Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: A mouse model of type 3 familial hemophagocytic lymphohistiocytosis

Karine Crozat, Kasper Hoebe, Sophie Ugolini, Nancy A. Hong, Edith Janssen, Sophie Rutschmann, Suzanne Mudd, Sosathya Sovath, Eric Vivier, Bruce Beutler

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl- N-nitrosourea-induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60-million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans. JEM

Original languageEnglish (US)
Pages (from-to)853-863
Number of pages11
JournalJournal of Experimental Medicine
Volume204
Issue number4
DOIs
StatePublished - Apr 16 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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