Genomic-based surveillance reveals high ongoing transmission of multidrug-resistant Mycobacterium tuberculosis in Southern Brazil.

Abstract

Genomic-based surveillance on drug resistance occurrence and its transmission dynamics has emerged as a powerful tool to tuberculosis control. Here, using whole genome sequencing approach along with phenotypic testing and clinical-epidemiological investigation, we carried out a retrospective population-based study on drug resistant- (DR) TB occurring in Rio Grande do Sul, the largest state from Southern Brazil. The analysis included 305 resistant Mycobacterium tuberculosis strains sampled statewide from 2011 to 2014 and covered 75.7% from total of DR-TB cases identified in this period. We found a predominance of Lineage 4 (99.3%) with high sublineage-level diversity composed mainly by 4.3.4.2 (LAM/RD174), 4.3.3 (LAM/RD115) and 4.1.2.1 (Haarlem/RD182) sublineages. The genomic diversity was also reflected on the variants underlying drug-resistance to first-line drugs. We observed a large number of distinct resistance-conferring mutations, including variants so far not reported in any other setting worldwide, and 22 isoniazid mono-resistant strains bearing mutations described as disputed at the rpoB gene but causing rifampicin resistance generally missed by automated phenotypic tests. Using a five-SNPs genome-wide cut-off, the estimated recent transmission rate was of 55.1% with 168 strains grouped into 28 genomic clusters. The most worrying fact concerns MDR strains, of which 73.4% were clustered. Along that, different resistance profiles and acquisition of novel drug resistance mutations intra-clusters, revealed an important amplification of resistance in the region. In this study we describe the M. tuberculosis strain diversity, drug-resistance basis and ongoing transmission dynamics across the largest state from Southern Brazil, stressing the urgent need for MDR-TB transmission control state-wide.