Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study

Mitjà, Oriol; Lukehart, Sheila A.; Pokowas, Gideon; Moses, Penias; Kapa, August; Godornes, Charmie; Robson, Jennifer; Cherian, Sarah; Houinei, Wendy; Kazadi, Walter; Siba, Peter; Lazzari, Elisa de; Bassat, Quique

doi:10.1016/s2214-109x(14)70019-1

Cited by 120 publications

(170 citation statements)

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“…There have been a few cases reports on Haemophilus ducreyi-associated skin lesions in the south Pacific islands [14][15][16] and more recently a study in Papua New Guinea, a yaws-endemic country, where 60% of lesions in children were found to be H. ducreyi-positive by PCR. 17 Further molecular studies to explore the full range of etiologies of skin ulcers in Vanuatu and other yaws-endemic regions are needed to improve our current understanding of yaws epidemiology and other tropical ulcer diseases and to better inform disease control efforts.…”

Section: Discussionmentioning

confidence: 99%

Molecular Differentiation of Treponema pallidum Subspecies in Skin Ulceration Clinically Suspected as Yaws in Vanuatu Using Real-Time Multiplex PCR and Serological Methods

Chi¹,

Danavall²,

Taleo³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. We developed a TaqMan-based real-time quadriplex polymerase chain reaction (PCR) to simultaneously detect Treponema pallidum subspecies pallidum, T. pallidum subsp. pertenue, and T. pallidum subsp. endemicum, the causative agents of venereal syphilis, yaws, and bejel, respectively. The PCR assay was applied to samples from skin ulcerations of clinically presumptive yaws cases among children on Tanna Island, Vanuatu. Another real-time triplex PCR was used to screen for the point mutations in the 23S rRNA genes that have previously been associated with azithromycin resistance in T. pallidum subsp. pallidum strains. Seropositivity by the classical syphilis serological tests was 35.5% among children with skin ulcerations clinically suspected with yaws, whereas the presence of T. pallidum subsp. pertenue DNA was only found in lesions from 15.5% of children. No evidence of T. pallidum subsp. pertenue infection, by either PCR or serology was found in~59% of cases indicating alternative causes of yaws-like lesions in this endemic area.

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Section: Discussionmentioning

confidence: 99%

Molecular Differentiation of Treponema pallidum Subspecies in Skin Ulceration Clinically Suspected as Yaws in Vanuatu Using Real-Time Multiplex PCR and Serological Methods

Chi¹,

Danavall²,

Taleo³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…pertenue, recent studies performed as part of a World Health Organization-directed yaws eradication campaign suggest that H. ducreyi is a major cause of this syndrome. In three large cross-sectional community surveys, the proportion of ulcers in which H. ducreyi DNA was detected greatly exceeded that of T. pallidum DNA (9)(10)(11). Considering the global prevalence of yaws, infections due to H. ducreyi may be much more common than was previously recognized.…”

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confidence: 94%

DksA and (p)ppGpp Have Unique and Overlapping Contributions to Haemophilus ducreyi Pathogenesis in Humans

et al. 2015

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jThe (p)ppGpp-mediated stringent response is important for bacterial survival in nutrient limiting conditions. For maximal effect, (p)ppGpp interacts with the cofactor DksA, which stabilizes (p)ppGpp's interaction with RNA polymerase. We previously demonstrated that (p)ppGpp was required for the virulence of Haemophilus ducreyi in humans. Here, we constructed an H. ducreyi dksA mutant and showed it was also partially attenuated for pustule formation in human volunteers. To understand the roles of (p)ppGpp and DksA in gene regulation in H. ducreyi, we defined genes potentially altered by (p)ppGpp and DksA deficiency using transcriptome sequencing (RNA-seq). In bacteria collected at stationary phase, lack of (p)ppGpp and DksA altered expression of 28% and 17% of H. ducreyi open reading frames, respectively, including genes involved in transcription, translation, and metabolism. There was significant overlap in genes differentially expressed in the (p)ppGpp mutant relative to the dksA mutant. Loss of (p)ppGpp or DksA resulted in the dysregulation of several known virulence determinants. Deletion of dksA downregulated lspB and rendered the organism less resistant to phagocytosis and increased its sensitivity to oxidative stress. Both mutants had reduced ability to attach to human foreskin fibroblasts; the defect correlated with reduced expression of the Flp adhesin proteins in the (p)ppGpp mutant but not in the dksA mutant, suggesting that DksA regulates the expression of an unknown cofactor(s) required for Flp-mediated adherence. We conclude that both (p)ppGpp and DksA serve as major regulators of H. ducreyi gene expression in stationary phase and have both overlapping and unique contributions to pathogenesis. Haemophilus ducreyi is the causative agent of chancroid, a sexually transmitted genital ulcer disease that facilitates both the transmission and acquisition of HIV-1 (1). Chancroid has a short duration of infectivity and is maintained only in populations with high sex partner change rates, such as commercial sex workers (2). Due to widespread implementation of syndromic management of genital ulcers, the epidemiology of chancroid is poorly defined, but its prevalence has declined in many areas where chancroid formerly was endemic (2). However, reports of chancroid persist from several countries in Africa and Asia, implying that these regions have clinical reservoirs of infected sex workers (3-8).Although non-sexually-transmitted cutaneous ulcers in children in the South Pacific islands and equatorial Africa are usually attributed to Treponema pallidum subsp. pertenue, recent studies performed as part of a World Health Organization-directed yaws eradication campaign suggest that H. ducreyi is a major cause of this syndrome. In three large cross-sectional community surveys, the proportion of ulcers in which H. ducreyi DNA was detected greatly exceeded that of T. pallidum DNA (9-11). Considering the global prevalence of yaws, infections due to H. ducreyi may be much more common than was previously recognized. Thu...

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“…Although the global prevalence of chancroid has declined due to syndromic management of genital ulcer disease, the disease is still prevalent in several regions of Africa, Latin America, and Asia (2). In addition to causing chancroid, H. ducreyi now is recognized as a leading cause of nonsexually transmitted cutaneous ulcers in children in regions of the South Pacific islands and equatorial Africa where yaws is endemic (3)(4)(5). Strains that cause cutaneous ulcers are almost genetically identical to the genital ulcer strain 35000HP and likely evolved from the 35000HP lineage ϳ180,000 years ago (6, 7).…”

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confidence: 99%

Haemophilus ducreyi Seeks Alternative Carbon Sources and Adapts to Nutrient Stress and Anaerobiosis during Experimental Infection of Human Volunteers

et al. 2016

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Spinola, mBio 5:e01081-13, 2014, http://dx.doi.org/10.1128/mBio.01081-13) suggested that H. ducreyi encounters growth conditions in human lesions resembling those found in stationary phase. However, how H. ducreyi transcriptionally responds to stress during human infection is unknown. Here, we determined the H. ducreyi transcriptome in biopsy specimens of human lesions and compared it to the transcriptomes of bacteria grown to mid-log, transition, and stationary phases. Multidimensional scaling showed that the in vivo transcriptome is distinct from those of in vitro growth. Compared to the inoculum (mid-log-phase bacteria), H. ducreyi harvested from pustules differentially expressed ϳ93 genes, of which 62 were upregulated. The upregulated genes encode homologs of proteins involved in nutrient transport, alternative carbon pathways (L-ascorbate utilization and metabolism), growth arrest response, heat shock response, DNA recombination, and anaerobiosis. H. ducreyi upregulated few genes (hgbA, flp-tad, and lspB-lspA2) encoding virulence determinants required for human infection. Most genes regulated by CpxRA, RpoE, Hfq, (p)ppGpp, and DksA, which control the expression of virulence determinants and adaptation to a variety of stresses, were not differentially expressed in vivo, suggesting that these systems are cycling on and off during infection. Taken together, these data suggest that the in vivo transcriptome is distinct from those of in vitro growth and that adaptation to nutrient stress and anaerobiosis is crucial for H. ducreyi survival in humans.T he Gram-negative bacterium Haemophilus ducreyi is the causative agent of the sexually transmitted disease chancroid. Chancroid facilitates the acquisition and transmission of human immunodeficiency virus type 1 (1). Although the global prevalence of chancroid has declined due to syndromic management of genital ulcer disease, the disease is still prevalent in several regions of Africa, Latin America, and Asia (2). In addition to causing chancroid, H. ducreyi now is recognized as a leading cause of nonsexually transmitted cutaneous ulcers in children in regions of the South Pacific islands and equatorial Africa where yaws is endemic (3-5). Strains that cause cutaneous ulcers are almost genetically identical to the genital ulcer strain 35000HP and likely evolved from the 35000HP lineage ϳ180,000 years ago (6, 7).The molecular pathogenesis of H. ducreyi 35000HP has been extensively characterized in a human challenge model (8). In this model, H. ducreyi is inoculated into the skin of healthy adults via puncture wounds made by an allergy-testing device. Within 24 h of inoculation, collagen and fibrin are deposited in the wounds; polymorphonuclear leukocytes (PMNs) and macrophages traffic onto collagen and fibrin, forming micropustules (9, 10). By 48 h, the micropustules coalesce to form an abscess, which eventually ulcerates through the epidermis (9, 10). In the abscess, H. ducreyi is found in aggregates and colocalizes with PMNs and macrophages, which fail to ingest the ...

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Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study

Abstract: Newcrest Mining Company.

Cited by 120 publications

References 19 publications

Molecular Differentiation of Treponema pallidum Subspecies in Skin Ulceration Clinically Suspected as Yaws in Vanuatu Using Real-Time Multiplex PCR and Serological Methods

Molecular Differentiation of Treponema pallidum Subspecies in Skin Ulceration Clinically Suspected as Yaws in Vanuatu Using Real-Time Multiplex PCR and Serological Methods

DksA and (p)ppGpp Have Unique and Overlapping Contributions to Haemophilus ducreyi Pathogenesis in Humans

Haemophilus ducreyi Seeks Alternative Carbon Sources and Adapts to Nutrient Stress and Anaerobiosis during Experimental Infection of Human Volunteers

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