Peter Small

Senior Program Officer for Tuberculosis

Research

The Small laboratory is integrating ecological and evolutionary principles to study the nature and consequences of genetic variability within Mycobacterium tuberculosis. In a recent study, we showed that genomic deletions or large sequence polymorphisms (LSPs) can be used to construct robust phylogenies for M. tuberculosis. We are currently using comparative whole-genome hybridization to identify phylogenetically informative LSPs.Our results show that M. tuberculosis can be divided into a limited number of phylogenetic lineages, which are each associated with different geographic regions. We are also establishing a SNP-based high-throughput genotyping tool which will allow us to study the population structure ofM. tuberculosis in more details. We are using two complementary approaches to identify SNPs, i) multilocus sequence typing and ii) comparative whole-genome sequencing.

There is currently no evidence that genetic variability within M. tuberculosis has direct consequences for the effectiveness of new diagnostics, drugs or vaccines. However, our new definition of the global population structure of M. tuberculosis is robust and allows us to address these issues based on a rational selection of representative strains. For example, in collaboration with the MRC in The Gambia, we are investigating the human host-response to different lineages of M. tuberculosis in tuberculosis cases and contacts. Complementary studies are being carried out using a series of in vitro assays in order to identify mycobacterial lineage specific differences in host-pathogen interactions.

Our laboratory is also interested in the ecology of drug-resistant M. tuberculosis. Recent mathematical models suggest that the future spread of drug-resistant M. tuberculosis depends on the relative fitness of resistant versus susceptible strains. We are using molecular epidemiology combined with comparative genomics to determine the impact of different drug-resistance conferring mutations and different strain genetic backgrounds on the transmission of drug-resistant strains in San Francisco. We are complementing these population-based epidemiological studies with in vitro experiments in which the relative fitness of isogenic drug-resistant and susceptible strains is determined as a function of the specific drug-resistance conferring mutation, strain genetic background, and compensatory evolution.