and CCR5 during infection. Silencing of CCR5 and TLR2 markedly reduced the number of intracellular parasites in macrophages by host protective cytokine responses, while raft disruption using β-MCD affected TLR2/CCR5 cross-talk and resulted in a significant reduction in parasite invasion. In vivo RNA interference of TLR2 and CCR5 using shRNA plasmids rendered protection in Leishmania donovani-infected mice. Thus, this study for the first time demonstrates the importance of TLR2/CCR5 crosstalk as a significant determinant of Leishmania donovani entry in host macrophages.

Defects in blood dendritic cell subsets in HIV-1 subtype C infected Indians.

Background & objective: DCs trigger both innate and adaptive immune responses to control HIV infection and represent a viral reservoir acting as target and HIV carriers for infection of permissive CD4+ T-cells. DCs thus form a very attractive study subject to further our existing knowledge of HIV induced immunopathogenesis due to its diverse and crucial role in HIV infection establishment, viral dissemination, immune evasion, viral persistence, etc. We aimed to characterize the effect of HIV infection on myeloid and plasmacytoid dendritic cell subsets in a group of HIV-1 subtype C infected treated or untreated Indian individuals. Methods: Blood DC subset numbers and immunophenotype were studied for 79 HIV infected subjects at various stages of disease and compared with 13 HIV-uninfected controls. Comparisons were also made between groups of subjects based on their CD4+ T cell counts and also experience of antiretrovirals. Results: Significant decreases were observed in blood DC counts and the two DC subsets in HIV infected individuals. Subjects with lowest CD4+ T cell counts also had a drastically reduced DC subset pool which correlated positively with plasma viraemia and negatively with CD4+ T cell counts. DC subsets from HIV infected subjects showed higher expression of co-stimulatory molecules CD40 and CD86, and HIV-1 co-receptors CXCR4 and CCR5 which correlated positively with HIV-1 plasma viraemia. The alterations in blood DCs were partly resolved in ART receiving study subjects. Interpretation & conclusions: Correlation between DC subset activation state and viraemia supports the role of DC activation on viral replication and CD4+ T cell depletion.

Chemokine Receptor Expression of Hepatitis B Virus-Specific CD8+ Lymphocyte in Chronic B Viral Infection / 대한간학회지

BACKGROUND/AIMS: The protective role of HBV-specific CD8+ cells is dependent on their ability to efficiently migrate to the infected liver, where they may exert an effector function. The migratory behavior of CD8+ cells is influenced by their expression of different chemokine receptors. This study was intended to analyse the pattern of chemokine receptor expression of HBV specific CD 8+ cells in chronic B viral infection. METHODS: We analysed the CCR5 and CCR3 profile of HBV-specific CD8+ cells isolated from the blood and liver of patients with different patterns of HBV infection. Purified T cells were stained directly ex vivo, or after antigen-specific stimulation, using HBV peptide-specific HLA tetramers and monoclonal antibodies to CD8, CCR5 and CCR3, with analysis by flow cytometry. RESULTS: In patients with chronic hepatitis B characterised by low levels of virus (serum HBV DNA <0.5pg/mL) and minimal liver inflammation, analysis of circulating and intrahepatic CD8+ cells demonstrated that liver infiltrating Tc18-27-specific cells were preferentially CCR5+ (up to 80% of HBV-specific CD8+ cells), in contrast to cells of the same specificity within the circulating compartment (up to 35% of HBV-specific CD8+ cells). Furthermore, CCR3 was expressed by about 10% of Tc18-27+ cells infiltrating the liver, but was absent from circulating cells. Following HBV-specific stimulation in vitro the CCR5 expression of circulating Tc18-27-specific cells was up-regulated, to levels found in liver infiltrating cells, whereas CCR3 expression was unchanged. CONCLUSIONS: The chemokine receptor profile of HBV-specific CD8+ cells is influenced by the anatomical site of these cells, and the clinical pattern of disease. The ability of circulating HBV-specific CD8+ cells of patients with low replicating virus to upregulate CCR5 suggests that these cells may respond to increases in virus replication by efficiently migrating into the infected liver.