Haemophilus ducreyi, the etiological agent of the genital ulcer disease chancroid, is a significant public health problem in several regions woridwide. We propose to continue structure/function studies of the outer membrane protein DsrA of H. ducreyi and determine its vaccine potential. The long-term goal of this research is to develop a vaccine against chancroid. DsrA is a multifunctional trimeric autotransporter protein conferring high levels of serum resistance to H. ducreyi. Additionally, DsrA binds the extracellular matrix components fibronectin and vitronectin and confers upon H. ducreyi the ability to attach to keratinocytes. Each of these 4 functions of DsrA is considered a virulence factor in other bacterial systems.
Specific aim 1 proposes to continue investigating the structural components of DsrA involved in its multiple functions. The domain(s) required for keratinocyte binding will be identified using a panel of dsrA mutants. The specific residues required for each of the 4 functions of DsrA will also be pinpointed using peptide libraries and site-directed mutagenesis. Defined dsrA mutants will be tested in the experimental human model of chancroid to determine which function of DsrA is required for infection. The results from these experiments will focus and inform efforts for the vaccine studies described in aim 2.
Specific aim 2 proposes to determine if DsrA is an effective vaccine in the experimental swine model of chancroid. Active immunization with rDsrA or passive immunization with an anti-DsrA monoclonal antibody will be done to examine the efficacy of DsrA as a vaccine against chancroid. Non-toxic adjuvants will be examined as substitutes for Freund's adjuvant.

Public Health Relevance

In developing countries of Africa, Asia and other continents, chancroid is an important co-factor for the heterosexual transmission of HIV. Furthermore, increasing antibiotic resistance of H. ducreyi can negatively impact chancroid treatment. Control of chancroid, using a properiy administered effective vaccine, would likely reduce chancroid incidence and HIV transmission

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI031496-23
Application #
8519216
Study Section
Special Emphasis Panel (ZAI1-MMT-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
23
Fiscal Year
2013
Total Cost
$231,827
Indirect Cost
$40,589
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kissinger, Patricia J; White, Scott; Manhart, Lisa E et al. (2016) Azithromycin Treatment Failure for Chlamydia trachomatis Among Heterosexual Men With Nongonococcal Urethritis. Sex Transm Dis 43:599-602
Kandler, Justin L; Acevedo, Rosuany Vélez; Dickinson, Mary Kathryne et al. (2016) The genes that encode the gonococcal transferrin binding proteins, TbpB and TbpA, are differentially regulated by MisR under iron-replete and iron-depleted conditions. Mol Microbiol 102:137-51
Kandler, Justin L; Holley, Concerta L; Reimche, Jennifer L et al. (2016) The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother 60:4690-700
Woolf-King, Sarah E; Muyindike, Winnie; Hobbs, Marcia M et al. (2016) Vaginal Prostate Specific Antigen (PSA) Is a Useful Biomarker of Semen Exposure Among HIV-Infected Ugandan Women. AIDS Behav :
Scheidell, Joy D; Lejuez, Carl W; Golin, Carol E et al. (2016) Borderline Personality Disorder Symptom Severity and Sexually Transmitted Infection and HIV Risk in African American Incarcerated Men. Sex Transm Dis 43:317-23
Samo, Melissa; Choudhary, Neelima R; Riebe, Kristina J et al. (2016) Immunization with the Haemophilus ducreyi trimeric autotransporter adhesin DsrA with alum, CpG or imiquimod generates a persistent humoral immune response that recognizes the bacterial surface. Vaccine 34:1193-200
Khan, M R; Golin, C E; Friedman, S R et al. (2015) STI/HIV Sexual Risk Behavior and Prevalent STI Among Incarcerated African American Men in Committed Partnerships: The Significance of Poverty, Mood Disorders, and Substance Use. AIDS Behav 19:1478-90
Unemo, Magnus; Shafer, William M (2015) Future treatment of gonorrhea--novel emerging drugs are essential and in progress? Expert Opin Emerg Drugs 20:357-60
Cash, Devin R; Noinaj, Nicholas; Buchanan, Susan K et al. (2015) Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae. Infect Immun 83:4438-49
Gallo, Maria F; Warner, Lee; Hobbs, Marcia M et al. (2015) Differences in misreporting of sexual behavior over time: implications for HIV trials. Sex Transm Dis 42:160-1

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