The long-term association between Mycobacterium tuberculosis and modern humans and its impact on virulence

Sebastien Gagneux
Swiss Tropical and Public Health Institute, Basel, Switzerland

Mycobacterium tuberculosis (Mtb) is an obligate human pathogen killing close to 2 million people each year. Tuberculosis has been regarded as a typical "crowd disease", thought to have emerged as a result of animal domestication 10,000 years ago. Recent comparative genomic data however indicate that Mtb emerged as a human pathogen in Africa, suggesting it might in fact predate the Neolithic Revolution. To explore the evolutionary history of Mtb, we resequenced the genomes of 259 clinical isolates representative of Mtb's global phylogeographic diversity. Comparison to a global set of 4,955 human mitochondrial genomes (mtDNAs) revealed a striking congruence between the Mtb and mtDNA phylogenies. Moreover, coalescent analyses using our Mtb genome data support the "multiple dispersal model" of modern humans out of Africa, with a first migration along the Indian Ocean around 65,000 years ago, followed by second wave into Eurasia around 40,000 years ago. Calculation of the effective population sizes revealed a strong correlation between Mtb and human mtDNAs, with both measures exhibiting an increase around 8-10,000 years ago. These data suggest that in contrast to other typical "crowd diseases", Mtb has co-existed with modern humans for tens of thousands of years, most of the time in a quasi-commensal relationship, and then expanded as a consequence of increases in human populations during the Neolithic Revolution. We hypothesized that increased access to susceptible hosts might have selected for the enhanced virulence characteristic of modern Mtb. To start addressing this possibility, we performed sequenced-based transcriptional profiling of Mtb clinical isolates representative of different phylogenetic lineages of Mtb.  We observed a constitutive overexpression of the ‘dosR regulon' in Lineage 2. This regulon has recently been proposed to be involved in the successful transmission of Mtb, and Lineage 2 has been associated with higher virulence in animal models and increased transmission in human population.