Haemophilus ducreyi Infection Induces Oxidative Stress, Central Metabolic Changes, and a Mixed Pro- and Anti-inflammatory Environment in the Human Host

Brothwell, Julie A.; Fortney, Kate R.; Gao, Hongyu; Wilson, Landon; Andrews, Caroline F; Tran, Tuan M.; Hu, Xin; Batteiger, Teresa A.; Barnes, Stephen; Liu, Yunlong; Spinola, Stanley M.

doi:10.1128/mbio.03125-22

mBio

2022

DOI: 10.1128/mbio.03125-22

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Haemophilus ducreyi Infection Induces Oxidative Stress, Central Metabolic Changes, and a Mixed Pro- and Anti-inflammatory Environment in the Human Host

Julie A. Brothwell

Kate R. Fortney

Hongyu Gao

et al.

Abstract: Interactions between the host and bacteria at sites of infection in humans are poorly understood. We inoculated human volunteers on the upper arm with the skin pathogen H. ducreyi or a buffer control and biopsied the resulting infected and sham-inoculated sites.

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A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers

Fortney,

Brothwell,

Batteiger

et al. 2024

Infect Immun

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Haemophilus ducreyi causes the genital ulcer disease chancroid and painful cutaneous ulcers in children who live in the tropics. To acquire heme from the host, H. ducreyi expresses a TonB-dependent hemoglobin receptor, HgbA, which is necessary and sufficient for H. ducreyi to progress to the pustular stage of disease in a controlled human infection model. HgbA transports hemoglobin across the outer membrane; how heme is transported across the cytoplasmic membrane is unclear. In previous studies, transcripts encoding the YfeABCD heme transporter were upregulated in experimental lesions caused by H. ducreyi in human volunteers, suggesting the latter may have a role in virulence. Here we constructed a double deletion mutant, 35000HPΔ yfeAB Δ yfeCD , which exhibited growth defects relative to its parent 35000HP in media containing human hemoglobin as an iron source. Five human volunteers were inoculated at three sites on the skin overlying the deltoid with each strain. The results of the trial showed that papules formed at 100% (95% CI, 71.5, 100) at both 35000HP and 35000HPΔ yfeAB Δ yfeCD -inoculated sites ( P = 1.0). Pustules formed at 60% (95% CI, 25.9, 94.1) at parent-inoculated sites and 53% (95% CI, 18.3, 88.4) at mutant-inoculated sites ( P = 0.79). Thus, the ABC transporter encoded by yfeAB and yfeCD was dispensable for H. ducreyi virulence in humans. In the absence of YfeABCD, H. ducreyi likely utilizes other periplasmic binding proteins and ABC-transporters such as HbpA, SapABCDF, and DppBCDF to shuttle heme from the periplasm into the cytoplasm, underscoring the importance of redundancy of such systems in gram-negative pathogens.

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A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers

Fortney,

Brothwell,

Batteiger

et al. 2024

Infect Immun

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Formate production is dispensable for Haemophilus ducreyi virulence in human volunteers

Brothwell,

Fortney,

Williams

et al. 2023

Infect Immun

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Haemophilus ducreyi is a causative agent of cutaneous ulcers in children who live in the tropics and of the genital ulcer disease chancroid in sexually active persons. In the anaerobic environment of abscesses and ulcers, anaerobic respiration and mixed acid fermentation (MAF) can be used to provide cellular energy. In Escherichia coli , MAF produces formate, acetate, lactate, succinate, and ethanol; however, MAF has not been studied in H. ducreyi . In human challenge experiments with H. ducreyi 35000HP, transcripts of the formate transporter FocA and pyruvate formate lyase (PflB) were upregulated in pustules compared to the inocula. We made single and double mutants of focA and pflB in 35000HP. Growth of 35000HPΔ focA was similar to 35000HP, but 35000HPΔ pflB and 35000HPΔ focA-pflB had growth defects during both aerobic and anaerobic growth. Mutants lacking pflB did not secrete formate into the media. However, formate was secreted into the media by 35000HPΔ focA , indicating that H. ducreyi has alternative formate transporters. The pH of the media during anaerobic growth decreased for 35000HP and 35000HPΔ focA , but not for 35000HPΔ pflB or 35000HPΔ focA-pflB , indicating that pflB is the main contributor to media acidification during anaerobic growth. We tested whether formate production and transport were required for virulence in seven human volunteers in a mutant versus parent trial between 35000HPΔ focA-pflB and 35000HP. The pustule formation rate was similar for 35000HP (42.9%)- and 35000HPΔ focA-pflB (62%)-inoculated sites. Although formate production occurs during in vitro growth and focA-pflB transcripts are upregulated during human infection, focA and pflB are not required for virulence in humans.

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Haemophilus ducreyi Infection Induces Oxidative Stress, Central Metabolic Changes, and a Mixed Pro- and Anti-inflammatory Environment in the Human Host

Abstract: Interactions between the host and bacteria at sites of infection in humans are poorly understood. We inoculated human volunteers on the upper arm with the skin pathogen H. ducreyi or a buffer control and biopsied the resulting infected and sham-inoculated sites.

Cited by 2 publications

References 74 publications

A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers

A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers

Formate production is dispensable for Haemophilus ducreyi virulence in human volunteers

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