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Novel Approaches to Determine Molecular Mechanisms of Pathogenesis in Tuberculosis

Final Report Summary - TB-PATH (Novel Approaches to Determine Molecular Mechanisms of Pathogenesis in Tuberculosis)

Tuberculosis (TB) is a complex infectious disease with the underlying mechanisms of pathogenesis still not fully understood. This in part has been due to the lack of an experimental mouse model of TB that has held back scientific progress in the field. Using large cohorts of TB patients and healthy volunteers, together with complementary analytical approaches of modular, pathway and gene level analysis, the O’Garra group has provided global knowledge of the immune response and potential factors leading to TB pathogenesis in the past. These studies have allowed the identification of a striking interferon (IFN)-inducible blood signature of active TB, that correlated with the extent of radiographic disease (Berry et al., Nature 2010; Bloom et al., Plos One 2013; Blankley et al., ERJ, 2016; Blankley et al., Plos One, 2016) and diminished upon successful treatment (Berry et al., Nature 2010; Bloom et al., PLoS One 2012), highlighting a previous unknown potential negative role for an immune molecule known as type I IFN in TB.

In the present project funded by the ERC, Anne O’Garra supported by her team has proposed to create a modular tool at the gene level to study complex transcriptional data in blood and tissue from mouse models of disease, as has been done for human disease, to allow accurate comparison of mouse models with human TB, to test it across different mouse and Mtb strains across different doses and time points to help establish a mouse model by identifying gene signatures that resemble those observed in human TB (Aim 1). Blood and tissue samples have been collected and processed from thirteen different experimental mouse models of infection and inflammation with the help of collaborators worldwide and subjected to microarray and RNA-sequencing technology with success. These transcriptomic high-throughput technologies are key in identifying biological processes perturbed at the whole genome level in various states of infection and inflammation and have been analyzed by latest genomic approaches and algorithms to identify and establish modules of co-expressed genes that represent gene signatures with distinct biological processes. This modular tool is now being applied to different variations of mouse models of TB to reproduce the gene signature that we have described in human TB thus leading to improvement of the mouse model. This will significantly benefit the field of TB in further understand the pathogenesis of disease. Moreover, this modular tool generated as part of this project will be available to other scientists worldwide and can be used to better understand other diseases as well, and the whole study will provide a valuable transcriptomic resource across various mouse models of diseases which when published will become publicly available in GEO.

Additionally, Anne O’Garra proposed to apply the knowledge obtained from the human TB to study in depth the mechanisms under-pinning the detrimental role of type I IFN in mouse models of TB. Expression of type I IFN and its inducible genes was unexpected in TB since type I IFN and its inducible genes are known as crucial in fighting viral infections. From our work and that of other labs now it is clear that type I IFN and its inducible genes have a pathogenic role in bacterial infections including TB (Aims 2 and 3). Molecular mechanisms underlying the role of type I IFN in TB pathogenesis and protection in mice infected with different strains of Mtb in vivo and in vitro have been defined - and eight manuscripts have been published on the topic. We described the role of type I IFN in exacerbation of TB in experimental mouse models, where pathways of type I IFN are perturbed either by host gene mutations or by viral coinfection. Although it is now clear that high levels of type I IFN are detrimental during Mtb infection, findings resulting from this project have also shown that early and low amount of type I IFN contribute to host protection in specific conditions where other protective pathways are perturbed. The ERC support has also allowed the generation of mutant mouse lines targeting specific molecules that are induced by type I IFN and that have also been correlated with human TB. Studies to understand the role of these molecules in TB pathogenesis and protection are now being performed and these new generated mutant mouse lines will also be used to understand the role of these molecules in a broader context of the immune response to infections.