Genomic Epidemiology of Multidrug-resistant Mycobacterium tuberculosis During Transcontinental Spread.

Coscolla M1, Barry PM2, Oeltmann JE3, Koshinsky H4, Shaw T2, Cilnis M2, Posey J3, Rose J5, Weber T2, Fofanov VY4, Gagneux S1, Kato-Maeda M5, Metcalfe JZ5.

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Abstract

The transcontinental spread of multidrug-resistant tuberculosis (MDR-TB) is poorly characterized in molecular epidemiologic studies. We utilized genomic sequencing to understand the establishment and dispersion of MDR-Mycobacterium tuberculosis within an immigrant group to the United States. We used a genomic epidemiology approach to study a genotypically-matched (spoligotype, IS6110, MIRU-VNTR) Lineage 2/Beijing MDR strain implicated in an outbreak among refugees in Thailand and consecutive cases within California, USA. All 46 MDR genomes from both Thailand and California were highly related with a median difference of 10 single nucleotide polymorphisms (SNPs). The WTK strain is a new sequence type distinguished from all known Beijing strains by 55 SNPs and a genomic deletion (Rv1267c) associated with increased fitness. Sequence data revealed a highly prevalent MDR strain that included several closely related but distinct allelic variants within Thailand, rather than a single outbreak. In California, sequencing data supported multiple independent introductions of WTK with subsequent transmission and reactivation within the state, and a potential "super spreader" with a prolonged infectious period. Twenty-seven drug resistance-conferring mutations and four putative compensatory mutations were found within WTK strains. Genomic sequencing has substantial epidemiologic value in both low- and high-burden settings in understanding transmission chains of highly prevalent MDR strains.