NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans

Velez, Digna R.; Hulme, William; Myers, Jamie L.; Weinberg, J. Brice; Levesque, Marc C.; Stryjewski, Martín E.; Abbate, Eduardo; Estevan, Rosa; Patillo, Sara G.; Gilbert, John R.; Hamilton, Carol; Scott, William K.

doi:10.1007/s00439-009-0713-y

Cited by 71 publications

(64 citation statements)

References 45 publications

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“…Gene-gene interactions play an important role in an individual's susceptibility to develop a disease, but gene-gene interactions in infectious diseases such as TB have been poorly studied until recently. Multilocus analyses have identified significant interactions between SNPs in NOS2A and those in TLR4 and IFNGR1 in promoting TB susceptibility (250). These findings are particularly interesting because the SNPs in TLR4 and IFNGR1 alone did not show significant effects and would not have been identified as associated with TB without the interaction with NOS2A.…”

Section: Factors That Influence the Functions Of Innate Immune Gene Pmentioning

confidence: 97%

“…In other instances, polymorphisms in innate immune genes, such as INT4 and D543N of SLC11A1 (271) and R753Q of TLR2 (55), were found to be involved in altering the progression of M. tuberculosis infection to active TB. Further evidence for the potential contribution of innate immune genes in clinical TB stems from reported interactions of the innate immune genes NOS2A and TLR4 with the adaptive immunity-related gene IFNGR1 (250) or NRAMP1 with IFNGR1 (62) in influencing susceptibility to TB. Taken together, the results overwhelmingly support a strong genetic component in infectivity, disease progression, and the clinical manifestation of TB, while the relative contribution of each gene in these processes needs to be clarified.…”

Section: Role Of Innate Immune Gene Polymorphisms In Susceptibility Tmentioning

confidence: 99%

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Innate Immune Gene Polymorphisms in Tuberculosis

2012

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ABSTRACTTuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C-type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB.

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Section: Factors That Influence the Functions Of Innate Immune Gene Pmentioning

confidence: 97%

Section: Role Of Innate Immune Gene Polymorphisms In Susceptibility Tmentioning

confidence: 99%

Innate Immune Gene Polymorphisms in Tuberculosis

2012

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“…However, in vivo evidence suggests some protective role for iNOS in human tuberculosis (TB). Genome-wide association studies link NOS2 with an increased incidence of TB (4)(5)(6)(7)(8), although the expression and/or activity of iNOS resulting from these polymorphisms are unknown. Still other investigators reported that iNOS and NO production in TB patients correlates with less severe disease, and NO production by human alveolar MFs ex vivo inhibits mycobacterial growth (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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Microbicidal NO production is reliant on inducible NO synthase–mediated l-arginine metabolism in macrophages (MΦs). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography–tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette–Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in l-arginine. Furthermore, we found that arginase-expressing MΦs preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

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“…Gene-gene interaction has been shown in some studies. A single gene that is not associated with susceptibility to TB will show an association if combined with other genes [38,39]. Besides, gene-agent interaction showed association of a certain host gene with a certain strain of Mycobacterium tuberculosis [40,41].…”

Section: Discussionmentioning

confidence: 99%

Is There Any Impact of VDR Gene Polymorphism in Bataks Ethnic to Have Tuberculosis?

Siregar¹,

Sinaga²

2017

JHS

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Abstract:The active metabolite of vitamin D activates macrophages and results in the restriction of growth of Tuberculosis (TB) pathogen M. tuberculosis. The effect of vitamin D is achieved through binding to the Vitamin D Receptor (VDR), which ultimately produces the antimicrobial peptide Cathelicidin. Matched case-control study with 76 pulmonary tuberculosis Indonesian Batak ethnic patients and 76 healthy normal control were completed. Genetic polymorphisms of VDR gene were analysed using PCR and RFLP. The genotype frequencies of ApaI were AA 10.6%, Aa 44.7%, aa 44.7% for the control group and AA 10.6%, Aa 43.4%, aa 46% for the PTB patients. For the FokI genotype the frequencies were FF 39.5%, Ff 44.7%, ff 15.8% for the control group and FF 35.5%, Ff 55.3%, ff 9.2% for the PTB patients. In these two genotypes there were no significant differences found between the control group and the PTB patients (P > 0.05). Besides, there genotypic frequencies were in agreement with the Hardy-Weinberg Equilibrum (P > 0.05). However, for the BsmI genotype frequencies, BB 2.6%, Bb 23.7% and bb 73.7% for the control group and BB 0%, Bb 68.4%, bb 31.6% for the PTB patients, there was a significant association found with PTB; the bb genotype is correlated with a decreased risk for PTB (OR 0.22, 95% CI: 0.11-0.45). ApaI and FokI polymorphisms of VDR gene do not appear to be responsible for host susceptibility to pulmonary tuberculosis in the Indonesian Batak ethnic population but BsmI polymorphism had association with host resistant to PTB.

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NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans

Cited by 71 publications

References 45 publications

Innate Immune Gene Polymorphisms in Tuberculosis

Innate Immune Gene Polymorphisms in Tuberculosis

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Is There Any Impact of VDR Gene Polymorphism in Bataks Ethnic to Have Tuberculosis?

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