Host-pathogen genomic interactions and their phenotypic impact in human tuberculosis

Tuberculosis (TB) is still a major health problem worldwide. Every year, 1.7 million people die from this infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Although TB is often fatal when untreated, the course of the disease differs enormously in people infected with Mtb. The objective of this project is to determine the role of genetic diversity of both the patient and the bacterium in these different disease courses.

Objective of the Research Project

Mtb has adapted to the human immune system over thousands of years. Conversely, the host immune system has developed so strongly that an infection with Mtb causes no symptoms in most individuals. However, some people are more TB sensitive than others, and also the Mtb bacteria are different. Certain Mtb variants are more contagious than others and are much more prevalent in the world than less successful ones. Most people who become infected with Mtb do not show any symptoms, in others, the bacteria infect the lungs, while in others again, many different organs are attacked simultaneously.

The aim of this project is to explore the interaction between human diversity and Mtb bacteria and to determine how this interaction affects the course of the disease. We use complementary approaches: i) a simultaneous genome comparison of the TB patients themselves and the Mtb bacteria they are infested with, ii) a detailed analysis of the epidemiological and clinical data of the TB patients, iii) determination of different characteristics of the Mtb bacteria within host cells artificially infected in the laboratory. The genome data of TB patients and their Mtb bacteria will be then integrated with the epidemiological data and laboratory characteristics.

Scientific and Social Context of the Research Project

Our work will generate important information that will lead to a better understanding of TB. Specifically, we will identify those parts of the Mtb genome that interact with the human immune system and show possible foundations for the success of certain Mtb variants and TB susceptibility of certain population groups. These results will i.a. be highly relevant for the development of new vaccines and better diagnostic methods.

Exposure to M. tuberculosis may lead to sterile or active but also subclinical, latent and reactivation forms of infection. Tuberculosis is normally cured upon appropriate diagnosis and treatment but patients can also relapse. In addition to environmental and socio-economic factors and excepting immunosuppression, these variable outcomes are thought to be influenced by host and bacterial genetic variations, a cocktail accounting for immune response flavors capable or not to prevent TB disease progression. This project combines genome-to-genome analyses with microbiological and immunological assays on tuberculosis (TB) patients and their cognate mycobacterial isolates to i) detect genomic and/or functional signatures of host-pathogen co-evolution, ii) identify genomic loci that interact between the host and the pathogen to jointly affect clinically relevant phenotypes, and iii) explore the respective and combined effects of host- and pathogen genomic variation on clinical, microbiological and immunological phenotypes related to bacterial virulence and transmissibility.


Sébastien Gagneux

Project Facts