Correlates of exacerbated and ameliorated pathogenesis in experimental and clinical tuberculosis

• Applicant: Professor Dr. Ulrich E. Schaible
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 380282378

Tuberculosis (TB) still remains a highly relevant public health problem as leading cause of mortality and morbidity from a single infectious agent, Mycobacterium tuberculosis. Many aspects of host-mycobacteria interaction and pathogenesis remain poorly characterized. We will employ refined experimental mouse TB models that take into account host genetics as denominators of susceptibility and resistance, which will be analyzed together with human TB patient samples to facilitate a comparative study in order to identify correlates of exacerbated or ameliorated pathogenesis. We have two genetically defined mouse strains of the same background, which differ from their wild type littermates in one gene each. These genes determine whether these strains are more susceptible to experimental TB or not. One gene determines innate and the other one acquired T cell immune responses. One of these two mouse models has been developed by our Russian partner. The other one is available through close collaboration with our Russian colleague in the US. Pathogenesis of experimental TB infections in these mouse strains will be monitored by global gene expression and immune parameter profiling in infected lungs. These profiles will be compared to those of tissue samples from Russian TB patients, which have undergone surgery to reduce bacterial loads by removing TB infected parts of their lungs. Determinants of disease exacerbation or amelioration as identified by this approach will be functionally further evaluated by adoptive cell transfer, depletion or inhibition experiments in the mouse models. Based on previous data we will focus on the roles of neutrophil-macrophage interactions, B cells and antigen presenting cell functions as well as certain cytokines such as IL-11. As translationally relevant outcome, we expect to identify factors, which determine TB exacerbation and represent putative targets for diagnosis or host directed therapies. These proposed joined studies employing two defined mouse models together with relevant TB patient samples is only possible through close collaboration with our Russian partners.

• DFG Programme: Research Grants
• International Connection: Russia, USA
• Cooperation Partners: Professor Dr. Alexander S. Apt; Professor Dr. Igor Kramnik; Dr. Vladimir Yeremeev, Ph.D.