Priority Research Area Infections

Molecular and Experimental Mycobacteriology

Mission   Projects   Funding   Techniques   Publications    Staff

Projects

Research interests of the working group are focused on the analysis of the epidemiology of tuberculosis (TB) by applying molecular epidemiological tools, the analysis of resistance mechanisms, the analysis of the global population structure, genomic diversity and virulence, and the microevolution of clinical M. tuberculosis complex isolates.

Molecular epidemiology:

All “gold standard” methods for molecular typing of M. tuberculosis complex isolates are available for molecular epidemiological studies. In recent years, we have already carried out several studies on the epidemiology of TB in different settings that provided e.g. for the first time precise data on transmission dynamics of TB strains, risk factors for recent transmission or the spread of multidrug resistant strains in Germany. In the coming years, ongoing and newly initiated molecular epidemiological studies will be focused on hot topic research questions e.g. the analysis of specific pathogenic properties of strains of particular phylogenetic lineages (e.g. the Beijing genotype) such as a higher virulence or an enhanced propensity to acquire drug resistance. To address these questions, already established population based investigations in Germany will be continued as longitudinal model studies for low incidence countries. Furthermore, the initiation of studies in high incidence countries with a focus on Eastern Europe is intended. All strains will be archived and provide a unique bio bank for future research studies. 

 

 

Resistance mechanisms:

The investigation of resistance mechanisms of clinical M. tuberculosis isolates has long been a main focus of research that should be continued and intensified in the next years. In addition to classical analysis methods, new tools for comparative genomics such as ultra fast massively parallel genome sequencing will be used to decipher new resistance mechanisms.

The significance of genetic variants for the development of particular resistances will be validated by screening of available strain collections and by generating isogenic mutants by allelic exchange that can be further investigated in vitro and in vivo in the mouse model for the presence of phenotypic resistance (in co-operation with the group of S. Ehlers).
Further studies aim to improve the detection of resistance conferring mutations by new detection systems e.g. micro arrays.

Global population structure, genomic diversity and virulence.

There is growing evidence that the genetic heterogeneity of M. tuberculosis complex isolates is greater than previously thought, and influences the transmissibility and virulence of clinical isolates as well as the immune response and clinical picture they evoke. Clinical TB, then, must be seen as the result of specific, genetically determined pathogenicity traits of mycobacteria encountering specific, genetically determined defects in antimycobacterial pathways of the patient. Ongoing studies applying high resolution genomic markers have already revealed insights into the global population structure of the M. tuberculosis complex that is composed of several phylogenetic lineages with large difference in geographical prevalence. Based on this, we have established a reference collection of well characterized clinical isolates representing the major phylogenetic lineages. These will be used to further explore the level of genomic diversity by comparative genome, transcriptome and proteome studies. Selected strains will be analyzed in infection model systems to investigate the importance of genomic diversity for differences in virulence and host-pathogen interaction.

Microevolution

Clinical M. tuberculosis complex isolates are characterized by a relative low level of genomic variation and a highly clonal population structure. Evolutionary changes are mainly based on the acquisition of single nucleotide polymorphisms. However, the mode and speed of evolutionary processes in M. tuberculosis have not been defined so far. Here, the newly available high throughput sequencing technologies offer new perspectives to address this question.