Summary
Background
Multidrug-resistant tuberculosis (MDR-TB) is a significant threat to
tuberculosis elimination worldwide. Understanding the transmission pattern
is crucial for its control. We used a genomic epidemiological approach to
assess the recent transmission of MDR-TB and potential risk factors for
transmission.
Methods
In a population-based retrospective study, we performed
variable-number-of-tandem-repeat (VNTR) genotyping, followed by whole-genome
sequencing (WGS) of isolates from all MDR-TB patients in Shanghai, China,
2009-2012. We measured strain diversity within and between genomically
clustered patients. Genomic and epidemiologic data were combined to
construct transmission networks.
Findings
367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and
324 (88%) of these had isolates available for genomic analysis. 103 (32%) of
the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer
single nucleotide polymorphisms (SNPs), indicating recent transmission of
MDR strains. Patients who had delayed diagnosis or were older than 45 years
had high risk of recent transmission. 235 (73%) patients with MDR
tuberculosis probably had transmission of MDR strains. Transmission network
analysis showed that 33 (87%) of the 38 clusters accumulated additional
drug-resistance mutations through emergence or fixation of mutations during
transmission. 68 (66%) of 103 clustered MDR strains had compensatory
mutations of rifampicin resistance.
Interpretation
Recent transmission of MDR strains, with increasing drug-resistance,
helps drive the MDR-TB epidemic in Shanghai, China. WGS provides a measure
of the heterogeneity of drug-resistant mutations within and between hosts
and enhances our ability to determine the transmission patterns of
MDR-TB.
Funding
National Science and Technology Major Project, National Natural
Science Foundation of China, and US National Insitutes of Health.
The Beijing family is the most successful genotype of Mycobacterium tuberculosis and responsible for more than a quarter of the global tuberculosis epidemic. As the predominant genotype in East Asia, the Beijing family has been emerging in various areas of the world and is often associated with disease outbreaks and antibiotic resistance. Revealing the origin and historical dissemination of this strain family is important for understanding its current global success. Here we characterized the global diversity of this family based on whole-genome sequences of 358 Beijing strains. We show that the Beijing strains endemic in East Asia are genetically diverse, whereas the globally emerging strains mostly belong to a more homogenous subtype known as “modern” Beijing. Phylogeographic and coalescent analyses indicate that the Beijing family most likely emerged around 30,000 y ago in southern East Asia, and accompanied the early colonization by modern humans in this area. By combining the genomic data and genotyping result of 1,793 strains from across China, we found the “modern” Beijing sublineage experienced massive expansions in northern China during the Neolithic era and subsequently spread to other regions following the migration of Han Chinese. Our results support a parallel evolution of the Beijing family and modern humans in East Asia. The dominance of the “modern” Beijing sublineage in East Asia and its recent global emergence are most likely driven by its hypervirulence, which might reflect adaption to increased human population densities linked to the agricultural transition in northern China.
A small number of high-burden countries account for the majority of tuberculosis cases worldwide. Detailed data are lacking from these regions. To explore the evolutionary history of M. tuberculosis in China — the third highest TB burden country — we analyzed a countrywide collection of 4,578 isolates. Little genetic diversity was detected within the large M. tuberculosis population in China, with 99.4% of the bacterial population belonging to lineage 2 and three sublineages of lineage 4. The deeply rooted phylogenetic positions and geographic restriction of these four genotypes indicate that their populations expanded in situ following a small number of introductions to China. Coalescent analyses suggest that these bacterial sub-populations emerged in China around 1,000 years ago, expanded in parallel from the 12th century onward, and the whole population peaked in the late 18th century. More recently, sublineage L2.3, which is indigenous to China and exhibited relatively high transmissibility and extensive global dissemination, came to dominate the population dynamics of M. tuberculosis in China. Our results indicate that historical expansion of four M. tuberculosis strains shaped the current TB epidemic in China, and highlight the long-term genetic continuity of the indigenous M. tuberculosis population.
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