title: Impaired innate immunity in mice deficient in interleukin-1 receptor-associated kinase 4 leads to defective type 1 T cell responses, B cell expansion, and enhanced susceptibility to infection with Toxoplasma gondii.
abstract: Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a member of the IRAK family and has an important role in inducing the production of inflammatory mediators. This kinase is downstream of MyD88, an adaptor protein essential for Toll-like receptor (TLR) function. We investigated the role of this kinase in IRAK4-deficient mice orally infected with the cystogenic ME49 strain of Toxoplasma gondii. IRAK4(-/-) mice displayed higher morbidity, tissue parasitism, and accelerated mortality than the control mice. The lymphoid follicles and germinal centers from infected IRAK4(-/-) mice were significantly smaller. We consistently found that IRAK4(-/-) mice showed a defect in splenic B cell activation and expansion as well as diminished production of gamma interferon (IFN-γ) by T lymphocytes. The myeloid compartment was also affected. Both the frequency and ability of dendritic cells (DCs) and monocytes/macrophages to produce IL-12 were significantly decreased, and resistance to infection with Toxoplasma was rescued by treating IRAK4(-/-) mice with recombinant IL-12 (rIL-12). Additionally, we report the association of IRAK4 haplotype-tagging single nucleotide polymorphisms (tag-SNPs) with congenital toxoplasmosis in infected individuals (rs1461567 and rs4251513, P < 0.023 and P < 0.045, respectively). Thus, signaling via IRAK4 is essential for the activation of innate immune cells, development of parasite-specific acquired immunity, and host resistance to infection with T. gondii.
authors.affiliation: Centro de Pesquisas René Rachou, CPqRR-Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Béla
authors.forename: Míriam S
authors.initials: MS
authors.lastname: Dutra
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Oliveira
authors.forename: Sérgio C
authors.initials: SC
authors.lastname: Oliveira
authors.forename: Rosa M E
authors.initials: RM
authors.lastname: Arantes
authors.forename: Lis R
authors.initials: LR
authors.lastname: Antonelli
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014125:Toxoplasmosis, Congenital / Q000235:genetics* / Q000276:immunology / Q000469:parasitology / Q000473:pathology
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases