Genomics and the evolution, pathogenesis, and diagnosis of tuberculosis

Abstract

Tuberculosis kills nearly 2 million people annually, and current approaches to tuberculosis control are expensive, have limited efficacy, and are vulnerable to being overcome by extensively drug-resistant strains of Mycobacterium tuberculosis. Determination of the genome sequence of M. tuberculosis has revolutionized tuberculosis research, contributed to major advances in the understanding of the evolution and pathogenesis of M. tuberculosis, and facilitated development of new diagnostic tests with increased specificity for tuberculosis. In this review, we describe some of the major progress in tuberculosis research that has resulted from knowledge of the genome sequence and note some of the problems that remain unsolved.

Figure 1. Evolutionary scheme for the M. tuberculosis complex.

The phylogenetic scheme is based on informative markers present or absent in the progeny of each lineage. Markers in boxes include lost RD regions, SNPs, lost spoligotype spacers, and deletions in the pks15/1 and TbD1 loci. The seven species of the M. tuberculosis complex and their respective natural hosts are shown, as well as the three principal genetic groups of M. tuberculosis and their representative strains. Adapted with permission from the Journal of Theoretical Biology (1), Proceedings of the National Academy of Sciences of the United States of America (11), and Microbiology (16).

Figure 2. The RD1 locus and components of the ESX-1 secretion system.

ESAT-6 and CFP-10 dimer secretion (A) by M. tuberculosis depends on other genes in the RD1 locus (B). The product of Rv3870 is a membrane protein that interacts directly with Rv3871, a predicted cytoplasmic protein. Based on homology to the SpoIIIE/FtsK family, Rv3870 and Rv3871 are thought to form a membrane-bound ATPase that provides energy for export of secretion substrates; the carboxyl terminus of CFP-10 interacts directly with the carboxyl terminus of Rv3871. Rv3877 encodes a protein with 12 membrane-spanning domains and is likely to form a secretion pore. Rv3876 is essential for secretion of CFP-10 and ESAT-6 dimers, but its role has not been determined. Secretion substrates encoded by genes outside the BCG RD1 locus include the product of Rv3616c (57), and additional genes essential for ESAT-6 secretion that are outside of the BCG RD1 include Rv3614c, Rv3615c, and Rv3616c (57, 60). The products of Rv3614c and Rv3882c have been found to directly interact (60).

Figure 3. Role of ESX-1 in cell-to-cell transmission of M. tuberculosis in vivo.

(A) Macrophages infected with ESX-1–replete mycobacteria signal to recruit uninfected macrophages to the surrounding area (i), including in close proximity to the initially infected macrophage (ii). After intracellular replication, ESX-1–replete bacteria spread to the closely apposed, newly recruited macrophages, with or without lysis of the initially infected macrophage (iii). After spread to the newly recruited macrophages (and dendritic cells), the mycobacteria replicate further (iv), to sustain the cycle of cell-to-cell spread until the onset of adaptive immunity. (B) ESX-1–deficient mycobacteria are defective in the ability to recruit uninfected macrophages and to form aggregates with the initially infected cell and in the ability to spread to adjacent cells. As a consequence, ESX-1–deficient mycobacteria are less efficient in expanding the size of the pool of infected cells but replicate efficiently in the initially infected cells.