The role of host soluble inflammatory mediators induced by the BCG vaccine for the initiation of in vitro monocyte apoptosis in healthy Brazilian volunteers

Submitted by sandra infurna ([email protected]) on 2016-05-19T13:22:18Z No. of bitstreams: 1 jessica_lima_etal_IOC_2015.pdf: 744742 bytes, checksum: 99a63cc9c9e60f83c0f69452eda1cef9 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-05-19T13:31:12Z (GMT) No. of bitstreams: 1 jessica_lima_etal_IOC_2015.pdf: 744742 bytes, checksum: 99a63cc9c9e60f83c0f69452eda1cef9 (MD5)Made available in DSpace on 2016-05-19T13:31:12Z (GMT). No. of bitstreams: 1 jessica_lima_etal_IOC_2015.pdf: 744742 bytes, checksum: 99a63cc9c9e60f83c0f69452eda1cef9 (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.BACKGROUND: Tuberculosis (TB) is the second greatest killer worldwide that is caused by a single infectious agent. For its control, studies of TB vaccines are needed. Since Bacillus Calmette-Guerin (BCG) is the only vaccine against TB currently in use, studies addressing the protective role of BCG in the context of inducible inflammatory mediators are urgently required. METHODS: In this study, groups of HIV-negative adult healthy donors (HD; n = 42) and neonates (UV; n = 18) have been voluntarily enrolled, and BCG Moreau strain was used for the in vitro mononuclear cell infections for an initial period of 48 h. Subsequently, harvested conditioned medium (CM) was added to autologous resting cells for an additional 24, 48, and 120 h, and Annexin V, in conjunction with a vital dye, was then used for apoptosis detection. CM was also assayed for nitric oxide (NO), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), interferon (IFN)-β, and transforming growth factor (TGF)-β1 levels. The p values were set up for any differences between two groups of individuals using Student's t-test and considered significant when ≤ 0.05. RESULTS: At 120 h, CM induced the highest apoptosis levels in both group studied, but necrosis was high in UV group only (p-value < 0.05). NO was released equally during BCG infection in both groups, but higher levels were found in HD when compared with UV group (p-value < 0.05). Overall, BCG Moreau triggered high PGE2, LTB4 and IFN-β productions in macrophages from the UV group (p-value ≤ 0.05), whereas the prostanoid PGE2 and TGF-β1 had an opposite pattern in the HD group. CONCLUSIONS: This study uncovers critical roles for endogenous compounds in the instruction of host macrophage cell death patterns. Understanding the regulation of human immune responses is critical for vaccine development and the treatment of infectious diseases. These findings shed new light on the potential condition for a booster immunization in individuals already vaccinated with BCG for TB protection, and further studies are warranted

Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study

<p>Abstract</p> <p>Background</p> <p>Approximately 5-10% of persons infected with <it>M. tuberculosis </it>develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated with extrapulmonary disease is important.</p> <p>Findings</p> <p>We performed a pilot genome-wide association study among 24 persons with previous extrapulmonary tuberculosis and well-characterized immune defects; 24 pulmonary tuberculosis patients and 57 patients with <it>M. tuberculosis </it>infection served as controls. The Affymetrix GeneChip Human Mapping Xba Array was used for genotyping; after careful quality control, genotypes at 44,175 single nucleotide polymorphisms (SNPs) were available for analysis. Eigenstrat quantified population stratification within our sample; logistic regression, using results of the Eigenstrat analysis as a covariate, identified significant associations between groups. Permutation testing controlled the family-wise error rate for each comparison between groups. Four SNPs were significantly associated with extrapulmonary tuberculosis compared to controls with <it>M. tuberculosis </it>infection; one (rs4893980) in the gene PDE11A, one (rs10488286) in KCND2, and one (rs2026414) in PCDH15; one was in chromosome 7 but not associated with a known gene. Two additional variants were significantly associated with extrapulmonary tuberculosis compared with pulmonary tuberculosis; one (rs340708) in the gene FAM135B and one in chromosome 13 but not associated with a known gene. The function of all four genes affects cell signaling and activity, including in the brain.</p> <p>Conclusions</p> <p>In this pilot study, we identified 6 novel variants not previously known to be associated with extrapulmonary tuberculosis, including two SNPs more common in persons with extrapulmonary than pulmonary tuberculosis. This provides some support for the hypothesis that the pathogenesis and genetic predisposition to extrapulmonary tuberculosis differs from pulmonary tuberculosis. Further study of these novel SNPs, and more well-powered genome-wide studies of extrapulmonary tuberculosis, is warranted.</p

The Fiocruz Latest Contribution for Understanding Human Tuberculosis Vaccine Development and its Pathogenesis

Made available in DSpace on 2015-05-27T13:39:46Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) paulo_antas3_IOC_2014.pdf: 594642 bytes, checksum: d282c7d2fedf4dd5ec6dd73942532da4 (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil

Perceptions of Human Tuberculosis Vaccine: The Fiocruz Latest Contribution

Made available in DSpace on 2015-05-27T13:39:46Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) paulo_antas2_IOC_2014.pdf: 206516 bytes, checksum: a8a98702e5eb7bde4c5774d2f55edc85 (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.As globally reported, tuberculosis (TB) is a major cause of illness and death worldwide, with increased burden mainly in developing countries. The Stop TB Partnership goals embrace dropping the global TB burden by half in 2015 and eliminating TB as a public health problem by 2050. As an ancient microbe highly adapted to the host, Mycobacterium tuberculosis infects humans through an oral route. TB can be caught by persons that inhale droplets containing the bacteria when an infected person coughs or sneezes. But the majority of these infected subjects will remain asymptomatic. In fact, this huge reservoir is blamed for the TB burden mainly in developing countries, causing the global resurgence of TB, which is further fueled by the HIV pandemic and the rise of M. tuberculosis multi (MDR)-, extremely (XDR)-, and totally (TDR)-drug resistant strains....

Comments on the Neonatal Bacillus Calmette-Gue´rin Vaccination: Adding Notes in Proof of Nonspecific Effect

Submitted by sandra infurna ([email protected]) on 2016-07-21T16:38:05Z No. of bitstreams: 1 carlos_ponte_etal_IOC_2013.pdf: 186833 bytes, checksum: c64260e9cdccc45d5532900189f4d864 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-07-21T16:50:21Z (GMT) No. of bitstreams: 1 carlos_ponte_etal_IOC_2013.pdf: 186833 bytes, checksum: c64260e9cdccc45d5532900189f4d864 (MD5)Made available in DSpace on 2016-07-21T16:50:21Z (GMT). No. of bitstreams: 1 carlos_ponte_etal_IOC_2013.pdf: 186833 bytes, checksum: c64260e9cdccc45d5532900189f4d864 (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / La Jolla Institute for Allergy and Immunology. La Jolla, CA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / La Jolla Institute for Allergy and Immunology. La Jolla, CA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil

Data from: Population genetic structure in hyacinth macaws (Anodorhynchus hyacinthinus) and identification of the probable origin of confiscated individuals

Understanding the intraspecific genetic composition of populations in different geographic locations is important for the conservation of species. If genetic variability is structured, conservation strategies should seek to preserve the diversity of units. Also, origin of individuals can be determined, which is important for guiding actions against animal trafficking. The hyacinth macaw (Anodorhynchus hyacinthinus) is located in allopatric regions, vulnerable to extinction and suffering animal trafficking pressure. Therefore, we characterized its population genetic structure based on 10 microsatellites from 98 individuals and 2123bp of mitochondrial sequence (ND5, cytochrome b, and ND2) from 80 individuals. Moderate to high levels of differentiation were observed among 3 geographic regions of Brazil: the north/northeast of the country, the north Pantanal, and the south Pantanal. Differentiation between the 2 regions within the Pantanal was not expected, as they are relatively close and there is no known barrier to macaw movement between these regions. These genetically differentiated groups were estimated to have diverged 16000 to 42000 years ago. The low genetic variability observed seems not to be the result of past bottlenecks, although a star-shaped haplotype network and the mismatch distribution suggest that there was recent demographic expansion in the north and northeast. Environmental changes in the Holocene could have caused this expansion. Given the genetic structure observed, the most probable regions of origin of 24 confiscated individuals were identified. Thus, these data helped to trace illegal traffic routes and identify natural populations that are being illegally harvested

Polymorphisms in IL-1beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis

Submitted by Sandra Infurna ([email protected]) on 2018-05-17T13:37:24Z No. of bitstreams: 1 paulorz_antas_etal_IOC_2010.pdf: 388528 bytes, checksum: a3221660e0f6bf9677d1e185f0c331cf (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-05-17T13:52:37Z (GMT) No. of bitstreams: 1 paulorz_antas_etal_IOC_2010.pdf: 388528 bytes, checksum: a3221660e0f6bf9677d1e185f0c331cf (MD5)Made available in DSpace on 2018-05-17T13:52:37Z (GMT). No. of bitstreams: 1 paulorz_antas_etal_IOC_2010.pdf: 388528 bytes, checksum: a3221660e0f6bf9677d1e185f0c331cf (MD5) Previous issue date: 2010North Carolina State University. Bioinformatics Research Center. Department of Statistics. Raleigh, NC, USA.Vanderbilt University School of Medicine. Department of Medicine. Division of Infectious Dieseases. Nashville, Tennessee, USANorth Carolina State University. Bioinformatics Research Center. Department of Statistics. Raleigh, NC, USA.Vanderbilt University School of Medicine. Department of Biomedical Informatics. Nashville, Tennessee, USA.National Institutes of Health. Laboratory of Clinical Infectious Diseases. Bethesda, MD, USA.Vanderbilt University School of Medicine. Department of Medicine. Division of Infectious Dieseases. Nashville, Tennessee, USA / Vanderbilt University School of Medicine. Department of Medicine.. Center for Health Services Research. Nashville, TN, USA.. Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Background: Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear. Methods: We conducted a pilot case-control study to identify genetic variants associated with extrapulmonary tuberculosis in patients with previously characterized immune defects: low CD4+ lymphocytes and low unstimulated cytokine production. Two genetic association approaches were used: 1) variants previously associated with tuberculosis risk; 2) single nucleotide polymorphisms (SNPs) in candidate genes involved in tuberculosis pathogenesis. Single locus association tests and multifactor dimensionality reduction (MDR) assessed main effects and multi-locus interactions. Results: There were 24 extrapulmonary tuberculosis cases (18 black), 24 pulmonary tuberculosis controls (19 black) and 57 PPD+ controls (49 black). In approach 1, 22 SNPs and 3 microsatellites were assessed. In single locus association tests, interleukin (IL)-1b +3953 C/T was associated with extrapulmonary tuberculosis compared to PPD+ controls (P = 0.049). Among the sub-set of patients who were black, genotype frequencies of the vitamin D receptor (VDR) Fok1 A/G SNP were significantly different in extrapulmonary vs. pulmonary TB patients (P = 0.018). In MDR analysis, the toll-like receptor (TLR) 2 microsatellite had 76% prediction accuracy for extrapulmonary tuberculosis in blacks (P = 0.002). In approach 2, 613 SNPs in 26 genes were assessed. None were associated with extrapulmonary tuberculosis. Conclusions: In this pilot study among extrapulmonary tuberculosis patients with well-characterized immune defects, genetic variants in IL-1b, VDR Fok1, and TLR2 were associated with an increased risk of extrapulmonary disease. Additional studies of the underlying mechanism of these genetic variants are warranted

Kinetics of T cell-activation molecules in response to mycobacterium tuberculosis antigens

The phenotypic features acquired subsequent to antigen-specific stimulation in vitro were evaluated by means of the kinetic expressions of CD69 and CD25 activation molecules on T lymphocytes and assayed by flow cytometry in response to PPD, Ag85B, and ferritin in PPD-positive healthy control individuals. In response to PHA, CD69 staining on both CD4+ and CD8+ T cells became initially marked after 4 h, peaked at 24 h, and quickly decreased after 120 h. For CD25, a latter expression was detected around 8 h, having increased after 96 h. As expected, the response rate to the mycobacterial antigens was much lower than that to the mitogen. Positive staining was high after 96 h for CD25 and after 24 h for CD69. CD69 expression was significantly enhanced (p &lt; 0.05) on CD8+ as compared to CD4+ T cells. High levels were also found between 96-120 h. Regarding Ag85B, CD25+ cells were mostly CD4+ instead of CD8+ T cells. Moreover, in response to ferritin, a lower CD25 expression was noted. The present data will allow further characterization of the immune response to new mycobacterial-specific antigens and their evaluation for possible inclusion in developing new diagnostic techniques for tuberculosis as well in a new vaccine to prevent the disease