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Transmissibility of drug-resistant tuberculosis in a high-endemic setting as explained by bacterial genetic epistasis

G A Goig(1,2) Z Salaam-Dreyer(3) F Menardo(8) A Dippenaar(4) J Daniels(5) S Borrell(1,2) M Reinhard(1,2) A Doetsch(1,2) C Beisel(6) A Reuter(5) R M Warren(7) H Cox(3) S Gagneux(1,2)

1:Swiss Tropical and Public Health Institute; 2:University of Basel; 3:University of Cape Town; 4:University of Antwerp; 5:Médecins Sans Frontières; 6:ETH Zürich; 7:Stellenbosch University; 8:University of Zürich

The role that bacterial factors play in the transmission of drug-resistant tuberculosis (DR-TB) remains unclear. It is well established that drug resistance mutations often decrease replicative fitness in bacteria, and that this fitness cost can be alleviated by additional compensatory mutations. However, whether compensatory evolution also increases replicative fitness in vivo and, ultimately enhances transmission, is still controversial. In this study, we sequenced all bacterial genomes available from patients routinely diagnosed with rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between 2008, and 2018. We performed Bayesian phylodynamic analysis to delineate transmission of DR-TB and assess host and bacterial factors associated with being a transmitter. Multivariable regression analysis showed multidrug-resistance (versus mono-resistance), bacterial genetic background (lineage 2), the rifampicin resistant mutation rpoB S450L, compensatory mutations and later diagnosis date to be associated with being a transmitter. Interestingly, the transmission benefit provided by the mutation rpoB S450L was dependent on the genetic background in which it evolved. Additionally, we show that compensatory mutations are associated with higher sputum bacterial load, and with the acquisition of drug resistance mutations. Our findings suggest that bacterial factors largely determine the epidemiological success of certain genotypes, and that previous measures of replicative fitness in vitro are mirrored in vivo, and are linked to bacterial transmissibility.

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