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MM M. tuberculosis TLR2 TLR4 TNF "Learning from strains in the field" Man, migration, and M. tuberculosis evolution Stefan Niemann Molecular Mycobacteriology Research Center Borstel, Borstel, Germany I have no, real or perceived, conflicts of interest that relate to this presentation.

"Everything existing in the universe is the fruit of chance and necessity.“ Democritus, B.C. Evolution and adaptation

M. tuberculosis complex  Human pathogenic species  M. tuberculosis  M. africanum  M. canettii  Animal pathogenic species  M. bovis  M. caprae  M. pinnipedii  M. microti  Gram-positive, acid fast  Characteristic cell wall  Genetically monomorph  Differentiation based on phenotypical characteristics  Obligate intracellular pathogens

Diverse population structure Phylogenetic tree: 24 Loci MIRU Mycobacterial Interspersed repetitive Units-VNTRs 352 strains (Clade I) (Clade II) M.africanum M.tb. Wirth et al. Plos Path 2008

Evolution and global phylogeography

Pathobiological adaptation ?

 Investigation of 5 different genotypes  3 clinical isolates per genotype  Reference strains: H37Rv, CDC1551  Representatives of major lineages:  Haarlem  EAI  Beijing  Uganda  West African 2 Homolka et al. PLoS Pathogens in press Pathobiological adaptation

Homolka et al. PLoS Pathogens 2010 Pathobiological adaptation

Biological diversity Growth profile of all strains in activated murine macrophages  MOI 3:1  Determination of CFU on 7H10/OADC solid media Homolka et al. PLoS Pathogens 2010

H37Rv Uganda Haarlem Beijing EAI West African 2 CDC1551 Genotype specific expressionprofiles In vitro Resting MØ– 24hr Pathobiological diversity Homolka et al. PLoS Pathogens 2010

Haarlem West African 2 H37Rv Uganda EAI Beijing Definition of a „Intracellular“ core transcriptome Pathobiological diversity Homolka et al. PLoS Pathogens 2010

MBL2 G57E cases M. africanum controlsOR (CI) AA % % 1 AC % % 0.92 ( ) p = 0.45 CC % % 0.57 ( ) p = Host – Pathogen adaptation Prospective study in Ghana 2001 – patients, 2000 controls Intemann et al. PLoS Pathog 2009

15 M. tuberculosis antigens Comas et al. Nat Gen 2010

16 c After exclusion of the three outlier antigens esxH, pstS1 and Rv1986 M. tuberculosis antigens Comas et al. Nat Gen 2010

Summary Clade specific transcription signatures Genetic diversity translates to biological diversity Reduced purifying selection results in high functional diversity Future research should try to integrate diversity of the pathogen and the host Antigens are hyperconserved Diverse population structure

Thanks to TB-Team Borstel All other cooperation partners MIRU MLST P. Supply Institute Pasteur Lille T. Wirth Muséum National d'Histoire Naturelle Paris P. Small, S. Gagneux Institute for Systems Biology, Seattle MRC, London Funding: Transcriptome D. Russel, K. Rhode Cornell University Molecular Mycobacteriology