Trichuris Muris Whey Acidic Protein Induces Type 2 Protective Immunity Against Whipworm

<p>Human whipworm (<em>Trichuris trichiura</em>) infects approximately 1 in 15 people worldwide, representing the leading infectious cause of colitis and subsequent, inflammatory bowel disease (IBD). Current control measures focused on mass deworming have had limited success due to low drug efficacies. Vaccination would be an ideal, cost-effective strategy to induce protective immunity, leading to control of infection and transmission. Here we report the identification of whey acidic protein, a whipworm<em> </em>secretory protein, as a strong immunogen for inducing protective efficacy in a surrogate mouse <em>T. muris</em> infection model. The near full-length recombinant WAP protein (r<em>Tm</em>-WAP49), as well as a single, highly conserved repeat within WAP (fragment 8) expressed as an <em>Na-</em>GST-1 fusion protein (r<em>Tm</em>-WAP-F8+<em>Na</em>-GST-1), generate a strong T helper type 2 (TH2) immune response when delivered as subcutaneous immunization formulated with Montanide ISA 720. Oral challenge with <em>T. muris</em> infective eggs following vaccination led to a significant reduction in worm burden of 48% by r<em>Tm</em>-WAP49 and 33% by r<em>Tm</em>-WAP-F8+<em>Na</em>-GST-1. The cellular immune correlates of protection included significant antigen-specific production of TH2 cytokines IL-4, IL-9, and IL-13 by cells isolated from the vaccine-draining inguinal lymph nodes, parasite-draining mesenteric lymph nodes, and spleen in mice vaccinated with either r<em>Tm</em>-WAP49 or r<em>Tm</em>-WAP-F8+<em>Na</em>-GST-1. The humoral immune correlates included a high antigen-specific ratio of IgG1 to IgG2a, without eliciting an IgE-mediated allergic response. Immunofluorescent staining of adult <em>T. muris </em>with WAP antisera identified the worm’s pathogenic stichosome organ as the site of secretion of native <em>Tm</em>-WAP protein into the colonic mucosa. While both r<em>Tm</em>-WAP49 or r<em>Tm</em>-WAP-F8+<em>Na</em>-GST-1 have high purity and stability properties by analytical analysis, r<em>Tm</em>-WAP49 has a more complex biophysical profile, with oligomerization to dimers and trimers through intermolecular disulfide bond formation. Recognition of r<em>Tm</em>-WAP49 by endemic patient serum samples suggests that conserved epitopes may exist between <em>T. muris and T. trichiura </em>(or possibly non-<em>Trichuris </em>nematodes) derived WAPs<em>.</em> To our knowledge, this is the first study identifying a promising immunogen for further investigation of its vaccine potential against <em>T. muris </em>and eventually against <em>T. trichiura</em>.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Authors dc:creator

• Briggs, Neima
• <p>https://orcid.org/0000-0002-5583-7057</p>

Contributors dc:contributor

• Jagannadha Sastry, Ph.D.
• Peter Hotez, M.D., Ph.D.
• Maria Elena Bottazzi, Ph.D.

• Trichuris trichiura
• whipworm
• vaccine development
• helminth
• Medicine and Health Sciences
• Parasitic Diseases
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/883

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1929