Identification of Leishmania donovani and Mycobacterium tuberculosis- derived proteins on the surface of infected macrophages that are associated with ADCC induction
Led by Dr Mohamed Osman (University of York), with Prof Paul Kaye (University of York), Dr John Pearl (University of Leicester) and Prof Andrea Cooper (University of Leicester)
Project Aims
Leishmaniasis and tuberculosis (TB) are globally important infectious diseases, with a major impact on human health. They are caused by pathogens that have adopted an intracellular lifestyle, living within cells of the immune system called phagocytes. Both diseases have a negative prognosis when associated with HIV infection. No effective vaccines are available, despite intense effort, particularly in the case of TB. Drugs treatment regimens are prolonged which may result in patient non-adherence and increased toxicity, and the emergence of drug resistance and / or an increase in treatment failures is a major threat.
Our understanding of what constitutes protective immunity in TB or leishmaniasis is incomplete and indeed it is possible that immune responses not normally provoked during infection may prove more amenable to manipulation and have greater efficacy than those induced during natural infection. We propose to investigate the potential for a form of immunity which involves the production of antibodies against pathogen-derived molecules expressed on the surface of infected cells and their recognition by “killer cells”. Our hypothesis is that these antibodies will be able to help the killer cells to remove Leishmania and Mycobacterium tuberculosis (Mtb)-infected cells from the body. In this proposal, we will identify pathogen-derived molecules expressed on the surface of infected phagocytes and determine whether they are recognised by pathogen-specific antibodies. This is a critical first step to evaluating whether enhancing this mechanism of immunity will help control disease. This project has the potential to provide new candidate molecules for vaccine development and to promote the development of novel recombinant antibodies that can be used to treat patients. Hence, this proposal seeks to generate new tools for the fight against leishmaniasis and TB.
Project Outcomes
Leishmaniasis and Tuberculosis (TB) are globally important infectious diseases, with a major impact on human health. They are caused by pathogens that have adopted an intracellular lifestyle, living within cells of the immune system called phagocytes. Both diseases have a negative prognosis when associated with HIV infection. No effective vaccines are available, despite intense effort, particularly in the case of TB. Drugs treatment regimens are prolonged which may result in patient non-adherence and increased toxicity, and the emergence of drug resistance and / or an increase in treatment failures is a major threat.
Understanding of what constitutes protective immunity in TB or leishmaniasis is incomplete and indeed it is possible that immune responses not normally provoked during infection may prove more amenable to manipulation and have greater efficacy than those induced during natural infection. We proposed to investigate the potential for a form of immunity which involves the production of antibodies against pathogen-derived molecules expressed on the surface of infected cells and their recognition by “killer cells”. Our hypothesis is that these antibodies will be able to help the killer cells to remove Leishmania and Mycobacterium tuberculosis (Mtb) infected cells from the body. In this study using mass spectrometer (MS), we have identified 45 Leishmania-derived molecules which were significantly expressed on the surface of biotinylated infected cells in comparison to non-biotinylated infected cells. Bioinformatics analysis showed that some of these proteins have the potential of binding to MHC-I and MHC-II. To further validate the surface expression of these proteins, we have in-vivo tagged three proteins using CRISPAR/Cas9 system. These three tagged Leishmania donovani lines will be used for in-vitro and in-vivo infection to identify their sub-cellular localizations. For future studies, we are planning to identify whether these surface proteins are targets for ADCC, and the technology will be applied to TB. This project has the potential to provide new candidate molecules for vaccine development and to promote the development of novel recombinant antibodies that can be used to treat patients.
