Cysteine-cysteine Chemokine Receptor 5 Research Articles

Hematopoietic Growth Factors Regulate the Entry of Monocytes into the Adult Brain via Chemokine Receptor CCR5.

Monocytes are circulating macrophage precursors generated from bone marrow hematopoietic stem cells. In adults, monocytes continuously replenish cerebral border-associated macrophages under physiological conditions. Monocytes also rapidly infiltrate the brain in pathological settings. The mechanisms of recruiting monocyte-derived macrophages into the brain under pathological conditions have been extensively studied. However, it remains unclear how monocytes enter the brain to renew border-associated macrophages under physiological conditions. Using both in vitro and in vivo approaches, this study reveals that a combination of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), complementarily and synergistically enhances the adhesion of monocytes to cerebral endothelial cells in a dose-dependent manner. Cysteine-cysteine chemokine receptor 5 (CCR5) in brain endothelial cells, but not the cell adhesion molecules mediating neuroinflammation-related infiltration of monocyte-derived macrophages, modulates SCF+G-CSF-enhanced monocyte-endothelial cell adhesion. Blocking CCR5 or genetically deleting CCR5 reduces monocyte-endothelial cell adhesion induced by SCF+G-CSF. The SCF+G-CSF-enhanced recruitment of bone marrow-derived monocytes/macrophages into the cerebral perivascular space is also reduced in adult CCR5 knockout mice. This study demonstrates the role of SCF and G-CSF in regulating the entry of monocytes into the adult brain to replenish perivascular macrophages.

Cysteine-cysteine chemokine receptor 5 (CCR5) profile of HIV-infected subjects attending University of Calabar Teaching Hospital, Calabar, Southern Nigeria

BackgroundCysteine-cysteine chemokine receptor 5 is the main HIV co-receptor involved in the virus and cell-to-cell spread. A variant of the CCR5 gene known as CCR5-Δ32 which is a product of 32 base pair deletion in the gene plays critical role in the infection and progression to AIDS. The study was carried out to determine the CCR5 genotype of HIV-infected subjects attending University of Calabar Teaching Hospital, Calabar.MethodsA total of 100 subjects attending HIV clinic, University of Calabar Teaching Hospital were purposively recruited for this study. DNA was extracted from each sample using the Quick gDNA miniprep DNA extraction kit, Zymo Research. Polymerase chain reaction (PCR) was used in the amplification of CCR5 gene in each DNA in a 9700 ABI Thermo cycler and then resolved on 4% agarose gel electrophoresis.ResultOut of the 100 samples assessed, 100 (100%) were homozygous for the CCR5 wild type gene (CCR5-wt), while none (0%) was homozygous for the CCR5-Δ32 (mutant type), and heterozygosity was not observed.ConclusionThis study observed absence of CCR5-Δ32 deletion gene among the studied subjects in Calabar, implying lack of genetic advantage in HIV infection and possible rapid progression towards AIDS if other precautions are not checked.

Involvement of CCR5 in bone resorption associated to apical periodontitis

Abstract The involvement of Cysteine-cysteine chemokine receptor 5 (CCR5) in the protection or stimulation of bone resorption associated with apical periodontitis that occur as consequence of endodontic infection has not yet been elucidated. The present study proposes to characterize the involvement of CCR5 in the genesis and progression of apical periodontitis, using animals deficient for this molecule. Experimental induction of periapical lesions was performed in CCR5 −/− (knockout) or wild type transgenic mice through the coronary opening of the lower 1st molars and exposure of the root canals to the oral environment for their contamination. After the death of the animals (at 0, 7, 21 and 42 days), the samples obtained in different experimental periods were evaluated by conventional microscopy and fluorescence (morphometry and characterization of the lesions), histoenzimology (TRAP for osteoclasts), immunohistochemistry, immunofluorescence and real-time PCR, to characterize the inflammatory cell in the presence or absence of CCR5 (neutrophils, macrophages and CD4 and CD8 lymphocytes), expression of cytokines (IL-1±, TNF-±, IFN-³, IL 4, IL-6 and IL-10), their ligands (RANTES and MIP- 1±) and factors involved in bone formation and resorption (RUNX2, NFATc1, ALP, RANK, RANKL, OPG and cathepsin K) and infection of tissues. Our results shows that CCR5 knockout mice developed more extense and severe inflammation and alveolar bone destruction at periapical region at 21 and 42 days after endodontic infection. It was concluded that CCR5 deficiency results in development of more severe periapical alveolar bone resorption associated to endodontic infection.

Distribution of Genetic Polymorphism in the CCR5 among Caucasians, Asians and Africans: A Systematic Review and Meta-Analysis

Background: Cysteine-Cysteine Chemokine Receptor 5 (CCR5), also referred to as CD195, is a component of the mammalian cell membrane and is receptor for chemokines that are activated during cell damage and inflammations. This receptor is coded by a gene located in the human chromosome 3. A Mutation on this CCR5 through deletion of 32 base pairs results into a non-destructive gene CCR5Δ32. It enables protection against HIV infection to its homozygous carriers and slows progression of the disease to heterozygous carriers. Objective: To systematically review and establish global distribution of CCR5Δ32 allele in HIV-1 infected individuals over the history of the epidemic and compare regions inhabited by Caucasians, Asians and Africans. Methodology: This meta-analysis comprised of published papers with over 10,000 individuals from whom CCR5-Delta 32 allele was successfully genotyped and recorded. The study review period was from 1984 to 2017. The search targeted online sources such as Hinari specifically PubMed Central, Google scholar, Science Direct, Research4Life, National Center for Biotechnology Information (NCBI), OVID databases, AIDS Journal and Google. The searches were not limited to a particular publication language or study design but excluded letters of correspondence and conference presentations. Search strategy using key words from a combination of Medical Subject Heading (MeSH) and free text including terms related to CCR5, CCR5Δ32 and HIV were performed in Medical Literature Analysis and Retrieval System Online (MEDLINE) through Ovid Open Access. Additional studies were identified by perusing the reference list of relevant and included articles. The review considered studies conducted among general population, both HIV positive and HIV negative individuals, exposed seronegatives (ESN), exposed seropositives (ESP) and highly exposed seronegatives (HESN) and resultant data pooled using a fixed effect model. Results: A total of 40 studies comprising 10,871 participants were reviewed. These were from three main regions: Europe, Africa and Asia. Of the studies accessed and reviewed, Caucasians were 22.5%, Africans were 12.5%, Europeans were 27% and others (not specified) were 37.5%. The distribution of CCR5Δ32 allele among different populations in comparison to its heterozygosity displayed significant association with a pooled Odds Ratio (OR) of 0.08 (95% CI, 0.03 - 0.18, P < 0.00001), test of subgroup differences at I2 = 0% and a P value of 0.50. Among the Caucasians alone the OR was at 0.04 (95% CI, 0.01 - 0.19, I2 = 96%) and a significant P value of < 0.00001 displaying a high presence of CCR5Δ32 homozygosity as compared to Europeans with OR of 0.09 (95% CI, 0.04 - 0.19, I2 = 21%, P = 0.25) and Africans with OR 0.25 (95% CI, 0.03 - 2.29, I2 = 0%, P = 0.81); an indication that race can be a factor that determines CCR5Δ32 homozygosity or heterozygosity and it highly favors the Caucasians. Out of 136 homozygous carriers found in the review Europeans had 6%, Caucasian 93%, Africans 0% and others combined 0.7%. Conclusion: The distribution of CCR5Δ32, an allele that is associated with lower acquisition of HIV/AIDS is at 93% among the Caucasians. The remaining 7% is shared amongst the rest of the populations, hence high susceptibility to the disease. Minimal availability of recorded data experienced in this study is a clear indication that there exist major gaps in studies that could further associate CCR5Δ32 allele frequency and HIV infection in different populations. The review recommends a mixture of population genetics and epidemiological studies in trying to understand the increasing rates of HIV prevalence among selected groups.

Cysteine-cysteine chemokine receptor 5 (CCR5) profiling in HIV infected individuals attending Federal Medical Centre, Yenagoa, Bayelsa State.

Abstract Cysteine-cysteine chemokine receptor 5 (CCR5) is a protein found on the surface of CD4 cells which Human immunodeficiency virus (HIV-1) uses as a co-receptor when entering the host’s target cells. There is a variant of CCR5 known as CCR5 delta 32 that results due to a deletion mutation. CCR5 delta 32 plays an important role in the acquisition of HIV-1 and progression to AIDS. This study was done to determine the CCR5 genotype of HIV positive patients attending Heart to Heart clinic in Federal Medical Centre, Yenagoa, Bayelsa State. A total of 50 whole blood samples were collected by simple random sampling from 50 HIV positive patients attending Heart to Heart clinic in Federal Medical Centre, Yenagoa, Bayelsa State. DNA was extracted from each sample using ZR mini prep DNA extraction kit. CCR5 gene in each DNA extract was amplified by polymerase chain reaction on a 9700 ABI Thermo Cycler and then resolved on 1% agarose gel electrophoresis. Out of the 50 samples examined, 50 (100%) were homozygous for the normal CCR5 gene, 0(0%) were homozygous for the CCR5 delta 32 gene and no heterozygosity was recorded. This study revealed a very low or absence of CCR5 delta 32 deletion gene among HIV patients in Yenagoa suggestive of their rapid progression towards AIDS if other measures are not observed.

No Association between the CCR5Δ32 Polymorphism and Sporadic Esophageal Cancer in Punjab, North-West India

Chemokines and their receptors influence carcinogenesis and cysteine-cysteine chemokine receptor 5 (CCR5) directs spread of cancer to other tissues. A 32 base pair deletion in the coding region of CCR5 that might alter the expression or function of the protein has been implicated in a variety of immune-mediated diseases. The action of antiviral drugs being proposed as adjuvant therapy in cancer is dependent on CCR5 wild type status. In the present study, distribution of CCR5Δ32 polymorphism was assessed in North Indian esophageal cancer patients to explore the potential of using chemokine receptors antagonists as adjuvant therapy. DNA samples of 175 sporadic esophageal cancer patients (69 males and 106 females) and 175 unrelated healthy control individuals (69 males and 106 females) were screened for the CCR5Δ32 polymorphism by direct polymerase chain reaction (PCR). The frequencies of wild type homozygous (CCR5/CCR5), heterozygous (CCR5/Δ32) and homozygous mutant (Δ32/Δ32) genotypes were 96.0 vs 97.72%, 4.0 vs 1.71% and 0 vs 0.57% in patients and controls respectively. There was no difference in the genotype and allele frequencies of CCR5Δ32 polymorphism in esophageal cancer patients and control group. The CCR5Δ32 polymorphism is not associated with esophageal cancer in North Indians. As the majority of patients express the wild type allele, there is potential of using antiviral drug therapy as adjuvant therapy.

Overproduction of Toxoplasma gondii cyclophilin-18 regulates host cell migration and enhances parasite dissemination in a CCR5-independent manner

BackgroundToxoplasma gondii hijacks host cells to allow it to disseminate throughout a host animal; however, the migratory machinery involved in this process has not been well characterized. We examined the functional role of T. gondii cyclophilin 18 (TgCyp18) in host cell recruitment using recombinant parasites transfected with TgCyp18.ResultsHigh levels of TgCyp18 enhanced IL-12 production in cysteine-cysteine chemokine receptor 5 (CCR5) knockout mice (CCR5−/−) that had been infected peritoneally with T. gondii. Recruitment of CD11b+ cells to the infection site was enhanced in a CCR5-independent manner. T. gondii spread to several organs, particularly the liver, in a TgCyp18-dependent and CCR5-independent manner. Additionally, CCL5 levels were upregulated in macrophages treated with recombinant protein TgCyp18 and in the peritoneal fluids of the infected CCR5−/− mice. Furthermore, the chemokines involved in macrophage migration, CCL2 and CXCL10, were upregulated in the livers of CCR5−/− mice infected with recombinant parasites that had been transfected with TgCyp18.ConclusionTgCyp18 may play a crucial role in macrophage migration, and in assisting with transport of T. gondii via CCR5-independent mechanisms. TgCyp18 may also play a role with CCL5 in the migration of macrophages to the site of infection, and with CCL2 and CXCL10 in the transport of T. gondii-infected cells to the liver.

Toxoplasma gondiiCyclophilin 18 Regulates the Proliferation and Migration of Murine Macrophages and Spleen Cells

Toxoplasma gondii is an intracellular parasite that shows a unique capacity to infect a variety of cell types in warm-blooded animals. It can invade and survive well inside immune cells, such as macrophages, that disseminate the parasite around the body because of their migratory properties. The aim of the present study was to evaluate the role of T. gondii cyclophilin 18 (TgCyp18) in the proliferation and migration of macrophages and spleen cells (mainly T lymphocytes) in order to understand the effects of TgCyp18 on the dynamics of the infection. A high dose of TgCyp18 enhanced the proliferation of macrophages and spleen cells in a cysteine-cysteine chemokine receptor 5 (CCR5)-independent way. In contrast, TgCyp18 controlled the migration of macrophages and spleen cells in dose- and CCR5-dependent manners. Our data suggest that TgCyp18 recruits cells and enhances the growth of host cells at the site of infection for maintenance of the interaction between the parasite and host.

Toxoplasma gondiiCyclophilin 18-Mediated Production of Nitric Oxide Induces Bradyzoite Conversion in a CCR5-Dependent Manner

Toxoplasma gondii modulates pro- and anti-inflammatory responses to regulate parasite multiplication and host survival. Pressure from the immune response causes the conversion of tachyzoites into slowly dividing bradyzoites. The regulatory mechanisms involved in this switch are poorly understood. The aim of this study was to investigate the immunomodulatory role of T. gondii cyclophilin 18 (TgCyp18) in macrophages and the consequences of the cellular responses on the conversion machinery. Recombinant TgCyp18 induced the production of nitric oxide (NO), interleukin-12 (IL-12), and tumor necrosis factor alpha through its binding with cysteine-cysteine chemokine receptor 5 (CCR5) and the production of gamma interferon and IL-6 in a CCR5-independent manner. Interestingly, the treatment of macrophages with TgCyp18 resulted in the inhibition of parasite growth and an enhancement of the conversion into bradyzoites via NO in a CCR5-dependent manner. In conclusion, T. gondii possesses sophisticated mechanisms to manipulate host cell responses in a TgCyp18-mediated process.

No Association Between Selected Candidate Gene Polymorphisms and Severe Chronic Periodontitis

Chronic periodontitis (CP) risk is influenced by environmental and genetic factors. Using a case-control design, we tested for associations between CP and selected DNA sequence variations (single nucleotide polymorphisms [SNPs]) in or near genes coding for proteins that play a role in the pathogenesis of this disease. DNA was analyzed from 219 whites who were examined clinically. Cases (N=137) were >or=35 years of age with eight or more teeth having >or=5 mm of proximal clinical attachment loss. Controls (N=82) were >or=45 years of age with minimal or no proximal attachment loss or pocketing. Nine diallelic polymorphisms (gene and SNP descriptor) were studied in subjects: cytotoxic T-lymphocyte antigen-4 (CTLA-4, 49 A>G), human beta-defensin-1 (DEFB1, 692 G>A), intercellular adhesion molecule-1 (ICAM-1, 1548 A>G), Fas ligand (fasL, -844 C>T), inducible costimulator (ICOS, 3990 G>T), interleukin-6 (IL-6, -174 G>C), cysteine-cysteine chemokine receptor-5 (CCR5, 59653 C>T), osteoprotegerin (OPG, 245 T>G), and osteopontin (OPN, 707 C>T). Genotypes were determined using an automated fluorogenic 5'-nuclease, polymerase chain reaction-based assay. Gender and smoking history (pack-years) were included as covariates in logistic regression analyses. Heavy smoking (>10 pack-years) and male gender were significantly associated with disease (P<0.001). For all SNPs tested, the allele frequencies and distributions of genotypes did not differ between cases and controls (P>0.05). No unadjusted or adjusted odds ratios (comparing genotypes in cases versus controls) were significantly different than 1.0 (P>0.05) under any additive, dominant, or recessive inheritance model. None of the SNPs tested were strongly associated with generalized severe chronic periodontitis in North American whites. A potentially more fruitful approach in future studies will be to test for associations between periodontitis and haplotype blocks constructed from either multiple SNPs in candidate gene regions or from panels of markers that span the entire genome.