Development Of Tuberculosis Infection Research Articles

Role of RIG-I-Like Receptors in the Activation of Innate Immunity in Tuberculosis

—Despite the efforts to develop the strategies of tuberculosis control, this disease still takes more than a million lives annually. The development of tuberculosis infection can be considered as an imbalance between the immune response of the host organism and the growth of Mycobacterium tuberculosis bacteria. In order to gain a foothold successfully in an infected organism, M. tuberculosis must overcome the mechanisms of innate immunity, including those that aim at the recognition of alien nucleic acids. RIG-I-like receptors (RLR) is a system of intracellular receptors (sensors of alien RNA), which is involved in the recognition of viruses and bacterial pathogens. The RIG-I, MDA5, and LGP2 receptors interact directly with RNA in the cell cytoplasm and trigger a cascade of interactions, which leads to the synthesis of type I interferons and proinflammatory cytokines. To date, it has been proven that the activation of RLR during tuberculosis infection is the most important component of innate immunity. Their obvious role in the activation of type I interferons (which, however, can be not only protective, but also negative for the immune system) was demonstrated. The review considers the latest data on the functioning of RLR in tuberculosis on the example of model organisms and humans.

The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents

BackgroundRatios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease.MethodsIn this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment.ResultsAt baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 × 106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005).ConclusionsIn contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity.Trial registrationClinicaltrials.gov NCT02712424. Date of registration: March 14, 2016.

Validation of the Results of Genome-Wide Association Studies of Tuberculosis in Russians of West Siberia

The genetically mediated ability of the host to provide an adequate immune response to the pathogen plays an important role in the development of tuberculosis infection. Genome-wide association studies performed in different populations revealed the association of a number of chromosomal regions with the development of tuberculosis (TB). At the same time, full characteristics of the factors of genetic susceptibility to the disease remains an unresolved problem, and the associations identified are not always reproduced in studies in other populations. A total of 45 single nucleotide polymorphisms (SNPs) were analyzed in 768 individuals, including 323 tuberculosis patients and 445 healthy individuals. Analysis of associations of tuberculosis with genetic markers was carried out using logistic regression. Permutations were used to account for multiple comparisons. Nominal statistically significant association with tuberculosis was detected for two SNPs, rs10515787 (intronic variant of the EBF1 gene) and rs10956514 (intronic variant of the ASAP1 gene) (p = 0.005 and 0.049, respectively). After the permutation test, only one of the associations was preserved, for rs10515787 (p = 0.003). Thus, in Russians from the city of Tomsk, the association of rs10515787 at the EBF1 gene with the development of tuberculosis was confirmed. However, the results of this study identify rare A allele as a risk factor for the development of TB, while in an earlier study, it was identified as being protective relative to the risk for developing of tuberculosis. The revealed “reverse association” is an interesting fact that requires further investigation.

Association of IL-37 gene polymorphisms with susceptibility to tuberculosis in Saudi subjects.

Tuberculosis (TB) is one of the most common infectious diseases worldwide. IL-37, a novel member of the IL-1 family, has anti-inflammatory activity. Various cytokine genes polymorphisms are reportedly associated with susceptibility to TB infection. However, an association between genetic variations in the IL-37 gene and susceptibility to TB infection has not been investigated. The aim of this case-control study was therefore to identify such an association in Saudi subjects, in which five single-nucleotide polymorphisms (SNPs) in the IL-37 gene were assessed. Serum concentrations of IL-37 were evaluated using ELISA, and genetic variants genotyped by multiplex PCR and ligase detection reaction. It was found that the C/C genotype of rs2723176 (-6962 A/C) occurs significantly more frequently in patients with active TB and that the C allele of this SNP is associated with TB. In addition, the C allele of rs2723176 SNP was associated with high circulating concentrations of IL-37. However, the genotype and allele frequency of the other four SNPs (rs3811046, rs3811047, rs2723186 and rs2723187) were not significantly associated with TB infection. In conclusion, the present data suggest that rs2723176 SNP of IL-37 is involved in the development of TB infection. Furthermore, high circulating concentrations of IL-37 may have a negative effect on protective immunity against TB infection.

Mycobacterium tuberculosis antigens MPT63 and MPT83 increase phagocytic activity of murine peritoneal macrophages.

Macrophages (MΦ) are the most described and characterized target and host of mycobacteria. Like other cells of innate immunity MΦ have a wide range of receptor molecules which interact with different pathogen associated molecular patterns (PAMPs). Immunodominant proteins MPT63 and MPT83 that are synthesized in abundance by Mycobacterium bovis or Mycobacterium tuberculosis strains could be involved in development of tuberculosis infection. The aim of this study was to search for effects of these mycobacterial antigens on target cells. For this aim full-sized sequences of MPT83 (rMPT83full) and MPT63 antigens were cloned into plasmid pET24a(+). The increase of phagocytic activity of murine peritoneal macrophages was demonstrated, but not of macrophage-like cells from J774 cell line, which were treated by rMPT63 and rMPT83full proteins for 24 h. This effect of such antigens can be considered as a way to facilitate the consumption of mycobacterial cells by macrophages to avoid other effector mechanisms of innate and adaptive immunity.

Treatment of tuberculosis with rifabutin in a renal transplant recipient

Development of tuberculosis infection in a renal transplant patient is infrequent in Spain, although the prevalence is higher than in the general population. These patients usually receive calcineurin inhibitors as the main component of their immunosuppressive treatment. The metabolism of these drugs, whether cyclosporine or tacrolimus, involves cytochrome P-450 3A. Rifampin, a widely used agent in the treatment of tuberculosis, is also an important inducer of cytochrome P-450 3A metabolism and has the capacity to decrease serum levels of the calcineurin inhibitors. This metabolic interaction makes pharmacologic management of tuberculosis-infected transplant patients more complex and can result in a higher risk of acute rejection caused by decreased levels of the immunosuppressant in the blood. The authors present a case of a renal transplant patient with a soft tissue infection caused by Mycobacterium tuberculosis who was treated with rifabutin instead of rifampin, with excellent results in terms of graft survival and overall survival. The use of rifabutin allowed the authors to achieve better control of circulating immunosuppressant levels and a lower probability of acute graft rejection. Development of tuberculosis infection in a renal transplant patient is infrequent in Spain, although the prevalence is higher than in the general population. These patients usually receive calcineurin inhibitors as the main component of their immunosuppressive treatment. The metabolism of these drugs, whether cyclosporine or tacrolimus, involves cytochrome P-450 3A. Rifampin, a widely used agent in the treatment of tuberculosis, is also an important inducer of cytochrome P-450 3A metabolism and has the capacity to decrease serum levels of the calcineurin inhibitors. This metabolic interaction makes pharmacologic management of tuberculosis-infected transplant patients more complex and can result in a higher risk of acute rejection caused by decreased levels of the immunosuppressant in the blood. The authors present a case of a renal transplant patient with a soft tissue infection caused by Mycobacterium tuberculosis who was treated with rifabutin instead of rifampin, with excellent results in terms of graft survival and overall survival. The use of rifabutin allowed the authors to achieve better control of circulating immunosuppressant levels and a lower probability of acute graft rejection.

Effect of water extract of Turkish propolis on tuberculosis infection in guinea-pigs

Mycobacterium tuberculosis (H 37R v)-infected guinea-pig model was used to investigate the effect of water extract of propolis (WEP). After subcutaneous inoculation of tubercle bacilli, each animal received oral WEP ( n=9), isoniazid ( n=5) or saline ( n=6) as placebo and were sacrificed 30 days later. Formation of necrosis was less prominent in the group treated with WEP, but was not statistically significant ( P>0.05). The granuloma formation in the same group was more prominent than the placebo and isoniazid groups; however, this finding failed to reach statistical significance by the Kruskal–Wallis test ( P>0.05). These findings suggest that Turkish WEP may have a limited effect on the development of tuberculosis infection in this guinea-pig model.