Haemophilus ducreyi is the etiologic agent of chancroid, a genital ulcer disease that facilitates transmission of the Human Immunodeficiency Virus (HIV). Our understanding of the pathogenesis of chancroid, virulence determinants, and immune responses to H.ducreyi has been hampered by a total lack of longitudinally collected clinical specimens from naturally infected patients. H. ducreyi is a strict human pathogen that expresses cell surface components that mimic human antigens. To study the pathogenesis of chancroid, we have developed an experimental model of skin infection in human volunteers. We have refined the model so that the course of experimental infection mimics naturally occurring disease. The focus of this application is to develop and study the model so that we can test hypotheses about pathogenesis, host immune responses and candidate virulence determinants. In the experimental model, papular lesions may either spontaneously resolve or progress to pustule formation. Our data suggests that the outcome of infection is modulated by local factors, and this is the first evidence that the human host can mount an effective immune response to H. ducreyi. The focal point of the immune response is a cutaneous infiltrate of CD4+ cells. Our first hypothesis is that the T Cell infiltrate and cytokines produced in the experimental lesions change over time and influence the outcome of infection in the model. H. ducreyi adheres to human keratinocytes and adheres to and sometimes in vades human fibroblasts in vitro. Our second hypothesis is the H. ducreyi adheres to keratinocytes and to fibroblasts and that some of the bacteria successfully invade eukaryotic cells, allowing the organism to evade host defenses. Bacterial surface structures such as outer membranes proteins (OMPs) and pili have important roles in the pathogenesis of gram negative bacterial infections. Our laboratory has characterized several conserved surface components of H. ducreyi including the major outer membrane protein (MOMP) and pili. Using a genetic approach, we wish to asses the role MOMP and pili in pathogenesis. Our third hypothesis is that the experimental infection model can discriminate between the virulence of the parental strain and isogeneic mutants in candidate virulence determinants. To test these hypotheses, our specific aims include: standardization of the human challenge model of experimental H. ducreyi infection; immunohistopathological and cytokine analysis of experimental lesions biopsied at different times during the course of infection; localization of the bacteria in the lesions; construction of isogeneic mutants in the MOMP, pilus, or a pilus associated adhesion; assessment of the ability of the human challenge model to discriminate between the parental strain and isogeneic mutants in candidate virulence determinants.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
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Gangaiah, Dharanesh; Zhang, Xinjun; Baker, Beth et al. (2016) Haemophilus ducreyi Seeks Alternative Carbon Sources and Adapts to Nutrient Stress and Anaerobiosis during Experimental Infection of Human Volunteers. Infect Immun 84:1514-1525
Singer, Martin; Li, Wei; Morré, Servaas A et al. (2016) Host Polymorphisms in TLR9 and IL10 Are Associated With the Outcomes of Experimental Haemophilus ducreyi Infection in Human Volunteers. J Infect Dis 214:489-95
van Rensburg, Julia J; Lin, Huaiying; Gao, Xiang et al. (2015) The Human Skin Microbiome Associates with the Outcome of and Is Influenced by Bacterial Infection. MBio 6:e01315-15
Gangaiah, Dharanesh; Webb, Kristen M; Humphreys, Tricia L et al. (2015) Haemophilus ducreyi Cutaneous Ulcer Strains Are Nearly Identical to Class I Genital Ulcer Strains. PLoS Negl Trop Dis 9:e0003918
Holley, Concerta L; Zhang, Xinjun; Fortney, Kate R et al. (2015) DksA and (p)ppGpp have unique and overlapping contributions to Haemophilus ducreyi pathogenesis in humans. Infect Immun 83:3281-92
Trombley, Michael P; Post, Deborah M B; Rinker, Sherri D et al. (2015) Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro. PLoS One 10:e0124373
Holley, Concerta; Gangaiah, Dharanesh; Li, Wei et al. (2014) A (p)ppGpp-null mutant of Haemophilus ducreyi is partially attenuated in humans due to multiple conflicting phenotypes. Infect Immun 82:3492-502
Gangaiah, Dharanesh; Zhang, Xinjun; Baker, Beth et al. (2014) Haemophilus ducreyi RpoE and CpxRA appear to play distinct yet complementary roles in regulation of envelope-related functions. J Bacteriol 196:4012-25
Zhang, Xinjun; Gangaiah, Dharanesh; Munson Jr, Robert S et al. (2014) Correcting imbalanced reads coverage in bacterial transcriptome sequencing with extreme deep coverage. Int J Comput Biol Drug Des 7:195-213
Gangaiah, Dharanesh; Labandeira-Rey, Maria; Zhang, Xinjun et al. (2014) Haemophilus ducreyi Hfq contributes to virulence gene regulation as cells enter stationary phase. MBio 5:e01081-13

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