Genetic diversity of <italic>Mycobacterium tuberculosis</italic> PE_PGRS genes and its clinical and epidemiological relevance.

Abstract

Tuberculosis continues to be a leading cause of death worldwide. There may be genetic differences among strains of <italic>Mycobacterium tuberculosis, </italic> the causative agent of tuberculosis, that affect their transmissibility, pathogenecity, or virulence. It has been proposed that members of the unique multigene family named PE_PGRS may be a source of antigenic variation in <italic> M. tuberculosis</italic> and some PE_PGRS genes may have specific functions related to persistence in the host. This dissertation work integrates comparative genomics with epidemiological data analysis to investigate the genetic diversity of members of the PE_PGRS gene family among clinical <italic>M. tuberculosis </italic> isolates and the associations of PE_PGRS gene polymorphisms with clinical and epidemiological characteristics. Of 123 clinical <italic>M. tuberculosis </italic> strains, 84 (68.3%) had at least one of the 25 different sequence variations that were observed in the PE_PGRS33 gene, which included single nucleotide polymorphisms (SNPs), insertions/deletions, and a frameshift. In a population-based study of 649 clinical <italic>M. tuberculosis</italic> isolates, large changes to PE_PGRS33 were significantly associated with clustering of tuberculosis cases [adjusted OR=1.89; 95% CI: (1.10--3.25)] and absence of cavitations in the lungs [adjusted OR = 1.61; 95% CI: (1.03--2.51)], compared to isolates having no or minimal change to the PE_PGRS33 protein, suggesting that PE_PGRS33 may have an important role in <italic>M. tuberculosis </italic> persistence. Two other members of the gene family, PE_PGRS 16 and PE_PGRS26, which were hypothesized to have a role in mediating latency through differential regulation by previous studies, also exhibited a high level of genetic diversity among 200 clinical <italic>M. tuberculosis</italic> strains. Examining the genetic diversity of these three PE_PGRS genes demonstrates the potential for generating differences in available antigenic repertoire between <italic>M. tuberculosis</italic> strains. Understanding the antigenic variation generated by genetic changes in the PE_PGRS genes and the impact of the genetic changes on the specific function of the PE_PGRS protein will further our knowledge of how <italic>M. tuberculosis</italic> is able to evade the immune system and persist in the host.