Interrogating NFKBID dependent humoral immunity to Toxoplasma gondii - 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, suggests that protective immunity is genetically determined. In this grant submission, we highlight a published forward genetic approach using an AxB,BxA mouse panel that revealed the transcriptional regulator of NF-κB, IκBNS, encoded by Nfkbid, is required for humoral immunity to T. gondii. However, the mechanism by which IκBNS mediates protective immunity against T. gondii is not fully understood. We hypothesize that IκBNS determines the protective capacity of CD4 T follicular helper (Tfh) responses to Toxoplasma gondii. Experimental approaches from immunology and molecular biology will be utilized to test these hypotheses. In Aim 1, a series of mouse lines with cell-specific deletions of Nfkbid will be used to understand the nature of the humoral defect in Nfkbid null animals. We hypothesize that Nfkbid- deficient Tfh cells are unable to help B cells mount antibody responses to T. gondii. We propose to define the transcriptional regulation mediated by IκBNS, including its impact on NF-κB-gene interactions, that confers enhanced Tfh responses and immunity to T. gondii. In Aim 2, we will explore how T and B cell intrinsic expression of Nfkbid influences immunity to virulent challenge with T. gondii, and the role of IκBNS-dependent antibodies in mediating this protection. With the overarching goal of preventing human toxoplasmosis, insights gained from this R21 proposal will guide future projects on vaccine and therapeutic strategies that best prevent toxoplasmosis in susceptible mice.
