ICVS 3Bs Research Group
ICVS 3Bs Research Group
Nebenzahl-Guimaraes H.,National Institute for Public Health and the Environment |
Nebenzahl-Guimaraes H.,University of Minho |
Nebenzahl-Guimaraes H.,ICVS 3Bs Research Group |
Van Laarhoven A.,Radboud University Nijmegen |
And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2017
Rationale: Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown. Objectives: To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses. Methods: Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors.Wesubjected these strains to wholegenome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility. Measurements and Main Results: We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis. Conclusions: In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro. © 2017 by the American Thoracic Society.
de Sa-Calcada D.,University of Minho |
de Sa-Calcada D.,Icvs 3Bs Research Group |
Roque S.,University of Minho |
Roque S.,Icvs 3Bs Research Group |
And 12 more authors.
Frontiers in Behavioral Neuroscience | Year: 2015
Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain. © 2015 de Sá-Calçada, Roque, Branco, Monteiro, Cerqueira-Rodrigues, Sousa, Palha and Correia-Neves.