Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Tyler S Brown, Lavanya Challagundla, Evan H Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C Auld, N Sarita Shah, Barry N Kreiswirth, James C M Brust, Kristin N Nelson, Apurva Narechania, Natalia Kurepina, Koleka Mlisana, Richard Bonneau, Vegard Eldholm, Nazir Ismail, Sergios-Orestis Kolokotronis, D Ashley Robinson, Neel R Gandhi, Barun Mathema, Tyler S Brown, Lavanya Challagundla, Evan H Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C Auld, N Sarita Shah, Barry N Kreiswirth, James C M Brust, Kristin N Nelson, Apurva Narechania, Natalia Kurepina, Koleka Mlisana, Richard Bonneau, Vegard Eldholm, Nazir Ismail, Sergios-Orestis Kolokotronis, D Ashley Robinson, Neel R Gandhi, Barun Mathema

Abstract

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

Keywords: antimicrobial resistance; epidemics; infectious disease; population genetics; tuberculosis.

Conflict of interest statement

The authors declare no competing interest.

Copyright © 2019 the Author(s). Published by PNAS.

Figures

Fig. 1.
Fig. 1.
Bayesian phylogenetic reconstruction for 318 XDR-TB isolates from KZN. Clades are labeled using previously described SNP-based classification for Mtb per Coll et al. (24) and annotated with HIV serostatus and history of prior MDR-TB (turquoise, LAM4/KZN/4.3.3; orange, non–LAM4/KZN lineage 4; red, lineage 2). (A) Terminal branch lengths for a BEAST-estimated phylogenetic tree by clade group. (B) TMRCA for drug-resistant clone groups for each clade (open violin plots, gyrA mutants; closed violin plots, rpoB mutants). All nodes corresponding to SNP-based clade labels (open circles) have posterior probability greater than 0.99.
Fig. 2.
Fig. 2.
Bayesian skyline plot for LAM4/KZN, HIV prevalence in antenatal clinics, TB incidence by year in KZN, and neutrality statistics for LAM4/KZN isolates. (A) BSP estimated using all variant sites. The white line indicates the median values for the product of the Ne, the effective population size, and τ, the generation time over time; 95% HPD range is indicated in turquoise. (B) BSP estimated using synonymous sites only. HIV prevalence and TB incidence data were obtained from publicly reported sources (66). The period following widespread introduction of combination antiretroviral therapy is shown as the gray region on the BSP.
Fig. 3.
Fig. 3.
Population-genetic signatures of range expansion from a common origin for LAM4/KZN isolates. (A) Pairwise FST vs. shortest road distance between isolates grouped by district. (B and C) Linear regression of nucleotide diversity (π) or the directionality index (ψ) vs. shortest road distance from uMkhanyakude district. Black solid lines show regression of π or ψ versus distance from uMkhanyakude for all locations. Red dashed lines show the regression of π or ψ versus distance from uMkhanyakude but excluding the π or ψ values for uMkhanyakude. (D) Average pairwise FST estimates for districts, with kriging interpolation between sampling points; red color indicates greater differentiation. (E and F) Spatial distribution of the correlations in B and C, with kriging interpolation between sampling points; red color indicates better evidence of origin. Districts are abbreviated as follows: eThekwini (ET), iLembe (IL), Ugu (UG), uThukela (UL), uThungulu (UT), uMgungundlovu (UV), uMkhanyakude (UY), uMzinyathi (UZ), and Zululand (ZU). Error bars indicate the SD of π or ψ based on 1,000 bootstrap replicates. The location of Tugela Ferry is indicated with a star.

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