Imbalance of NET and Alpha-1-Antitrypsin in Tuberculosis Patients Is Related With Hyper Inflammation and Severe Lung Tissue Damage

Background: Pulmonary tuberculosis (PTB) can lead to lung tissue damage (LTD) and compromise the pulmonary capacity of TB patients that evolve to severe PTB. The molecular mechanisms involved in LTD during anti-tuberculous treatment (ATT) remain poorly understood.Methods and findings: We evaluated the role of neutrophil extracellular trap (NET) and the occurrence of LTD through chest radiographic images, the microbial load in sputum, and inflammatory serum profile (IL-12p40/p70, IL-8, IL-17A, IL-23, VEGF-A, MMP-1, and -8, galectin-3, citrunillated histone H3—cit-H3, alpha-1-antitrypsin—α1AT, C-reactive protein—CRP and albumin) in a cohort of 82 PTB patients before and after 60 days of ATT. Using univariate analysis, LTD was associated with neutrophilia and increase of several inflammatory proteins involved in the neutrophil-mediated response, being cit-H3 the more related to the event. In the multivariate analysis, neutrophilia and cit-H3 appear as directly related to LTD. The analysis of the ROC curve at day 60 presented AUC of 0.97 (95.0% CI 0.95–1). Interestingly, at day 0 of ATT, these biomarkers demonstrated fine relation with LTD showing an AUC 0.92 (95.0% CI 0.86–0.99). Despite of that, the same molecules have no impact in culture conversion during ATT.Conclusions: Our data revealed that NETs may play a key role in the pathway responsible for non-specific inflammation and tissue destruction in PTB. High level of cit-H3 and low level of α1AT was observed in the serum of severe TB patients, suggesting a breakdown in the intrinsic control of NET-driven tissue damage. These data show a new insight to knowledge TB immunopathogenesis, the role of neutrophil and NET pathway. Likewise, we identified possible biomarkers to screening of PTB patients eligible to adjuvants therapies, as anti-inflammatories and alpha-1-antitrypsin

Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2020-02-03T11:53:23Z No. of bitstreams: 1 Cubillos-Angulo JM Polymorphisms in Interferon Int J Infect Dis.pdf: 2351156 bytes, checksum: 46b584145c4ea7161f673f992685ac9c (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2020-02-03T12:21:55Z (GMT) No. of bitstreams: 1 Cubillos-Angulo JM Polymorphisms in Interferon Int J Infect Dis.pdf: 2351156 bytes, checksum: 46b584145c4ea7161f673f992685ac9c (MD5)Made available in DSpace on 2020-02-03T12:21:55Z (GMT). No. of bitstreams: 1 Cubillos-Angulo JM Polymorphisms in Interferon Int J Infect Dis.pdf: 2351156 bytes, checksum: 46b584145c4ea7161f673f992685ac9c (MD5) Previous issue date: 2019-01-13Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Instituto Nacional de Ciência e Tecnologia (INCT, Journal Pre-proof grant number: 421703/2017-2) and Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ, grant number: E-26/110.974/2011). BBA, JRLS, and AK are senior investigators from CNPq and AK and JRLS receive senior fellowships from FAPERJ. The work from BBA and KFF was supported by intramural research program from FIOCRUZ and from the National Institutes of Health (U01AI115940). JMC-A was supported by the Organization of American States - Partnerships Program for Education and Training (OAS-PAEC) and his study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001. MBA receives a fellowship from the Fundação de Amparo à Pesquisa da Bahia (FAPESB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil.Universidade Federal do Rio de Janeiro. Centro de Pesquisas em Doenças Infecciosas e Parasitárias. Laboratório de Micobacteriologia Molecular. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Faculdade de Medicina e Complexo Hospitalar. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Pesquisas em Doenças Infecciosas e Parasitárias. Laboratório de Micobacteriologia Molecular. Rio de Janeiro, RJ, Brasil / Universidade Federal do Norte Fluminense Darcy Ribeiro. Centro de Biociências e Biotecnologia. Laboratório de Biologia do Reconhecer. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil / Universidad Franz Tamayo. Coordinación Nacional de Investigación. La Paz, Bolivia.Universidade Federal do Rio de Janeiro. Faculdade de Medicina e Complexo Hospitalar. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Medicina e Complexo Hospitalar. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Medicina e Complexo Hospitalar. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil.Vanderbilt University. School of Medicine. Nashville. Department of Medicine. Division of Infectious Diseases. Tennessee, USA.University of Washington. Department of Medicine. Seattle, WA, USA.Universidade Federal do Rio de Janeiro. Faculdade de Medicina e Complexo Hospitalar. Programa Acadêmico de Tuberculose. Rio de Janeiro, RJ, Brasil.University of Washington. Department of Medicine. Seattle, WA, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil / Vanderbilt University. School of Medicine. Nashville. Department of Medicine. Division of Infectious Diseases. Tennessee, USA / University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Disease Research in Africa. Cape Town, South Africa / Universidade Salvador. Laureate Universities. Salvador, BA, Brasil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil.Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection. Methods: We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models. Results: Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95%CI = 1.15–12.0; p=0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR= 24.84; 95%CI = 2.26–272.95; p=0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p=0.029). Conclusions: Polymorphisms in PYHIN1-IFI16-AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort

No-Budget Science Hack Week 2020

Repositório para os projetos desenvolvidos na edição remota da No-Budget Science Hack Week 2020 - https://www.reprodutibilidade.bio.br/hack-week-202