Does M. tuberculosis genomic diversity explain disease diversity?

Abstract

The outcome of tuberculosis infection and disease is highly variable. This variation has been attributed primarily to host and environmental factors, but better understanding of the global genomic diversity in the M. tuberculosis complex (MTBC) suggests that bacterial factors could also be involved. Review of nearly 100 published reports shows that MTBC strains differ in their virulence and immunogenicity in experimental models, but whether this phenotypic variation plays a role in human disease remains unclear. Given the complex interactions between the host, the pathogen and the environment, linking MTBC genotypic diversity to experimental and clinical phenotypes requires an integrated systems epidemiology approach embedded in a robust evolutionary framework.

Figure 1. Neighbour-joining phylogeny based on 9,037 variable common nucleotide positions across 21 human MTBC genome sequences

Six main lineages are defined within human-adapted MTBC. The six lineages correspond to groups previously detected with a variety of genotyping techniques. Asterisks indicate spoligotype patterns within the main lineages which are considered phylogenetically unrelated based on spoligotyping, but are in fact related based on LSP analysis and genome sequencing [108] (adapted from Ref. 38). Abbreviations: MLSA=Multi Locus Sequence Analysis; LSP=Long Sequence Polymorphisms; SNP= Single nucleotide polymorphism; PGG=Principal Genetic Group.

Figure 2. Theoretical approach defining a set of hierarchical strain groupings within a given bacterial species

Our capability to define different genetic entities as cluster, family, sub-lineage or lineage depends on the breadth of our sampling and molecular markers used. In this case, the species could be divided in different lineages, and within each lineage in different sub-lineages, clusters or families. The lower grouping is the strain or clone, which has been defined as a set of stocks that share many identical or similar properties due to a recent common clonal ancestry [109]. Here a clone represents genetically identical or almost identical bacteria, and can include different isolates from one patient, a transmission chain or any related units which share a very recent common ancestor.