Genetic mapping reveals Nfkbid as a central regulator of humoral immunity to Toxoplasma gondii

Scott P. Souza, Samantha D. Splitt, Juan C. Sanchez-Arcila, Julia A. Alvarez, Jessica N. Wilson, Safuwra Wizzard, Zheng Luo, Nicole Baumgarth, Kirk D.C. Jensen

Research output: Contribution to journalArticlepeer-review

Abstract

Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes lethal secondary infections in chronically infected mice. Here we report that unlike susceptible C57BL/ 6J mice, A/J mice were highly resistant to secondary infection. To identify correlates of immunity, we utilized forward genetics to identify Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice (“bumble”) did not generate parasite-specific IgM and lacked robust parasite-specific IgG, which correlated with defects in B-2 cell maturation and class-switch recombination. Though high-affinity antibodies were B-2 derived, transfer of B-1 cells partially rescued the immunity defects observed in bumble mice and were required for 100% vaccine efficacy in bone marrow chimeric mice. Immunity in resistant mice correlated with robust isotype class-switching in both B cell lineages, which can be fine-tuned by Nfkbid gene expression. We propose a model whereby humoral immunity to T. gondii is regulated by Nfkbid and requires B-1 and B-2 cells for full protection.

Original languageEnglish (US)
Article numbere1010081
JournalPLoS pathogens
Volume17
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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