Identification of immunodominant CD4+ T cell antigens as vaccine candidates for protection against the infection with Rickettsia typhi and characterization of the Rickettsia typhi-specific CD8+ T cell response

• Applicant: Dr. Anke Osterloh
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Immunology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397605306

During the previous funding period, several antigens of Rickettsia (R.) typhi were identified that have the potential to elicit a CD4+ T cell response, possibly also CD8+ T cell and B cell responses. Most of these antigens have already been cloned and recombinantly expressed. The immunogenicity of these recombinant proteins and their potential use as vaccines will now be tested. Restimulation of CD4+ and CD8+ T cells from R. typhi-infected mice and from the blood of patients will reveal which antigens actually generate a T and B cell response in mouse and human infection with this pathogen. In this context, the T cell response will be analyzed in detail, in particular with regard to the production of cytokines, proliferation and the expression of activation markers. The production of antibodies against these antigens will also be investigated and T and B cell epitopes will be determined. In the context of this work, a possible cross-reactivity towards other rickettsiae, in particular R. prowazekii, will also be examined. For this purpose, mice will be infected with R. prowazekii and the immune response against the recombinant antigens will be analyzed as described. Those antigens, protein fragments or epitopes that are found to be immunodominant in the restimulation of immune cells from infected mice and patients will be further used for immunization of mice and the induction of a T and B cell response will be investigated using the above methods. If immunization is successful, activated CD4+ and CD8+ T cells will be isolated from the immunized mice and adoptively transferred into R. typhi-infected BALB/c CB17 SCID mice that are highly susceptible to infection with this pathogen to test their protective effects. The planned work will reveal which antigens of R. typhi can induce a protective immune response and thus represent candidate vaccines. For the first time, the upcoming funding period will also provide the opportunity to study the response of blood cells from patients, so that their relevance to the human immune response to R. typhi can also be tested. This will give an indication whether an antigen can also be effective as a vaccine candidate in humans. Antigens that are recognized by B cells are further interesting tools for developing new diagnostic methods that are still severely limited. Those antigens could be used for the development of diagnostic by Western blotting and ELISA.

• DFG Programme: Research Grants