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Population genomic and phenotypic determinants of host tropism in the Mycobacterium tuberculosis Complex affecting livestock and humans

English title Population genomic and phenotypic determinants of host tropism in the Mycobacterium tuberculosis Complex affecting livestock and humans
Applicant Gagneux Sebastien
Number 188888
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Experimental Microbiology
Start/End 01.10.2019 - 30.09.2023
Approved amount 1'112'000.00
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All Disciplines (6)

Discipline
Experimental Microbiology
Medical Microbiology
Molecular Biology
Immunology, Immunopathology
Ecology
Infectious Diseases

Keywords (10)

virulence; fitness; coevolution; RNAseq; population genetics; mycobacteria; gene expression; innate immunity; zoonotic TB; gene expression

Lay Summary (German)

Lead
Die Tuberkulose (TB) ist nach wie vor weltweit ein grosses Gesundheitsproblem. Jedes Jahr sterben 1.6 Millionen Menschen in dieser Infektionskrankheit, die vom Bakterium Mycobacterium tuberculosis verursacht wird. Zusätzlich verursacht die TB bei Rindern und anderen domestizierten Tieren, die durch verwandte Mycobakterien Arten verursacht wird, einen jährlichen ökonomischen Schaden in Milliarden Höhe. Im Gegensatz zu M. tuberculosis, ist die globale Diversität und Evolution dieser Mycobacterien zur Zeit nicht gut erforscht.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Das Ziel dieses Projekts ist es, die weltweite genetische Vielfalt und die Evolution von Mycobacterium bovis, Mycobacterium caprae und Mycobacterium orygis zu erforschen. Diese drei Erreger verursachen den grössten ökonomischen Schaden in der Landwirtschaft und sind auch die wichtigsten TB Erreger, die von Tieren auf den Menschen übertragen werden können (ein Phänomen, das als TB Zoonose bekannt ist). Zusätzlich ist das Ziel, anhand von verschiedener experimentellen Methoden, die genetischen and phenotypischen Charakteristika dieser Erreger zu identifizieren, die für die jeweiligen Wirtsspäzifitäten verantwortlich sind.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit wird wichtige Information generieren, die zur einem besseren Verständnis der TB bei domestizierten Tieren und beim Menschen führen wird. Im speziellen werden wir diejenigen Teile des mycobakteriellen Genomes identifizieren, die mit dem Immunsystem der verschiedenen Wirtsspezies in Wechselwirkung stehen und mögliche Grundlagen für die Wirtsspezifitäten bestimmter bakteriellen Varianten aufzeigen. Diese Ergebnisse werden u.a. für die Entwicklung neuer Impfstoffe und besserer Diagnosemethoden für die TB beim Menschen und beim Tier relevant sein.

Direct link to Lay Summary Last update: 03.02.2021

Responsible applicant and co-applicants

Employees

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Associated projects

Number Title Start Funding scheme
166687 Integrating population and functional genomics with molecular epidemiology to explore the interaction between host and pathogen diversity in human tuberculosis 01.04.2016 Project funding (Div. I-III)
177163 Host-pathogen genomic interactions and their phenotypic impact in human tuberculosis 01.02.2018 Sinergia

Abstract

Tuberculosis (TB) in humans and animals remains a public health emergency and a global economic problem. TB causes more human deaths than any other infectious disease, and TB in livestock leads to a global estimated loss of three billion US dollars per year. The main agents of TB are a group of closely related bacteria known as the Mycobacterium tuberculosis Complex (MTBC), which differ in their host tropism. The MTBC Lineages 1 to 7 are human-adapted, and several other MTBC lineages, or ecotypes, mainly affect different wild and domestic animal species. Among the latter, Mycobacterium bovis and Mycobacterium caprae are the most important agents of TB in livestock and also the most important causes of zoonotic TB in humans. Recently, there has been an increase in cases of Mycobacterium orygis reported among immigrants from South Asia, indicating that this ecotype has the potential to cause zoonotic disease in humans. During the last few years, analyses of large globally representative collections of whole genome sequences from the human-adapted MTBC lineages have enhanced our understanding of the global population structure, phylogeography and evolutionary history of these pathogens. By contrast, little corresponding data exist for the various animal-adapted ecotypes of the MTBC. This is particularly true for M. bovis, M. caprae and M. orygis, for which most available data comes from convenience samples generated in high-income countries such as UK, USA and New Zealand. As a result, the global population structure, phylogeography and evolutionary history of these ecotypes remain unknown. Moreover, although we and others have shown that M. bovis, M. caprae and M. orygis are phylogenetically separate entities, whether these phylogenetic distances reflect ecological separation with respect to host tropism is unclear. The general view is that M. bovis has a broader host tropism compared to other members of the MTBC, but in M. caprae and M. orygis, the main maintenance host, and host tropism in general, are poorly defined, particularly with respect to their zoonotic potential. The overall goal of this project is to define the global population structure, phylogeography, evolutionary history and genomic diversity of M. bovis, M. caprae and M. orygis, and to explore the genomic and phenotypic determinants of host tropism in these animal-adapted members of the MTBC. We hypothesize that i) M. bovis, M. caprae and M. orygis exhibit a phylogeographical population structure that reflects events in domestication, animal husbandry, human migration and trade, ii) M. bovis, M. caprae and M. orygis differ in their host tropism and zoonotic potential, iii) these differences in host tropism are reflected in evolutionary signatures in the genomes of these pathogens, and iv) manifest in the phenotypic features of the corresponding host-pathogen interactions measured ex vivo. We will test these hypotheses by addressing the following three Specific Objectives:1.Determine the global population structure, phylogeography and evolutionary history of M. bovis, M. caprae and M. orygis;2.Explore the genomic basis of host tropism in M. bovis, M. caprae and M. orygis;3.Identify phenotypic correlates of host tropism in matched- and mismatched host macrophages infected with M. bovis, M. caprae or M. orygis.We propose an integrated and multidisciplinary approach, in which we combine i) detailed analyses of large, globally representative collections of M. bovis, M. caprae or M. orygis genome sequences generated using both short- and long sequencing read technologies, ii) application of state-of-the-art population genomic, phylogenomic, phylogeographic and molecular dating methods, and iii) functional assays based on host-pathogen matched- and mismatched macrophage infections analysed for intracellular bacterial growth, host-pathogen cross-talk using dual RNAseq, and host innate immune responses. In addition, we will study the relative zoonotic potential of these three ecotypes by infecting human macrophages. This project will generate fundamental new insights into the global genomic population structure, phylogeography and evolutionary history of the main agents of TB in livestock and the most important causes of zoonotic TB in humans. Moreover, it will shed new light into the genomic and phenotypic basis of host tropism in the animal-adapted MTBC, and thereby, contribute to an improved understanding of the biology of host-pathogen interaction in one of the world’s most important infectious diseases.
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