CCR2, MCP-1, SDF-1α & DC-SIGN gene polymorphisms in HIV-1 infected patients with & without tuberculosis

Background & Objectives: Variability in the clinical outcome of persons exposed to and infected with HIV-1 and tuberculosis (TB) is determined by multiple factors including host genetic variations. The aim of the present study was to find out whether chemokine, chemokine receptor and DC-SIGN gene polymorphisms were associated with susceptibility or resistance to HIV and HIV-TB in south India. Methods: CCR2 V64I (G/A), monocyte chemoattractant protein-1 (MCP-1) -2518 A/G, stromal cell derived factor-1α; (SDF-1α) 3'UTR G/A and DC-SIGN gene polymorphisms were studied by polymerase chain reaction based methods in HIV-1 infected patients without TB (n=151), with pulmonary TB (PTB) (n=81) and extrapulmonary TB (n=31), 155 PTB patients without HIV and 206 healthy controls. Results: The genotype frequencies of CCR2 V64I, MCP-1 -2518 and DC-SIGN polymorphisms did not differ significantly between the study groups. A significantly increased frequency of GG genotype of SDF-1alpha polymorphism was observed among HIV+PTB+ patients compared to healthy controls (P=0.009, Pc=0.027). Interpretation & Conclusions: Our data suggest that GG genotype of SDF-1alpha 3'UTR polymorphism may be associated with susceptibility to PTB in HIV-1 infected patients. A better understanding of genetic factors that are associated with TB could help target preventive strategies to those HIV patients likely to develop tuberculosis

Prostate Cancer Susceptibility Loci Identified on Chromosome 12 in African Americans

Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population

CCL2/MCP-I Genotype-Phenotype Relationship in Latent Tuberculosis Infection

Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted

Human macrophages differentiated in the presence of vitamin D3 restrict dengue virus infection and innate responses by downregulating mannose receptor expression

ABSTARCT: Severe dengue disease is associated with high viral loads and overproduction of pro-inflammatory cytokines, suggesting impairment in the control of dengue virus (DENV) and the mechanisms that regulate cytokine production. Vitamin D3 has been described as an important modulator of immune responses to several pathogens. Interestingly, increasing evidence has associated vitamin D with decreased DENV infection and early disease recovery, yet the molecular mechanisms whereby vitamin D reduces DENV infection are not well understood. METHODS AND PRINCIPAL FINDINGS: Macrophages represent important cell targets for DENV replication and consequently, they are key drivers of dengue disease. In this study we evaluated the effect of vitamin D3 on the differentiation of monocyte-derived macrophages (MDM) and their susceptibility and cytokine response to DENV. Our data demonstrate that MDM differentiated in the presence of vitamin D3 (D3-MDM) restrict DENV infection and moderate the classical inflammatory cytokine response. Mechanistically, vitamin D3-driven differentiation led to reduced surface expression of C-type lectins including the mannose receptor (MR, CD206) that is known to act as primary receptor for DENV attachment on macrophages and to trigger of immune signaling. Consequently, DENV bound less efficiently to vitamin D3-differentiated macrophages, leading to lower infection. Interestingly, IL-4 enhanced infection was reduced in D3-MDM by restriction of MR expression. Moreover, we detected moderate secretion of TNF-α, IL-1β, and IL-10 in D3-MDM, likely due to less MR engagement during DENV infection. CONCLUSIONS/SIGNIFICANCE: Our findings reveal a molecular mechanism by which vitamin D counteracts DENV infection and progression of severe disease, and indicates its potential relevance as a preventive or therapeutic candidate

Immunogenetics of HIV and HIV associated tuberculosis

Tuberculosis (TB) is the frequent major opportunistic infection in HIV-infected patients, and is the leading cause of mortality among HIV-infected patients. Genetic susceptibility to TB in HIV negative subjects is well documented. Since coinfections can influence the way in which immune system respond to different pathogens, genetic susceptibility to TB in HIV patients might also change. Studies from India and other parts of the world have shown that genetic susceptibility to TB is influenced by HIV infection. In the present review, we emphasize the role of genetic factors in determining susceptibility to HIV infection, disease progression and development of TB in HIV-infected patients. Polymorphisms in human leukocyte antigen (HLA), MBL2, CD209, vitamin D receptor, cytokine, chemokine and chemokine receptor genes have been shown to be associated with development of TB in HIV patients. However, the results are inconclusive and larger well-defined studies with precise clinical data are required to validate these associations. Apart from candidate gene approach, genome-wide association studies are also needed to unravel the unknown or to establish the previously reported genetic associations with HIV associated TB. Despite the preliminary status of the reported associations, it is becoming clear that susceptibility to development of TB in HIV patients is influenced by both environmental and genetic components. Understanding the genetic and immunologic factors that influence susceptibility to TB in HIV patients could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease

Stromal cell-derived factor-1 (SDF-1⁄CXCL12) gene polymorphisms in pulmonary tuberculosis patients of south India

CXCL12 gene polymorphisms influence CXCL12 levels and may be associated with the outcome of host– pathogen interaction. Hence, the present study was carried out to find out whether CXCL12 gene polymorphisms are associated with susceptibility or resistance to pulmonary tuberculosis (PTB). Intron and 3¢ untranslated region (UTR) polymorphisms of CXCL12 gene were investigated among 184 patients with PTB and 187 healthy controls (HC) using polymerase chain reaction-based methods. The results revealed an increased frequency of G⁄A genotype of In2 +5887 [P = 0.034; odds ratio (OR) 1.66; 95% confidence intervals 1.04–2.66] and a decreased frequency of G⁄A genotype of 3¢UTR +12197 polymorphisms (P = 0.051; OR 0.64; 95% CI 0.4–1.00) among patients than HCs. When the study subjects were categorized based on sex, significantly increased frequencies of G⁄A genotype (P = 0.013 Pc = 0.039; OR 2.41) of In2 +5887 and G⁄G genotype (P = 0.005, Pc = 0.015; OR 2.48) of 3¢UTR +12197 polymorphisms were observed among female patients with PTB as compared to female HC. A significantly decreased frequency of the haplotype GC- A-T (P = 0.006, Pc = 0.030; OR 0.48) was noticed among female patients with PTB as compared to female HC. The study suggests that G⁄A genotype of In2 +5887 and G⁄G genotype of 3¢UTR +12197 polymorphisms may be associated with susceptibility to PTB among females, and the haplotype G-C-A-T of CXCL12 gene may be associated with protection in females

CCL5 (RANTES) gene polymorphisms in pulmonary tuberculosis patients of south India

The chemokine CCL5 is known to play an important role in the formation of granuloma during infection with Mycobacterium tuberculosis. Production of CCL5 is influenced by polymorphisms in the CCL5 gene. Hence, in the present study, we investigated whether polymorphisms in the promoter and intron regions of CCL5 gene are associated with susceptibility or resistance to pulmonary tuberculosis in south Indian population. Polymorphisms in the promoter ()403G ⁄A and )28C ⁄ G) and intron (In1.1T ⁄ C) regions of CCL5 gene were studied in 212 pulmonary tuberculosis (PTB) patients and 213 healthy controls (HCs). Allele and genotype frequencies of CCL5 gene polymorphisms were not different between PTB patients and HCs. When the haplotype and diplotype frequencies were compared, a significantly decreased frequencies of the haplotype A-C-C [P = 0.037; Odds ratio (OR): 0.57; 95% confidence interval (CI): 0.34–0.97] and the diplotype G⁄ A-T ⁄C (P = 0.017; OR: 0.46; 95% CI: 0.24–0.88) were observed among PTB patients when compared with HCs. However, the significant differences observed for the haplotype and the diplotype were lost when corrected for multiple comparisons [Bonferroni correction: A-C-C P corrected (Pc) = 0.148 and G⁄ A-T ⁄C Pc = 0.136]. Though the present results suggest that the CCL5 gene haplotype A-C-C and the diplotype G⁄ A-T ⁄C may be associated with resistance to PTB, further studies with increased sample size may be useful to confirm this present finding as well as to understand the role of CCL5 haplotype and diplotype on genetic susceptibility to TB

Plasma 1,25 dihydroxy vitamin D3 level and expression of vitamin D receptor and cathelicidin in pulmonary tuberculosis.

Introduction Vitamin D3, which exerts its effect through vitamin D receptor (VDR), is known for its potent immunomodulatory activities. Associations between low serum vitamin D3 levels and increased risk of tuberculosis have been reported. Study Subjects and Methods Plasma 1,25 dihydroxy vitamin D3 levels (1,25(OH)2 D3) and ex vivo levels of VDR protein from peripheral blood mononuclear cells were studied in 65 pulmonary tuberculosis (PTB) patients and 60 normal healthy subjects (NHS) using enzyme-linked immunosorbent assay-based methods. Using real-time polymerase chain reaction (PCR), induction of VDR, cathelicidin, and CYP27B1 mRNA were studied in live Mycobacterium tuberculosis-stimulated macrophage cultures treated with or without 1,25 dihydroxy vitamin D3. VDR and CYP27B1 (-1077 A/T) gene polymorphisms were studied using PCR-based methods. Results 1,25(OH)2 D3 were significantly increased (p= 0.0004), while ex vivo levels of VDR protein were significantly decreased in PTB patients (p=0.017) as compared to NHS. 1,25(OH)2 D3 levels were not different between variant genotypes of CYP27B1. A trend towards decreased levels of VDR protein was observed among NHS with BsmI BB and TaqI tt genotypes compared to NHS with other genotypes. Relative quantification of mRNA using real-time PCR revealed increased VDR mRNA expression in live M. tuberculosis-stimulated culture in PTB patients (p<0.01) than normal healthy subjects. Cathelicidin mRNA expression was significantly increased in vitamin D3-treated cultures compared to unstimulated and M. tuberculosisstimulated culture in both patients (p<0.001) and NHS (p<0.05). Conclusions The present study suggests that PTB patients may have increased 1,25(OH)2 D3 levels, and this might lead to downregulation of VDR expression. Decreased VDR levels could result in defective VDR signaling. Moreover, addition of 1,25(OH)2 D3 might lead to increased expression of cathelicidin which could enhance the immunity against tuberculosis