Program Director/Principal Investigator (Last, First, Middle): Coleman, Matthew A Project Abstract Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections (STIs) worldwide affecting over 90 million people every year and the most common cause of preventable blindness worldwide. In the United States, STIs caused by C. trachomatis account for billions of dollars in annual costs (Gunn et al. 1998). Because the infection can be asymptomatic, it may go untreated for years and can result in pelvic inflammatory disease, ectopic pregnancy, and infertility. Therefore, a public health need for a vaccine to prevent diseases caused by C. trachomatis is justified. Despite considerable efforts to develop a chlamydial vaccine none has been forthcoming. Studies have shown immunization with the Chlamydia major outer membrane protein (MOMP) can induce significant protection against infection and disease in mice and non-human primates if its native structure is preserved. However, formulation of MOMP vaccines is a major hurdle given MOMP has 16 transmembrane domains, is 40% hydrophobic, assembles as a homotrimer and contains multiple cysteine's that can form disulfide bridges. We have now demonstrated that we can produce a trimeric, SDS- resistant, and active form of MOMP using nanolipoprotein particles (NLPs). This breakthrough was achieved by combining synthetic biology approaches and cell-free co-expression of MOMP with apolipoproteins. This proposal is focused on further developing NLPs formulated with MOMP as a vaccine platform. We will focus on demonstrating this technology using MOMP from Chlamydia muridarum engineered with adjuvants for inclusion within the nanoparticle to comprise our novel vaccine. We have two aims for this work: 1) Engineer synthetic murine MOMP for high-level co- expression and purification with Apolipoproteins to form a nanodisc complex, and 2) Show protection in mice against an intranasal challenge using the engineered, adjuvanted, MOMP-NLP particles. Page Continuation Format Page

Public Health Relevance

Coleman, Matthew A Project Narrative This project will involve bioengineering of a major outer membrane protein (MOMP) to produce a protective vaccine to C. trachomatis. C. trachomatis is the most common cause of bacterial STI worldwide and leads to pelvic inflammatory disease, ectopic pregnancy as well as infertility. Antibiotics for the treatment of Chlamydia, are available but these don't prevent reoccurrences of the STI. Despite considerable efforts to develop a chlamydial vaccine, none has been forthcoming and thus new formulation technologies will be explored. Page Continuation Format Page

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Hiltke, Thomas J
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Lawrence Livermore National Security, LLC
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Cleveland 4th, Thomas E; He, Wei; Evans, Angela C et al. (2018) Small-angle X-ray and neutron scattering demonstrates that cell-free expression produces properly formed disc-shaped nanolipoprotein particles. Protein Sci 27:780-789
Quinn, Steven D; Srinivasan, Shwetha; Gordon, Jesse B et al. (2018) Single-Molecule Fluorescence Detection of the Epidermal Growth Factor Receptor in Membrane Discs. Biochemistry :
He, Wei; Felderman, Martina; Evans, Angela C et al. (2017) Cell-free production of a functional oligomeric form of a Chlamydia major outer-membrane protein (MOMP) for vaccine development. J Biol Chem 292:15121-15132