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Molecular and clinical epidemiology of tuberculosis in Switzerland: Studies of populations infected and not infected with HIV

Applicant Egger Matthias
Number 125441
Funding scheme Project funding (special)
Research institution Institut für Sozial- und Präventivmedizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Infectious Diseases
Start/End 01.04.2009 - 31.03.2011
Approved amount 350'000.00
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All Disciplines (3)

Discipline
Infectious Diseases
Medical Microbiology
Molecular Biology

Keywords (29)

tuberculosis; Mycobacterium tuberculosis; clinical presentation; phenotype; genotype; SNP; spoligotyping; MIRU-VNTR; massARRAY; coinfection; molecular epidemiology; clinical epidemiology; microbiology; Swiss HIV cohort study; outcome; genetic diversity; drug resistance; drug resistance mutation; sub-Saharan Africa; haplotype; cluster; sympatric; genetic population structure; molecular biology; population genetics; public health; disease manifestation; strain variation; large nested project

Lay Summary (English)

Lead
Lay summary
Lead: Tuberculosis remains a public-health problem, especially in the context of HIV. This study aims to analyse differences in genetic population structure and correlates between genetic Mycobacterium tuberculosis strain variation and disease manifestation in HIV co-infected compared to HIV-negative tuberculosis patients.Summary: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, remains a major public-health problem worldwide, especially in the context of the HIV epidemic and the spread of drug-resistant TB. The disease manifestation of human infection with Mtb is extremely variable, ranging from lifelong asymptomatic infection to active lung disease and life-threatening meningitis. Human immunodeficiency virus infection (HIV) substantially increases the lifetime risk of active TB. Traditionally, host and environmental factors have been invoked to explain this variability, but there is growing evidence that bacterial factors could also be involved. M. tuberculosis has a global phylogeographic population structure consisting of six main phylogenetic lineages which are associated with specific, sympatric human populations; however it has been observed that allopatric lineages (e.g. European patient with an East-Asian strain) were more likely to spread in immunodeficient populations. The overall goal of this study is to analyse differences in the genetic population structure of M. tuberculosis and the associations between the genetic M. tuberculosis strain variation and disease manifestations in HIV co-infected compared to HIV-negative TB patients. We also intend to analyse genetic mutations conferring resistance to first-line anti-TB drugs, and to analyse the relationship between resistance mutations, genetic strain background and bacterial fitness. The results will shed a light on the impact of genetic strain variation on the disease manifestation and differences between populations infected and not infected with HIV. This is the first study describing the genetic diversity of M. tuberculosis in Switzerland and it is also the first time that novel genotyping techniques will be applied to M. tuberculosis in an epidemiological study. This study will provide the basis for a larger future project in sub-Saharan Africa where people disproportionally suffer from TB, within the framework of a network of HIV treatment programmes. This TB research initiative builds upon a research network of complementary expertise in epidemiology, bacterial population genetics, and clinical aspects in TB and HIV, and is embedded in the established Swiss HIV Cohort Study.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
134277 Swiss HIV Cohort Study (SHCS) 01.01.2011 Cohort Studies Large
153442 Population genomics of drug resistant tuberculosis 01.06.2014 Project funding (Div. I-III)
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
153442 Population genomics of drug resistant tuberculosis 01.06.2014 Project funding (Div. I-III)

Abstract

Background - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public-health problem worldwide, especially in the context of the HIV epidemic and the spread of drug-resistant Mtb. Human immunodeficiency virus infection (HIV) substantially increases the lifetime risk of active TB and HIV co-infection is driving the global increase of TB incidence. Mtb has a global phylogeographic population structure consisting of six main phylogenetic lineages which are associated with specific, sympatric human populations; however it has been observed that allopatric lineages were more likely to spread in immunodeficient populations. There is growing evidence that some of the genetic strain variation can have phenotypic, clinical implications and may contribute to the pathology of TB. Little is known, however, about the importance of Mtb genetic strain variation in the HIV-infected population, in Switzerland and elsewhere.Hypotheses - The genetic population structure of Mtb differs in HIV-coinfected TB patients when compared to HIV-negative patients and this difference is a function of the degree of immunodeficiency. Specifically, we hypothesize that (i) allopatric strains will be overrepresented and are more likely to reflect recent transmission in HIV-coinfected patients compared to HIV-negative patients; that (ii) drug resistance conferring mutations likely to affect bacterial fitness will be overrepresented; and that (iii) the relationship between strain genotype and clinical characteristics will differ. Objectives - The overall goal is to analyse and compare genotypic and phenotypic Mtb strain variation in HIV-coinfected and HIV-negative TB patients. For the HIV-infected patients, we will focus on individuals included in the Swiss HIV Cohort Study (SHCS) who have been followed from 1988 to 2008. The data from the HIV-infected patients will be compared to a random sample of HIV-negative TB patients diagnosed between 2000 and 2008, as well as to data previously published. Specifically, we intend (i) to compare the proportion and amount of epidemiological clustering of allopatric versus sympatric Mtb lineages in HIV-positive and HIV-negative TB patients; (ii) to compare the distribution of mutations conferring resistance to first-line drugs; and (iii) to study the relationship between particular Mtb genotypes and clinical characteristics.Methods - Main Mtb lineages will be defined by "signature" single nucleotide polymorphisms (SNPs) using multiplex real-time PCR, SNP-haplotypes within the main lineages will be identified by screening of 200 phylogenetic SNPs using a novel high-throughput genotyping platform (MassARRAY, Sequenom), and drug-resistance genotype will be defined by sequencing the relevant drug resistance targets. Spacer oligonucleotide typing and mycobacterial interspersed repetitive units will be used to define chains of TB transmission. Socio-demographic, laboratory and clinical information will be extracted from the SHCS database, by chart review, and from collaborating laboratories.Relevance of study - This study will lead to a better understanding (i) of the genetic population structure of Mtb in HIV-infected and HIV-negative TB patients, (ii) of the distribution of mutations conferring resistance in HIV-infected populations, and (iii) of the bacterial genotype factors that influence the clinical manifestation of TB. This is also the first time that SNP determination by MassARRAY technology will be applied to Mtb in an epidemiological study. Finally, this study will provide the basis for a larger future project in sub-Saharan Africa, within the framework of a network of HIV treatment programmes.
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