Bridging of Neisseria gonorrhoeae lineages across sexual networks in the HIV pre-exposure prophylaxis era

Williamson, Deborah A.; Chow, Eric P F; Gorrie, Claire L.; Seemann, Torsten; Ingle, Danielle J.; Higgins, Nasra; Easton, Marion; Taiaroa, George; Grad, Yonatan H.; Kwong, Jason C; Fairley, Christopher K; Chen, Marcus Y; Howden, Benjamin P

doi:10.1038/s41467-019-12053-4

Cited by 86 publications

(95 citation statements)

References 39 publications

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“…farA LOF mutations were associated with patient sex of sex partner (p = 5.06×10 -10 ; Fisher’s exact test) and site of infection (p = 1.76×10 -12 ; Fisher’s exact test) and overrepresented in cervical isolates: 33 out of 129 (25.6%) cervical isolates contained a farA LOF mutation compared to 117 out of 2246 urethral isolates (5.21%; OR = 6.25, 95% CI [3.90-9.83], p = 3.24×10 -13 ; Fisher’s exact test), 3 out of 106 pharyngeal isolates (2.83%; OR = 11.70, 95% CI [3.50-61.61], p = 3.80×10 -7 ; Fisher’s exact test), and 12 out of 246 rectal isolates (4.88%; OR = 6.66, 95% CI [3.19-14.80], p = 1.57×10 -8 ; Fisher’s exact test) (Figure 3). farA LOF mutations were prevalent also in our Australian validation dataset 38 (225/2180; 10.32%) and again associated with sex of sex partner (p < 2.20×10 -16 ; Fisher’s exact test) and site of infection (p < 2.20×10 -16 ; Fisher’s exact test) (Supplementary Figure 5). The phylogenetic distribution of farA LOF mutations overlapped with that of mtrA LOF mutations and indicated sustained transmission (Supplementary Figure 3).…”

Section: A Second Class Of Proton-dependent Efflux Pumps Appears To Cmentioning

confidence: 61%

“…mtrC LOF mutations were significantly associated with site of infection (p = 6.49×10 -5 ; Fisher’s exact test) and were overrepresented particularly in cervical isolates: 16 out of 129 (12.4%) cervical isolates contained an mtrC LOF mutation compared to 82 out of 2249 urethral isolates (3.65%; OR = 3.74, 95% CI [1.98-6.70], p = 4.71×10 -5 ; Fisher’s exact test), 3 out of 106 pharyngeal isolates (2.83%; OR = 4.83, 95% CI [1.33-26.63], p = 0.00769; Fisher’s exact test), and 4 out of 246 rectal isolates (1.63%; OR = 8.52, 95% CI [2.67-35.787], p = 2.39×10 -5 ; Fisher’s exact test) (Figure 3b). Because our meta-analysis collection comprises datasets potentially biased by preferential sampling for drug-resistant strains, we validated our epidemiological associations on a set of 2186 sequenced isolates, corresponding to all cultured isolates of N. gonorrhoeae in the state of Victoria, Australia in 2017 38 . We again observed significant associations between mtrC LOF and sex of sex partner (p = 0.0180; Fisher’s exact test) as well as anatomical site of infection (p = 0.0256; Fisher’s exact test) (Supplementary Figure 5, Supplementary Text).…”

Section: Loss Of the Mtrcde Efflux Pump Is Associated With Cervical Imentioning

confidence: 99%

“…As with mtrC LOF mutations, mtrA LOF mutations were significantly overrepresented in cervical isolates: 25 out of 129 (19.4%) cervical isolates contained an mtrA LOF mutation compared to 61 out of 2248 urethral isolates (2.71%; OR = 8.60, 95% CI [4.96-14.57], p = 4.60×10 -13 ; Fisher’s exact test), 4 out of 106 pharyngeal isolates (3.78%; OR = 6.09, 95% CI [2.00-24.93], p = 0.000240; Fisher’s exact test), and 4 out of 246 rectal isolates (1.63%; OR = 14.43, 95% CI [4.81-58.52], p = 3.00×10 -9 ; Fisher’s exact test). In the Australian validation cohort 38 , the majority (81/85, 95.3%) of mtrA LOF strains had concurrent mtrCDE overexpression mutations, so it was not possible to test for these associations. In such genetic backgrounds where overexpression mutations mask the effect of mtrA LOF, mtrC LOF is the preferred method of efflux pump downregulation: the majority of mtrC LOF mutations in both the global dataset (174/180, 96.7%) and the Australian cohort (33/35, 94.3%) occurred in backgrounds with known mtr overexpression mutations.…”

Section: Activator Loss-of-function Offers An Additional Level Of Adamentioning

confidence: 99%

“…a) Sex partner information in patients infected with isolates with either intact or LOF alleles of mtrC (left) or farA (right). MSMW patients were labelled as MSM in the validation dataset 38 . b) Site of infection in patients infected with isolates with either intact or LOF alleles of mtrC (left) or farA (right) datasets.…”

Section: Supplementary Tablementioning

confidence: 99%

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Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Mortimer

Hicks

et al. 2020

Preprint

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28Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and 29 antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that 30 have reverted to susceptibility regularly appear, prompting questions about which pressures 31 compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide 32 association on the largest collection of N. gonorrhoeae isolates to date (n=4882) to identify loss-33 of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased 34 antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical 35 isolates relative to urethral isolates (odds ratio (OR) = 3.74, 95% CI [1.98-6.70]). In support of a 36 model in which pump expression incurs a fitness cost in this niche, cervical isolates were also 37 enriched relative to urethral isolates in LOF mutations in the mtrCDE activator mtrA (OR = 8.60,) and in farA, a subunit of the FarAB efflux pump (OR = 6.25, 95% CI [3.90-39 9.83]). In total, approximately 1 in 3 cervical isolates (36.4%) contained a LOF mutation in either 40 the efflux pump components mtrC or farA or the activator mtrA. Our findings extend beyond N. 41 gonorrhoeae to other Neisseria: mtrC LOF mutations are rare (<1%) in the primarily 42 nasopharyngeal-colonizing N. meningitidis in a collection of 14,798 genomes but enriched in a 43 heterosexual urethritis-associated lineage (8.6%, p = 9.90×10 -5 ), indicating that efflux pump 44 downregulation contributes broadly to the adaptation of pathogenic Neisseria to the female 45 urogenital tract. Overall, our findings highlight the impact of integrating microbial population 46 genomics with host metadata and demonstrate how host environmental pressures can lead to 47 increased antibiotic susceptibility. 48 49 50 51Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. 52Antibiotics have played a key role in shaping gonococcal evolution 1-3 , with N. gonorrhoeae 53 gaining resistance to each of the first line antibiotics used to treat it 4-6 . As N. gonorrhoeae is an 54 obligate human pathogen, the mucosal niches it infects-most commonly including the urethra, 55 cervix, pharynx, and rectum-must also influence its evolution 7 . The gonococcal phylogeny 56 suggests the interaction of these factors, with an ancestral split between a relatively drug-57 susceptible lineage circulating primarily in heterosexuals and a relatively drug-resistant lineage 58 circulating primarily in men who have sex with men 3 . 59 60 Despite the deeply concerning increase in antibiotic resistance reported in gonococcal 61 populations globally 8 , some clinical isolates of N. gonorrhoeae have become more susceptible 62 to antibiotics 9,10 . This unexpected phenomenon prompts questions about which environmental 63 pressures could be drivers of increased susceptibility and the mechanisms by which 64 suppression or reversion of resistance may occur. To address these questions, we analy...

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Section: A Second Class Of Proton-dependent Efflux Pumps Appears To Cmentioning

confidence: 61%

Section: Loss Of the Mtrcde Efflux Pump Is Associated With Cervical Imentioning

confidence: 99%

Section: Activator Loss-of-function Offers An Additional Level Of Adamentioning

confidence: 99%

Section: Supplementary Tablementioning

confidence: 99%

See 2 more Smart Citations

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Mortimer

Hicks

et al. 2020

Preprint

Self Cite

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“…Chapter 2 has previously shown that S1 (previously described as G1) is sustained in 2012 and 2014 so it is interesting to note that isolates from New Zealand were collected in 2014 and 2015, suggesting a persisting heterosexual strain-type is present within multiple countries. Furthermore, S1 also appears to be present within a recent study investigating N. gonorrhoeae isolates from 2017 in the state of Victoria in Australia (referred to as clusters 24 and 91 in the study) (252). This finding highlights this strain has still remained prevalent within the Australian heterosexual population.…”

Section: Discussionsupporting

confidence: 54%

Factors that influence Neisseria gonorrhoeae antimicrobial resistance and transmission in Australia

Buckley¹

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There is a growing need to better understand increasing rates associated with Neisseria gonorrhoeae antimicrobial resistance and infection. The enhanced resolution of whole genome sequencing (WGS) not only allows the confirmation of resistance markers and those associated with epidemiological typing, but allows further exploration of unknown genomic differences. This thesis applies WGS to explore key gonococcal strains of interest, including prevalent strains throughout Australia and those associated with treatment failures.

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Characterization of outer membrane vesicles released by clinical isolates of Neisseria gonorrhoeae

Dhital,

Deo,

Stuart

et al. 2023

Proteomics

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The sexually transmitted pathogen Neisseria gonorrhoeae releases membrane vesicles including outer membrane vesicles (OMVs) during infections. OMVs traffic outer membrane molecules, such as the porin PorB and lipo‐oligosaccharide (LOS), into host innate immune cells, eliciting programmed cell death pathways, and inflammation. Little is known, however, about the proteome and LOS content of OMVs released by clinical strains isolated from different infection sites, and whether these vesicles similarly activate immune responses. Here, we characterized OMVs from four N. gonorrhoeae isolates and determined their size, abundance, proteome, LOS content, and activation of inflammatory responses in macrophages. The overall proteome of the OMVs was conserved between the four different isolates, which included major outer membrane and periplasm proteins. Despite this, we observed differences in the rate of OMV biogenesis and the relative abundance of membrane proteins and LOS. Consequently, OMVs from clinical isolates induced varying rates of macrophage cell death and the secretion of interleukin‐1 family members, such as IL‐1α and IL‐1β. Overall, these findings demonstrate that clinical isolates of N. gonorrhoeae utilize membrane vesicles to release proteins and lipids, which affects innate immune responses.

show abstract

Bridging of Neisseria gonorrhoeae lineages across sexual networks in the HIV pre-exposure prophylaxis era

Cited by 86 publications

References 39 publications

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Factors that influence Neisseria gonorrhoeae antimicrobial resistance and transmission in Australia

Characterization of outer membrane vesicles released by clinical isolates of Neisseria gonorrhoeae

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