The causes and consequences of historical contingencies in the evolution of extensively drug-resistant Mycobacterium tuberculosis
Project Abstract
Tuberculosis (TB) remains a global health emergency. With 1.3 million annual deaths, TB kills more people than HIV/AIDS and malaria combined. Multidrug-resistant TB (MDR-TB) is also a main cause of human death due to antimicrobial resistance (AMR).
Recently, the World Health Organization endorsed new regimens for the treatment of MDR-TB that combine the new and repurposed drugs bedaquiline, pretomanid, delamanid, linezolid with or without moxifloxacin (BPaL(M)). With BPaL(M) being rolled out globally, resistance to the new drugs is already emerging. However, the evolutionary drivers underlying this resistance emergence are unclear, hampering efforts to maintain the longevity of BPaL(M).
Previous work in model systems has shown that historical contingencies are key determinants of bacterial adaptation to novel environments; i.e. adaptation to one environment determines the adaptation of bacteria facing new environments. We and others have shown that in most high-burden settings, MDR-TB is driven by a few highly transmissible strains of the Mycobacterium tuberculosis complex (MTBC). These MDR-outbreak strains emerged during the last decades and are resistant to many first- and second-line drugs. Yet, the evolutionary forces that have led to the establishment of these strains are unclear. Moreover, how these past adaptive processes influence the emergence of resistance to BPaL(M) is unknown.
We recently showed that in the country of Georgia, a recognized hotspot of MDR-TB, 30% of the MDR-TB cases in the country were linked to incarceration. Thus, we hypothesize that prisons have played a fundamental role facilitating the emergence and spread of these MDR-outbreak strains. We further hypothesize that the development of resistance to BPaL(M) is contingent on the past evolutionary histories of the different MTBC genotypes circulating in Georgia.
Our goal is to test these hypotheses by exploring the role of prisons in the emergence of MTBC AMR in Georgia in general, and with a particular focus on the MDR-outbreak strains, and determining how previous adaptation influences the adaptation of MTBC strains exposed to BPaL(M). We will take advantage of past and ongoing natural experiments linked to the varying TB regimens used in Georgia during the last 30 years.
Our objectives are to
i) define the role of prisons in the emergence of AMR in the MTBC from Georgia,
ii) explore the evolutionary history, the genomic properties and phenotypic features of the MDR-outbreak strains dominating the MDR-TB epidemic in Georgia, and
iii) study the effect of historical contingencies and other bacterial and patient risk factors for the development of resistance to BPaL(M).
This project builds on a long-standing collaboration between the Swiss Tropical and Public Health Institute in Allschwil/Switzerland, the Institute for Tropical Medicine in Antwerp/Belgium, and the National Centre for Tuberculosis and Lung diseases in Tbilisi/Georgia. These institutions have complementary expertise, covering clinical and experimental mycobacteriology, genomic epidemiology, population and functional genomics, as well as TB diagnostics and clinical research.
Together, the applicants have assembled collections of MTBC strains totaling >30,000 clinical isolates from Georgia covering three decades, including many isolates from incarcerated TB patients. We also established a cohort of MDR-TB patients receiving BPaL(M) in Georgia, who have been followed since 2021. We will combine our retrospective MTBC strain collections with our prospective patient cohort, and apply quantitative drug susceptibility testing, long-read genome sequencing, RNAseq and proteomics to address our study objectives.
This project will generate fundamental insights into the role of historical contingencies in bacterial adaptation, and at the same time, inform the development of improved diagnostics and treatment strategies for one of humankind’s most deadly infectious diseases.
