[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
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, and Barun Mathema
PNAS first published October 28, 2019 / DOI: https://doi.org/10.1073/pnas.1906636116
Edited by Erwin Schurr, McGill University, Montreal, QC, Canada, and accepted by Editorial Board Member Carl F. Nathan October 3, 2019 (received for review April 17, 2019)
Epidemics of AMR pathogens are often only identified years or decades after they first evolved and distant from their place of origin. Consequently, evidence-based strategies for early containment of AMR epidemics are limited. This study employs whole-genome sequence data to reconstruct the “pre-detection” evolutionary and epidemiological history of an extensively drug-resistant Mycobacterium tuberculosis strain in KwaZulu-Natal, South Africa. We localize the geographic origin of this strain to an area hundreds of kilometers away from where the first clinical cases were reported and identify key host- and pathogen-specific factors that contributed to the rise of this important threat to global tuberculosis control. We propose that similar strategies can support the early identification and containment of AMR pathogens in the future.
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.
infectious disease – epidemics – tuberculosis – antimicrobial resistance – population genetics
Keywords: Antibiotics; Drugs Resistance; Rifampin; XDR-TB; Mycobacterium tuberculosis; TB; South Africa.