Sunday, June 1, 2025
6/1/2025
New requirements for immunity to parasitic pathogens - when vaccines work and why they fail - PROJECT SUMMARY Immunological memory is the ability of our immune system to respond with greater strength and quickness upon re-encounter with the same pathogen (i.e. secondary infection). Immunological memory is the basis for vaccination which remains the most successful method for preventing infectious disease. Yet, a fully protective vaccine that prevents a single human parasitic disease has not been realized to date. Why is immunity to parasitic pathogens so difficulty to achieve? Our current work on secondary infections with the apicomplexan parasite, Toxoplasma gondii, suggest that failure of immunological memory responses is genetically determined. In this grant submission, we have used a forward genetic approach to uncover new requirements for host immunity to highly virulent strains T. gondii. Both genetic and immunological data converge on a B-1b cell population that is specifically expanded in resistant mice. This cell type represents a bridge between innate and adaptive immune immunity, which can recognize both self- and foreign- antigen. Our central hypothesis is that memory B-1 cells control resistance to challenge with virulent T. gondii strains, and this response is determined by allelic variation of Nfkbid. IκBNS, encoded by Nfkbid, is a member of the atypical nuclear regulators of NF-κB-dependent transcription. Nfkbid null mice fail to develop B-1 cells and antibody responses to T-independent antigens, and as reported here, have massive defects in producing T. gondii-specific antibodies. Experimental approaches from immunology, genetics and molecular parasitology will be used to address questions surrounding our central hypothesis. In Aim 1, adoptive transfer experiments will be performed to delineate protection conferred by the B-1 lineage and the functional quality of parasite-specific antibodies they produce. In Aim 2, epigenetic approaches are proposed to study the mechanism by which IκBNS mediates protective B cell responses during a secondary infection. In Aim 3, we will explore whether antibody responses directed against GPI-moieties on T. gondii surface antigens explain parasite strain-differences in secondary infection virulence. Antigenic variation is the major mechanism by which protozoan pathogens such as African Trypanosomes, Plasmodium sp. and Giardia evade B cell- mediated antibody responses. Surface antigens of T. gondii are highly polymorphic. Immunity conferred by B-1 cells may depend on their ability to produce antibodies that recognize broadly conserved epitopes within variable surface antigens. Eliciting this response during vaccination could have major bearing on the prevention of human parasitic disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).