Interrogating nfkbid dependent humoral immunity to toxoplasma gondii

The National Institute of Allergy and Infectious Diseases (NIAID) awarded $435,875 to the University of California, Merced under the Allergy and Infectious Diseases Research program (CFDA 93.855) on July 18, 2025, for a project period extending through June 30, 2027. This Project Grant funds investigator-initiated biomedical research focused on understanding the role of the NFKBID gene and its encoded protein IKBNS in generating protective humoral (antibody-mediated) immunity against Toxoplasma gondii infection. The research addresses a critical gap in vaccine development by employing genetic analysis, immunological techniques, and molecular biology approaches to elucidate how IKBNS regulates CD4 T follicular helper cell responses and antibody production against this parasitic pathogen.

The award supports two primary research aims: (1) characterization of NFKBID-dependent defects in humoral immunity through analysis of genetically modified mouse models with cell-specific deletions, including examination of transcriptional regulation and NF-κB gene interactions; and (2) investigation of how T cell and B cell intrinsic expression of NFKBID influences protective immunity during virulent parasite challenge and the role of IKBNS-dependent antibodies in mediating protection. The ultimate objective is to advance understanding of parasitic disease immunity mechanisms with potential applications toward developing improved vaccines for human toxoplasmosis and related parasitic infections.

Abstract

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.