The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection
Milton Pereira,
Theresa Ramalho,
Warrison A. Andrade,
Danielle F. Durso,
Maria C. Souza,
Katherine A. Fitzgerald,
Douglas T. Golenbock,
Neal Silverman,
Ricardo T. Gazzinelli
Affiliations
Milton Pereira
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Corresponding author
Theresa Ramalho
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Warrison A. Andrade
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Danielle F. Durso
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Maria C. Souza
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Katherine A. Fitzgerald
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Douglas T. Golenbock
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Neal Silverman
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
Ricardo T. Gazzinelli
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil; Corresponding author
Summary: 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.
