Publicação

Influence of the variability of Mycobacterium tuberculosis strains on the host immune response

Detalhes bibliográficos
Resumo:	Mycobacterium tuberculosis (Mtb), one of the most successful human pathogens in the world, is initially sensed in the lung by pathogen recognition receptors such as TLRs, localized in macrophages, dendritic cells, and monocytes recruited from the bloodstream. This recognition via TLRs initiates a signal transduction pathway in the host cell that culminates with the induction of cytokines and chemokines that are critical for initiation of the innate immune response and the subsequent activation of adaptive immune defence against the pathogen. TLR2, TLR4 and TLR9 have been implicated as the main TLRs in the recognition of Mtb. However, the specific role of these receptors during Mtb infection remains unclear despite several studies that have been done. These studies have shown conflicting results regarding the role of individual TLRs or even in their cooperative work. One of the most important and intriguing characteristics of tuberculosis (TB) is the wide spectrum of the disease. After infection the variety of possible outcomes is undetermined and seems to depend on the particular genetic interplay between host and pathogen. Individual characteristics of each one could influence in a positive or negative way the final result of the infection. The variability in the immune response induced by different strains of Mtb, the distinct interaction with innate immune cells and their heterogeneous responses are other related issues, which could also impact the pathogenesis of the infection. This work was focused on understanding the molecular bases that determine the heterogeneity of the immune response induced by different strains of Mtb and to provide new insights on how the Mtb/host interaction can impact the immune response and pathogenesis. To achieve this, we selected Beijing (Bj) strains, a group of conserved genotypes of Mtb strains, included in the East- Asian lineage which have been associated with multidrug resistance and have been suggested to be more virulent and to elicit non-protective immune responses.Initially we confirmed the wide heterogeneity of the immune response induced by a panel of Bj strains using an in vitro model. We also hypothesized that TLRs may play an important role in the process. Using Mtb Bj strains and a mice model of infection we showed a differential recognition by the host to strains that belong to the same phylogenetic family. Depending on the infecting strain, recognition can occur preferentially via either TLR2 or TLR4, with a differential impact on the progression and outcome of the infection. Moreover, we showed that TLR4 has a critical role in the recognition of certain strains, namely 02-171 Bj strain. Our analysis showed a strong dependency on TLR4 recognition, inducing a particularly robust profile of cytokines in vitro and in vivo, with a prominent induction of IFN-β, which was not observed in strains preferentially recognized by TLR2. Moreover, in the absence of TLR4 we observed a higher bacterial burden in the lungs of mice infected with the 02-171 Bj strain as well a notable decrease of almost all measured cytokines, supporting a protective role for TLR4. Subsequently, differential activation of TLR by Mtb Bj strains has impact in the induction of molecules related with microbicidal activity such as a NO and LRG-47. An important differential role of TLR4 was detected during activation of these microbicidal mechanisms in macrophages. Importantly, this differential recognition was observed also in strains that belong to other phylogenetic families. Altogether, data presented throughout this work provide relevant input to better understand the molecular basis of the host immune innate cells during infection with Mtb strains, particularly how the Mtb/host interaction can impact on the heterogeneity of pathogenesis of TB.
Autores principais:	Carmona, J. A.
Ano:	2013
País:	Portugal
Tipo de documento:	tese de doutoramento
Tipo de acesso:	acesso restrito
Instituição associada:	Universidade do Minho
Idioma:	inglês
Origem:	RepositóriUM - Universidade do Minho