Impaired innate immunity in IRAK4 deficient mice leads to defective Type 1 T cell responses, B cell expansion and enhanced susceptibility to infection with Toxoplasma

Infect Immun. 2012 Oct 1. [Epub ahead of print]

Impaired innate immunity in IRAK4 deficient mice leads to defective Type 1 T cell responses, B cell expansion and enhanced susceptibility to infection with Toxoplasma gondi

Béla SR, Dutra MS, Mui E, Montpetit A, Oliveira FS, Oliveira SC, Arantes RM, Antonelli LR, McLeod R, Gazzinelli RT.

Centro de Pesquisas René Rachou, CPqRR - Fundação Oswaldo Cruz, Avenida Augusto de Lima 1517, Belo Horizonte 30190-002, MG, Brazil.

IL1R-associated kinase (IRAK) 4 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 Receptors (TLRs) function. Herein, we investigated the role of this kinase in IRAK4 deficient mice orally infected with the cystogenic ME49 strain of T. gondii. IRAK4(-/-) mice displayed higher morbidity, tissue parasitism and accelerated mortality, when compared to the control mice. Lymphoid folicles and germinal centers from infected IRAK4(-/-) mice were significantly smaller. Consistently, IRAK4(-/-) mice showed a defect on splenic B cell activation and expansion as well as diminished production of IFNγ by T lymphocytes. The myeloid compartment was also affected. Both frequency and ability of dendritic cells (DCs) and monocytes/macrophage to produce IL-12 were significantly decreased, and resistance to infection with Toxoplasma was rescued by treating IRAK4(-/-) mice with rIL-12. Additionally, we report the association of IRAK4 haplotype-tagging single nucleotide polymorphisms (tag-SNPs) with congenital toxoplasmosis in infected affected individuals (rs1461567 and rs4251513, p<0 .023=".023" acquired="acquired" activation="activation" and="and" br="br" cells="cells" development="development" essential="essential" for="for" gondii.="gondii." host="host" immune="immune" immunity="immunity" infection="infection" innate="innate" irak4="irak4" is="is" of="of" p="p" parasite="parasite" resistance="resistance" respectively="respectively" signaling="signaling" specific="specific" t.="t." thus="thus" to="to" via="via" with="with">
PMID: 23027530 [PubMed - as supplied by publisher]