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Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment

View ORCID ProfileKevin C Ma, View ORCID ProfileTatum D Mortimer, View ORCID ProfileAllison L Hicks, View ORCID ProfileNicole E Wheeler, Leonor Sánchez-Busó, Daniel Golparian, George Taiaroa, View ORCID ProfileDaniel HF Rubin, Yi Wang, View ORCID ProfileDeborah A Williamson, Magnus Unemo, View ORCID ProfileSimon R Harris, View ORCID ProfileYonatan H Grad
doi: https://doi.org/10.1101/2020.01.07.896696
Kevin C Ma
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
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Tatum D Mortimer
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
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Allison L Hicks
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
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Nicole E Wheeler
2Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
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Leonor Sánchez-Busó
2Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
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Daniel Golparian
3WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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George Taiaroa
4Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
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Daniel HF Rubin
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
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Yi Wang
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
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Deborah A Williamson
4Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
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Magnus Unemo
3WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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Simon R Harris
5Microbiotica Ltd, Biodata Innovation Centre, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
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Yonatan H Grad
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA
6Division of Infectious Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
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  • For correspondence: ygrad@hsph.harvard.edu
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Abstract

Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association on the largest collection of N. gonorrhoeae isolates to date (n=4852) to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical isolates relative to urethral isolates (odds ratio (OR) = 3.74, 95% CI [1.98-6.70]). In support of a model in which pump expression incurs a fitness cost in this niche, cervical isolates were also enriched relative to urethral isolates in LOF mutations in the mtrCDE activator mtrA (OR = 8.60, 95% CI [4.96-14.57]) and in farA, a subunit of the FarAB efflux pump (OR = 6.25, 95% CI [3.90-9.83]). In total, approximately 2 in 5 cervical isolates (42.6%) contained a LOF mutation in either the efflux pump components mtrC or farA or the activator mtrA. Our findings extend beyond N. gonorrhoeae to other Neisseria: mtrC LOF mutations are rare (<1%) in the primarily nasopharyngeal-colonizing N. meningitidis in a collection of 14,798 genomes but enriched in a heterosexual urethritis-associated lineage (8.6%, p = 9.90×10−5), indicating that efflux pump downregulation contributes broadly to the adaptation of pathogenic Neisseria to the female urogenital tract. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/gradlab/mtrC-GWAS

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 15, 2020.
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Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment
Kevin C Ma, Tatum D Mortimer, Allison L Hicks, Nicole E Wheeler, Leonor Sánchez-Busó, Daniel Golparian, George Taiaroa, Daniel HF Rubin, Yi Wang, Deborah A Williamson, Magnus Unemo, Simon R Harris, Yonatan H Grad
bioRxiv 2020.01.07.896696; doi: https://doi.org/10.1101/2020.01.07.896696
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Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment
Kevin C Ma, Tatum D Mortimer, Allison L Hicks, Nicole E Wheeler, Leonor Sánchez-Busó, Daniel Golparian, George Taiaroa, Daniel HF Rubin, Yi Wang, Deborah A Williamson, Magnus Unemo, Simon R Harris, Yonatan H Grad
bioRxiv 2020.01.07.896696; doi: https://doi.org/10.1101/2020.01.07.896696

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