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2025-12-31
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THE IRAK1/IRF5 AXIS INITIATES IL-12 RESPONSE BY DENDRITIC CELLS AND CONTROL OF TOXOPLASMA GONDII INFECTION.
CP: Microbiology
IL-12
IRAK
IRF5
Toll-like receptors
Toxoplasma gondii
cell signaling
dendritic cells
innate immunity
monocytes
myddosome
Author
Affilliation
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Department of Molecular, Cell, and Cancer Biology. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA/Universidade Federal de Minas Gerais. Centro de Tecnologia de Vacinas. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Department of Molecular, Cell, and Cancer Biology. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA.
Division of Infectious Diseases and Immunology. Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA/Universidade Federal de Minas Gerais. Centro de Tecnologia de Vacinas. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Abstract
Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.
Keywords
CP: ImmunologyCP: Microbiology
IL-12
IRAK
IRF5
Toll-like receptors
Toxoplasma gondii
cell signaling
dendritic cells
innate immunity
monocytes
myddosome
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