Centro Colombiano Of Investigacion En Tuberculosis Ccitb

Medellín, Colombia

Centro Colombiano Of Investigacion En Tuberculosis Ccitb

Medellín, Colombia
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Marin D.,University of Antioquia | Marin D.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Marin D.,Pontifical Bolivarian University | Marin N.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | And 16 more authors.
PLoS ONE | Year: 2017

Introduction The mechanisms of mononuclear phagocyte death have been associated with the permissiveness and resistance to mycobacterial replication, but it remains unknown whether or not they help predict the risk of developing TB. Objective To describe the factors associated with the induction of monocyte mitochondrial and membrane damage in response to PPD as well as determine if this type of damage might predict the susceptibility of developing active tuberculosis in a cohort of household contacts (HHCs) from Medellin, Colombia from 2005 to 2008. Methods The prospective cohort study contains 2060 HHCs patients with pulmonary tuberculosis who were meticulously followed for two years. A survey of the socio-demographic, clinical, epidemiological factors and blood samples were collected. Mononuclear cell cultures were stimulated with or without PPD and the type of monocyte death was determined by the flow of cytometry, an indicator was also used for its analysis. Logistic regression was adjusted by the Generalized Estimations Equations and the survival was estimated with the Kaplan-Meier and Cox regression. Confidence intervals were used for estimating the association. Results 1,859 out of 2,060 blood samples of the HHCs patients analyzed showed monocyte death. In response to PPD, 83.4% underwent mitochondrial damage while 50.9% had membrane damage. The membrane damage in response to PPD was higher in children under 4 years (OR: 1.57; (95% CI: 1.1 to 2.4) and the HHCs who slept regularly in the same household has an index case of (OR: 1.54; 95% CI: 1.0 to 2.3). After adjustment by age, comorbidities, nutritional status, proximity to index case and overcrowding, the risk of developing active TB among BCG vaccinated HHCs individuals with induction of mitochondrial damage was HR = 0.19 (95% CI: 0.1 to 0.5). Conclusions The induction of monocytes mitochondrial damage by PPD stimulation correlates with protection of TB disease development in BCG-vaccinated HHCs. This represents a potential tool to predict susceptibility of developing active disease in this population. © 2017 Marín et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Sanchez D.,University of Antioquia | Sanchez D.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Rojas M.,University of Antioquia | Rojas M.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | And 6 more authors.
Cellular Immunology | Year: 2010

Infection of macrophages with Mycobacterium tuberculosis (Mtb) induces cell death by apoptosis or necrosis. TLRs 2 and 4 recognition of mycobacterial ligands has been independently associated to apoptosis induction. To try to understand the particular contribution of these receptors to apoptotic or necrotic signaling upon infection with live Mtb H37Rv, we used macrophage lines derived from wild-type or TLR2-, TLR4-, and MyD88-deficient mouse strains. Mtb-infection triggered apoptosis depending on a TLR2/TLR4/MyD88/p38/ERK/PI-3K/NF-kB pathway; however, necrosis was favored in absence of TLR4 signaling independently of p38, ERK1/2, PI-3K or NF-κB activity. In conclusion, our results indicate that cooperation between TLR2- and TLR4-dependent mediated signals play a critical role in macrophage apoptosis induced by Mtb and the TLR4-mediated signaling has important role in the maintenance of the balance between apoptotic vs. necrotic cell death induced by macrophage infection with Mtb. © 2009 Elsevier Inc. All rights reserved.

Rojas C.M.,Centro Internacional Of Entrenamiento E Investigaciones Medicas Cideim | Rojas C.M.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Villegas S.L.,Centro Internacional Of Entrenamiento E Investigaciones Medicas Cideim | Villegas S.L.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | And 12 more authors.
Biomedica | Year: 2010

Introduction: The World Health Organization recommended strategy for global tuberculosis control is a short-course, clinically administered treatment, This approach has approximately 70% coverage in Colombia. Objective: The clinical, epidemiological and microbiological characteristics along with drug therapy outcomes were described in newly diagnosed, pulmonary tuberculosis patients. Materials and methods: This was a descriptive study, conducted as part of a multicenter clinical trial of tuberculosis treatment. A cohort of 106 patients with pulmonary tuberculosis were recruited from several public health facilities in Cali between April 2005 and June 2006. Sputum smear microscopy, culture, drug susceptibility tests to first-line anti-tuberculosis drugs, chest X- ray and HIV-ELISA were performed. Clinical and epidemiological information was collected for each participant. Treatment was administered by the local tuberculosis health facility. Food and transportation incentives were provided during a 30 month follow-up period. Results: The majority of patients were young males with a diagnostic delay longer than 9 weeks and a high sputum smear grade (2+ or 3+). The initial drug resistance was 7.5% for single drug treatment and 1.9% for multidrug treatments. The incidence of adverse events associated with treatment was 8.5%. HIV co-infection was present in 5.7% of the cases. Eighty-six percent of the patients completed the treatment and were considered cured. The radiographic presentation varied within a broad range and differed from the classic progression to cavity formation. Conclusion: Delay in tuberculosis diagnosis was identified as a risk factor for treatment compliance failure. The study population had similar baseline epidemiologic characteristics to those described in other cohort studies.

Reyes A.,University of Washington | Sandoval A.,Molecular Genetics | Cubillos-Ruiz A.,Molecular Genetics | Varley K.E.,University of Washington | And 14 more authors.
BMC Genomics | Year: 2012

Background: The insertion element IS6110 is one of the main sources of genomic variability in Mycobacterium tuberculosis, the etiological agent of human tuberculosis. Although IS 6110 has been used extensively as an epidemiological marker, the identification of the precise chromosomal insertion sites has been limited by technical challenges. Here, we present IS-seq, a novel method that combines high-throughput sequencing using Illumina technology with efficient combinatorial sample multiplexing to simultaneously probe 519 clinical isolates, identifying almost all the flanking regions of the element in a single experiment.Results: We identified a total of 6,976 IS6110 flanking regions on the different isolates. When validated using reference strains, the method had 100% specificity and 98% positive predictive value. The insertions mapped to both coding and non-coding regions, and in some cases interrupted genes thought to be essential for virulence or in vitro growth. Strains were classified into families using insertion sites, and high agreement with previous studies was observed.Conclusions: This high-throughput IS-seq method, which can also be used to map insertions in other organisms, extends previous surveys of in vivo interrupted loci and provides a baseline for probing the consequences of disruptions in M. tuberculosis strains. © 1900 Reyes et al.; licensee BioMed Central Ltd.

Sanchez D.,University of Antioquia | Sanchez D.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Sanchez D.,Louisiana State University | Lefebvre C.,University of Notre Dame | And 4 more authors.
Biomedica | Year: 2013

Introduction: Interferon gamma (IFNγ) is the most potent cytokine involved in the control of Mycobacterium tuberculosis (Mtb), the etiological agent of human tuberculosis (TB). Patients with active TB present reduced levels of IFNγ, which may explain the lack of effective immunity against Mtb in these patients. The diminished expression of or functional alterations in trans-acting factors that regulate IFNγ gene expression may explain the reduced levels of IFNγ in TB patients. Objective: To investigate the relationships of genetic variants in the transcription factors TBET, STAT1, STAT4, and HLX to susceptibility/resistance to pulmonary TB. Materials and methods: Eight candidate single-nucleotide polymorphisms (SNPs) were selected, and genotyped in 466 unrelated pulmonary TB patients and 300 healthy controls from Colombia, and the allelic and genetic associations with TB were analyzed. Results: The results indicate that no SNP in the transcription factors studied is associated with TB. However, polymorphism rs11650354 in the TBET gene may be associated with a decreased risk of TB; the TT genotype was significantly associated with TB protection in a recessive genetic model (OR=0.089, 95% CI: 0.01-0.73, p=0.0069), although this association was not maintained after multiple test correction (EMP2= 0.61). Conclusion: In this study, the rs11650354 variant of TBET was suggested to promote resistance to TB in a Colombian population. A future replication case-control study using additional samples will be necessary to confirm this suggestive association.

Sanchez D.,University of Antioquia | Sanchez D.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Lefebvre C.,Montreal Heart Institute | Lefebvre C.,University of Notre Dame | And 5 more authors.
International Journal of Immunogenetics | Year: 2012

Immunological studies have supported the idea that innate immunity is critical for the control of Mycobacterium tuberculosis (Mtb) infection in humans. Despite the overwhelming evidence showing the critical role of Toll-like receptors (TLRs) in the in vitro recognition of Mtb, the in vivo significance of individual TLRs has been more difficult to demonstrate consistently. We were interested in examining the role of genes of TLRs and molecules involved in their signalling cascades, and a case-control study was designed to test the association of polymorphisms of these innate immune genes with pulmonary tuberculosis (TB) in a Colombian population. In this study, we did not find an association with TLR2, TLR4, TLR9, MyD88 or MAL/TIRAP polymorphic variants. These findings suggest that those genes are not involved as risk factors for pulmonary TB in our population. © 2012 Blackwell Publishing Ltd.

Bueno J.,Instituto Nacional Of Salud | Bueno J.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | David Coy E.,National University of Colombia | Stashenko E.,Industrial University of Santander
Revista Espanola de Quimioterapia | Year: 2011

It is estimated that one-third part of the world population is infected with the tubercle bacillus. While only a small percentage of infected individuals will develop clinical tuberculosis, each year there are approximately eight million new cases and two million deaths. Mycobacterium tuberculosis is thus responsible for more human mortality than any other single microbial species. The goals of tuberculosis control are focused to cure active disease, prevent relapse, reduce transmission and avert the emergence of drug-resistance. For over 50 years, natural products have served us well on combating infectious bacteria and fungi. During the 20th century, microbial and plant secondary metabolites have helped to double our life span, reduced pain and suffering, and revolutionized medicine. Colombia is a megadiverse country with enormous potential to offer leads for new antimycobacterial drugs. The principal aim of this article is to show a state of the art on antimycobacterial natural products research in Colombia compared to the rest of the world, in order to develop programs for bioprospecting with a view to determining the biological activity for pharmaceutical and industrial application of natural products in our country.

Nino V.E.,University of Cauca | Nino V.E.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Garcia L.F.,University of Antioquia | Garcia L.F.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | And 10 more authors.
Tuberculosis | Year: 2014

Aiming to identify a possible biomarker that distinguishes immune cellular response of active tuberculosis from latent infection. Peripheral blood mononuclear cells (PBMCs) of pulmonary tuberculosis patients (PTB), tuberculin positive household contacts (TST+ HHC), and tuberculin negative non-household contacts (TST- Non HHC) were stimulated with PPD or CFP-10 and the percentage of CD69+ cells, proliferating precursor and IFN-γ producing CD4+, CD8+, CD56+CD3- and CD56+CD3+ cells were compared. IL-2, IL-12p70, IL-15, IL-18 and IL-10 were measured in culture supernatants. PTB and TST+ HHC presented higher percentages of CD69+ cells, IFN-γ+ and proliferating precursors in all subpopulations studied and higher IL-12p70 levels than TST- Non HHC. The increased percentage of IFN-γ producing CD56+CD3+ cells in response to CFP-10 in PTB, compared with TST- Non HHC and the ratios between the percentage of CD56+CD3+ cells/CD56+CD3- and CD8+ cells producing IFN-γ suggest that these parameters may distinguish active TB from latently infected individuals. © 2014 Elsevier Ltd.

Rueda C.M.,University of Antioquia | Marin N.D.,University of Antioquia | Garcia L.F.,University of Antioquia | Garcia L.F.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | And 2 more authors.
Tuberculosis | Year: 2010

Patients with pulmonary tuberculosis (PTB) frequently have reduced IFN-γ production in response to mycobacterial antigens, compared to individuals with latent Mycobacterium tuberculosis infection (LTBi). However, it is not clear whether this reduced responsiveness is restricted to a particular T cell subset. Herein, PBMCs from 26 PTB patients, 30 household contacts (HHCs) of PTB, and 30 tuberculin positive (TST+) healthy subjects not recently exposed to PTB, were stained with CFSE and stimulated non-specific (PPD) for 120 h, and specific (CFP-10/ESAT-6) and latency (HSpX) mycobacterial antigens for 144 h and the percentage of CD4 + and CD8 +IFN-γ + T cells responding determined by flow cytometry, in addition to their memory phenotype by the CD45RO and CD27 expression. PTB had decreased frequency of both CD4 + and CD8 + precursor cells, as well as decreased number of CD4 +IFN-γ + cells in response to all antigens, whereas CD8 +IFN-γ + cells were decreased in response to PPD and ESAT-6, but not to CFP-10 and HSpX. HHCs exhibited the highest precursor frequencies and IFN-γ responses, irrespective of the antigen employed. The CD4 +/CD8 + cell ratios showed that in response to PPD CD4 + precursor and IFN-γ-producer cells are more frequent than their CD8 + counterparts, and that PTB have a decreased CD4 +IFN-γ +/CD8 +IFN- γ + ratio in response to PPD, CFP-10, and ESAT-6. CD4 +IFN-γ + and CD8 +IFN-γ + cells exhibited a central memory phenotype (CD45RO +CD27 +), irrespective of the group of subjects and the antigen used for stimulation. In conclusion, PTB patients had a decreased percentage of CD4 + and CD8 + precursor cells and CD4 +IFN-γ +. HHCs exhibited the highest frequency of CD4 + and CD8 + precursors and CD4 +IFN-γ +-producing cells. © 2010 Elsevier Ltd. All rights reserved.

Quiroga J.,University of Valle | Diaz Y.,University of Valle | Bueno J.,Centro Colombiano Of Investigacion En Tuberculosis Ccitb | Insuasty B.,University of Valle | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Three series of novel 4-arylbenzo[h]pyrazolo[3,4-b]quinolin-5,6-diones 4, 7 and 9 have been efficiently obtained in good yields by three-component microwave assisted reaction between aminopyrazoles 1 or 6 (both 1-phenyl and 1-H substituted), 2-hydroxynaphthoquinone 2 and benzaldehydes 3. Compounds 4, 7 and 9 have been evaluated against fifteen Mycobacterium spp strains, and six of them have shown antimycobacterial activity. The highest inhibitory activity with MIC ≤2 μg/mL for three of these compounds (4a, 4b and 4g) was related with their highest lipophilicity and lesser polarity within these series. © 2014 Elsevier Masson SAS. All rights reserved.

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