Method For The Production Of Purified Invasin Protein And Use Thereof

University of Kansas
posted on 08/25/2009

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Shigella species are bacterial pathogens that elicit a self-limiting gastroenteritis (shigellosis) in humans. These bacteria synthesize and secrete proteins called the invasion plasmid antigens or Ipa proteins, which are required for the invasiveness, and thus the virulence, of this pathogen. One of the Ipa proteins, IpaC, is essential for promoting the uptake of Shigella by intestinal epithelial cells. During shigellosis, IpaC elicits a strong immune response in infected individuals and it was recently shown that IpaC is able to function as an immunological adjuvant that enhances the immune response to normally non-immunogenic substances when the two are co-administered at a mucosal site. In early experiments, IpaC was mixed with ovalbumin and the mixture was administered to mice by the intranasal route. Exposure to the IpaC/ovalbumin mixture led to a pronounced serum IgA and IgG response against ovalbumin. No such response is observed if IpaC is omitted from the mixture. Effective adjuvants that are safe for use in humans or animals are necessary for the development of new and more effective vaccines. Many virulent organisms are too dangerous to administer as live vaccines, even in the form of attenuated strains. However, heat-inactivated viruses or bacteria, or recombinant products from these pathogens, are not always immunogenic enough to elicit the strong immune response necessary for protective immunity. The use of adjuvants enhances both the immediate immune response generated to an antigen component of a vaccine, and extends the duration of its effectiveness. Most pathogens gain access to their host at mucosal sites (the gastrointestinal tract, respiratory tract, etc.) and the mucosal immune system is distinct from the peripheral immune system. In the peripheral immune system, lymphoid cells and effector molecules are confined to individual lymph nodes and the spleen and intercommunication occurs by cell trafficking through the lymphatic and blood circulation. In contrast, the mucosal immune system is an integrated network of tissues, lymphoid and constitutive cells, and effector molecules that protect the host from infection at mucous membrane surfaces. Because stimulation of the peripheral immune system does not result in significant mucosal immunity, protection against organisms that attack at the mucosa requires stimulation of the mucosal immune system. The ability to stimulate a mucosal immune response is a highly desirable property, as most adjuvants are used primarily for systemic immunizations and produce little or no secretory immunity. Such immunity is important for protecting against infective entities that first attack epithelial cells. To date, the best-known mucosal adjuvant is cholera toxin and a related E. coli enterotoxin (CT and LT, respectively), which elicit a pronounced IgA response in mucosal secretions and blood as well as a significant serum IgG response. Unfortunately CT and LT are toxic molecules and have required genetic modifications to render these adjuvants less toxic while maintaining their effectiveness. In initial studies, IpaC has been shown to be as effective as CT in eliciting a mucosal immune response to co-administered antigens. Furthermore, the IgG profile elicited by IpaC (like that induced by CT) is characteristic of a Th2 type response, indicating that it promotes a good mucosal immune response. Most importantly, however, the IgA and IgG response promoted by IpaC is not accompanied by any apparent toxicity and does not require genetic fusion between IpaC and the target antigen, as do some detoxified forms of CT. KU is willing to enter into a Confidential Disclosure Agreement for the purpose of negotiating a License Agreement. If you are interested in learning details of this invention, please contact: James G. Baxendale Director, Technology Transfer & Intellectual Property at: jbaxendale@ku.edu Or Christopher Zien, Ph.D. Licensing Associate, Technology Transfer & Intellectual Property at: czien@ku.edu Updated: August 25, 2009