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

• Type of Material: Article
• Authors: Tyler S. Brown, Columbia University; Lavanya Challagundla, University of Mississippi; Evan H. Baugh, Columbia University; Shaheed Vally Omar, National Institute for Communicable Diseases; Arkady Mustaev, Emory University; Sara Auld, Emory University; Nippie Shah, Emory University; Barry N. Kreiswirth, Rutgers University; James C. M. Brust, American Museum of Natural History; Kristin N. Nelson, Emory University; Apurva Narechania, University of Kwazulu Natal; Natalia Kurepina, Rutgers University; Koleka Mlisana, University of Kwazulu Natal; Richard Bonneau, Norwegian Institute of Public Health; Vegard Eldholm, University of Pretoria; Nazir Ismail, University of Witwatersrand; Sergios-Orestis Kolokotronis, Emory University; D. Ashley Robinson, University of Mississippi; Neel Gandhi, Emory University; Barun Mathema, Columbia University
• Language: English
• Date: 2019-11-12
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1906636116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 46
• Start Page: 23284
• End Page: 23291
• Grant/Funding Information: This work was supported by grants from the National Institute of Allergy and Infectious Disease, National Institutes of Health (R01AI089349, R01AI087465, R01AI114304, and R01AI138646); NIH career development awards and training grants (K24AI114444 to N.R.G.; K23AI134182 to S.C.A.; T32AI007061 to T.S.B.); and grants from the Emory University Center for AIDS Research (P30AI050409), Albert Einstein College of Medicine Center for AIDS Research (P30AI124414), and Albert Einstein College of Medicine Institute for Clinical and Translational Research (UL1 TR001073).; We would like to acknowledge in kind support from the American Museum of Natural History and the Flatiron Institute–Simons Foundation for providing computational resources.
• Keywords: Multidisciplinary Sciences; EMERGENCE; EPIDEMIOLOGY; IMPACT; EVOLUTION; MUTATIONS; antimicrobial resistance; POPULATION-GENETICS; TRANSMISSION; tuberculosis; COMMUNITY; infectious disease; population genetics; epidemics; HEALTH; Science & Technology - Other Topics; MYCOBACTERIUM-TUBERCULOSIS; Science & Technology
• Research Categories: Health Sciences, Public Health

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.