Influence of M. tuberculosis Lineage Variability within a Clinical Trial for Pulmonary Tuberculosis

Payam Nahid,Jason E Stout,Erin E Bliven,Sebastien Gagneux,Lois Diem,Elizabeth Y Kim,William R Mac Kenzie,John L Johnson,Midori Kato-Maeda,The Tuberculosis Trials Consortium¶ ,Philip C Hopewell

doi:10.1371/journal.pone.0010753

Abstract

Recent studies suggest that M. tuberculosis lineage and host genetics interact to impact how active tuberculosis presents clinically. We determined the phylogenetic lineages of M. tuberculosis isolates from participants enrolled in the Tuberculosis Trials Consortium Study 28, conducted in Brazil, Canada, South Africa, Spain, Uganda and the United States, and secondarily explored the relationship between lineage, clinical presentation and response to treatment. Large sequence polymorphisms and single nucleotide polymorphisms were analyzed to determine lineage and sublineage of isolates. Of 306 isolates genotyped, 246 (80.4%) belonged to the Euro-American lineage, with sublineage 724 predominating at African sites (99/192, 51.5%), and the Euro-American strains other than 724 predominating at non-African sites (89/114, 78.1%). Uneven distribution of lineages across regions limited our ability to discern significant associations, nonetheless, in univariate analyses, Euro-American sublineage 724 was associated with more severe disease at baseline, and along with the East Asian lineage was associated with lower bacteriologic conversion after 8 weeks of treatment. Disease presentation and response to drug treatment varied by lineage, but these associations were no longer statistically significant after adjustment for other variables associated with week-8 culture status.

Highlights

IntroductionWith the availability of whole genome sequences of several clinical isolates [2,3,4], the genetic diversity of M. tuberculosis has been chronicled in the form of insertions, deletions, and single nucleotide polymorphisms (SNP)
Mycobacterium tuberculosis is genetically more diverse than previously believed [1]
Given the diversity in insertions, deletions and single nucleotide polymorphisms (SNP) seen in M. tuberculosis, it is plausible that the genetics of the pathogen play a role in the natural history of tuberculosis infection and disease [11], and in presentation of disease and response to treatment

Summary

Introduction

With the availability of whole genome sequences of several clinical isolates [2,3,4], the genetic diversity of M. tuberculosis has been chronicled in the form of insertions, deletions, and single nucleotide polymorphisms (SNP). These polymorphisms have enabled researchers to genotype and classify clinical strains of M. tuberculosis into different groups. A group of insertions/ deletions ( known as region of difference or RD) that are unique event polymorphisms and define a robust phylogeny were described Based on this phylogeny, six lineages of M. tuberculosis have been defined [5]. Given the diversity in insertions, deletions and SNPs seen in M. tuberculosis, it is plausible that the genetics of the pathogen play a role in the natural history of tuberculosis infection and disease [11], and in presentation of disease and response to treatment

Methods

Results

Conclusion