Mathew A Beale1, Marc Noguera-Julian2, Charmie Godornes3, Maria Casadellà4, Camila González-Beiras5, Mariona Parera4, August Kapa Jnr6, Wendy Houinei7, James Wangi8, Marc Corbacho-Monne6, Roger Paredes9, Fernando Gonzalez-Candelas10, Michael Marks11, Sheila A Lukehart3, Nicholas R Thomson12, Oriol Mitjà13. 1. Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK. Electronic address: mathew.beale@sanger.ac.uk. 2. IrsiCaixa AIDS Research Institute, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; Universitat de Vic-Universitat Central de Catalunya, Vic, Spain. 3. Department of Medicine and Department of Global Health, University of Washington, Seattle, WA, USA. 4. IrsiCaixa AIDS Research Institute, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain. 5. Barcelona Institute for Global Health, Hospital Clinic-University of Barcelona, Barcelona, Spain. 6. Lihir Medical Center, International SOS-Newcrest Mining, Lihir Island, Papua New Guinea. 7. Disease Control Branch, National Department of Health, Port Moresby, Papua New Guinea. 8. Office of the WHO Representative for Papua New Guinea, WHO, Port Moresby, Papua New Guinea. 9. IrsiCaixa AIDS Research Institute, Badalona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; Universitat de Vic-Universitat Central de Catalunya, Vic, Spain; Fundació Lluita contra la Sida, Infectious Diseases Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 10. Joint Research Unit for Infection and Public Health, FISABIO-University of Valencia, Institute for Integrative Systems Biology (I2SysBio), Valencia, Spain; CIBER in Epidemiology and Public Health, Valencia, Spain. 11. Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; Hospital for Tropical Diseases, London, UK. 12. Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK; Department of Infectious and Tropical Diseases, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK. 13. Barcelona Institute for Global Health, Hospital Clinic-University of Barcelona, Barcelona, Spain; Lihir Medical Center, International SOS-Newcrest Mining, Lihir Island, Papua New Guinea; Fundació Lluita contra la Sida, Infectious Diseases Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Division of Public Health, School of Medicine and Health Sciences, University of Papua New Guinea, Port Moresby, Papua New Guinea. Electronic address: omitja@flsida.org.
Abstract
BACKGROUND: In a longitudinal study assessing the WHO strategy for yaws eradication using mass azithromycin treatment, we observed resurgence of yaws cases with dominance of a single JG8 sequence type and emergence of azithromycin-resistant Treponema pallidum subspecies pertenue (T p pertenue). Here, we analyse genomic changes in the bacterial population using samples collected during the study. METHODS: We did whole bacterial genome sequencing directly on DNA extracted from 37 skin lesion swabs collected from patients on Lihir Island, Papua New Guinea, between April 1, 2013, and Nov 1, 2016. We produced phylogenies and correlated these with spatiotemporal information to investigate the source of new cases and the emergence of five macrolide-resistant cases. We used deep amplicon sequencing of surveillance samples to assess the presence of minority macrolide-resistant populations. FINDINGS: We recovered 20 whole T p pertenue genomes, and phylogenetic analysis showed that the re-emerging JG8 sequence type was composed of three bacterial sublineages characterised by distinct spatiotemporal patterns. Of five patients with resistant T p pertenue, all epidemiologically linked, we recovered genomes from three and found no variants. Deep sequencing showed that before treatment, the index patient had fixed macrolide-sensitive T p pertenue, whereas the post-treatment sample had a fixed resistant genotype, as did three of four contact cases. INTERPRETATION: In this study, re-emergence of yaws cases was polyphyletic, indicating multiple epidemiological sources. However, given the genomic and epidemiological linkage of resistant cases and the rarity of resistance alleles in the general population, azithromycin resistance is likely to have evolved only once in this study, followed by onward dissemination. FUNDING: Wellcome and Provincial Deputation of Barcelona.
BACKGROUND: In a longitudinal study assessing the WHO strategy for yaws eradication using mass azithromycin treatment, we observed resurgence of yaws cases with dominance of a single JG8 sequence type and emergence of azithromycin-resistant Treponema pallidum subspecies pertenue (T p pertenue). Here, we analyse genomic changes in the bacterial population using samples collected during the study. METHODS: We did whole bacterial genome sequencing directly on DNA extracted from 37 skin lesion swabs collected from patients on Lihir Island, Papua New Guinea, between April 1, 2013, and Nov 1, 2016. We produced phylogenies and correlated these with spatiotemporal information to investigate the source of new cases and the emergence of five macrolide-resistant cases. We used deep amplicon sequencing of surveillance samples to assess the presence of minority macrolide-resistant populations. FINDINGS: We recovered 20 whole T p pertenue genomes, and phylogenetic analysis showed that the re-emerging JG8 sequence type was composed of three bacterial sublineages characterised by distinct spatiotemporal patterns. Of five patients with resistant T p pertenue, all epidemiologically linked, we recovered genomes from three and found no variants. Deep sequencing showed that before treatment, the index patient had fixed macrolide-sensitive T p pertenue, whereas the post-treatment sample had a fixed resistant genotype, as did three of four contact cases. INTERPRETATION: In this study, re-emergence of yaws cases was polyphyletic, indicating multiple epidemiological sources. However, given the genomic and epidemiological linkage of resistant cases and the rarity of resistance alleles in the general population, azithromycin resistance is likely to have evolved only once in this study, followed by onward dissemination. FUNDING: Wellcome and Provincial Deputation of Barcelona.
Authors: Noah Fongwen; Becca L Handley; Diana L Martin; Camila Beiras; Louise Dyson; Michael Frimpong; Oriol Mitja; Kingsley Asiedu; Michael Marks Journal: PLoS Negl Trop Dis Date: 2022-09-01