Insights into the origin, emergence, and current spread of a successful Russian clone of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis variant Beijing B0/W148 is regarded as a successful clone of M. tuberculosis that is widespread in the former Soviet Union and respective immigrant communities. Understanding the pathobiology and phylogeography of this notorious strain may help to clarify its origin and evolutionary history and the driving forces behind its emergence and current dissemination. I present the first review and analysis of all available data on the subject. In spite of the common perception of the omnipresence of B0/W148 across post-Soviet countries, its geographic distribution shows a peculiar clinal gradient. Its frequency peaks in Siberian Russia and, to a lesser extent, in the European part of the former Soviet Union. In contrast, the frequency of B0/W148 is sharply decreased in the Asian part of the former Soviet Union, and it is absent in autochthonous populations elsewhere in the world. Placing the molecular, clinical, and epidemiological features in a broad historical, demographic, and ecological context, I put forward two interdependent hypotheses. First, B0/W148 likely originated in Siberia, and its primary dispersal was driven by a massive population outflow from Siberia to European Russia in the 1960s to 1980s. Second, a historically recent, phylogenetically demonstrated successful dissemination of the Beijing B0/W148 strain was triggered by the advent and wide use of modern antituberculosis (anti-TB) drugs and was due to the remarkable capacity of this strain to acquire drug resistance. In contrast, there is some indication, but not yet systematic proof, of an enhanced virulence of this strain.

Fig 1

Positions of particular genomic loci on a circular map of M. tuberculosis H37Rv, along with their structure and analysis. (A) DR/CRISPR locus and 43-spacer-based spoligotyping. (B) Multiple VNTR loci, including 24 MIRU-VNTR (in bold) and 3 hypervariable loci, and their analysis using agarose gel electrophoresis. M, 100-bp ladder. (C) Rv2664-Rv2665 region in H37Rv and W-148 strains. (D) IS6110-RFLP typing, with hybridization of PvuII-digested DNAs of M. tuberculosis strains with an IS6110-derived probe. Beijing genotype strains are shown by asterisks. The characteristic double band in the profile of strain B0/W148 is shown by short arrows. M, strain Mt14323, used as a molecular size marker.

Fig 2

Global distribution of M. tuberculosis Beijing genotype and Beijing B0/W148 strains in autochthonous populations in Eurasia. Data are not shown for (i) prison settings and (ii) immigrant communities in Europe. Data on the Beijing family as a whole are shown only if the frequency of the B0/W148 strain could be verified by an IS6110-RFLP or multiplex PCR method (33). For Azerbaijan and Kyrgyzstan, no information on the Beijing family rate is shown, and estimated rates of B0/W148 prevalence are shown (see Table S1 in the supplemental material for details). Numbers in/at circles show percentages of the Beijing family and B0/W148 strain in the M. tuberculosis population in a given area; circle sizes are proportional to these percentages.

Fig 3

Meta-analysis of the association between M. tuberculosis Beijing B0/W148 and clustering, measured as the rate of IS6110-RFLP-clustered isolates among all isolates in a given group. Error bars indicate 95% confidence intervals (95% CI). Solid squares represent each study in the meta-analysis. The solid black diamond represents the pooled OR; the gray diamond shows the fixed-effect model pooled OR (in a test for overall effect, Z = 4.03 [P < 0.0001]). Both civilian and prison samples were considered for the study of Dubiley et al. (41), and drug-resistant strains were considered for the study of Krüüner et al. (29). (B) Begg's funnel plot with pseudo-95% confidence limits. The references in the figure correspond to references , , , , , , , and .

Fig 4

Minimum spanning tree of the VNTR types of B0/W148 cluster isolates from St. Petersburg and other locations in northwestern Russia, based on the combined use of 24 MIRU-VNTR and 3 hypervariable VNTR loci. Circle size is roughly proportional to the number of strains. VNTR digital profiles are shown in Table S2 in the supplemental material. The 24-MIRU component of the central type V1 corresponds to profile 100-32 in the MIRU-VNTRplus database. (Adapted from reference .)

Fig 5

(A) Meta-analysis of the association between M. tuberculosis Beijing B0/W148 variant and multidrug resistance. Error bars indicate 95% confidence intervals (95% CI). Solid squares represent each study in the meta-analysis. The solid black diamond represents the pooled OR; the gray diamond shows the fixed-effect model pooled OR (in a test for overall effect, Z = 5.64 [P < 0.0001]). (B) Begg's funnel plot with pseudo-95% confidence limits. The references in this figure correspond to references , , , , , , , and .

Fig 6

Phylogenetic analysis of 10-VNTR-locus profiles of Beijing strains from Novosibirsk, West Siberia, and St. Petersburg, northwestern European Russia. (A) Neighbor-joining tree for Beijing genotype strains. (B) Minimum spanning tree for Beijing B0/W148 strains. Type numbers are for convenience only. Digital VNTR profiles show copy numbers for the following loci: ETR-A, ETR-C, MIRU31, MIRU23, QUB26, QUB11b, Mtub29, Mtub39, MIRU40, and Mtub21. Each arm depicts one locus change.

Fig 7

Direction and timing of major flows of human migration associated with origin and dispersal of the Beijing B0/W148 strain. The thickness of arrows roughly reflects the volume of migration. Red arrows indicate the hypothesized dissemination of the B0/W148 strain.