Formate production is dispensable for Haemophilus ducreyi virulence in human volunteers

Author:

Brothwell Julie A.1ORCID,Fortney Kate R.1,Williams Jalan S.1,Batteiger Teresa A.2,Duplantier Rory2,Grounds Danielle2,Jannasch Amber S.3,Katz Barry P.4,Spinola Stanley M.125

Affiliation:

1. Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana, USA

2. Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana, USA

3. Bindley Bioscience Center, Purdue University , West Lafayette, Indiana, USA

4. Department of Biostatistics and Health Data Sciences, Indiana University School of Medicine , Indianapolis, Indiana, USA

5. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine , Indianapolis, Indiana, USA

Abstract

ABSTRACT 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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

Reference46 articles.

1. Spinola SM . 2008. Chancroid and Haemophilus ducreyi, p 689–699. In Holmes KK , PF Sparling , WE Stamm , P Piot , JN Wasserheit , L Corey , MS Cohen , DH Watts (ed), Sexually transmitted diseases, 4th ed. McGraw-Hill, New York.

2. Epidemiology ofHaemophilus ducreyiInfections

3. Yaws, Haemophilus ducreyi, and Other Bacterial Causes of Cutaneous Ulcer Disease in the South Pacific Islands

4. Genital ulcers caused by sexually transmitted agents

5. Standardization of the Experimental Model ofHaemophilus ducreyiInfection in Human Subjects

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