Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor-dependent innate antiviral immune responses.
BACKGROUND
Engagement of all known Toll-like receptors (TLRs) causes the production of inflammatory cytokines, including TNF-alpha, whereas in humans, engagement of TLRs 3, 7, 8, and 9 also induces type I IFNs. IRAK-4 is a critical effector in signaling by TLRs and the IL-1 receptor, which share homology in their intracellular domain and recruit IRAK-4 via the adaptor myeloid differentiation factor 88 (MyD88). Patients with IRAK-4 deficiency are susceptible to invasive bacterial infections but have so far not been reported to be susceptible to viral infection. Blood cells from these patients are impaired in their ability to make TNF-alpha in response to activation by TLRs. A recent report has described concomitant impairment of type I IFN production after activation of TLRs 7, 8, and 9, but not TLR3.


OBJECTIVE
We sought to evaluate the role of IRAK-4 in TLR-induced production of the type I IFN, IFN-alpha, in humans.


METHODS
We examined TLR-induced production of TNF-alpha and IFN-alpha in PBMCs from an IRAK-4-deficient patient, his heterozygous carrier parents, and normal controls.


RESULTS
TNF-alpha production in response to TLR agonists was severely impaired in the patient. IFN-alpha production induced by TLR7, TLR8, and TLR9, as well as TLR3 agonists, was low or absent.


CONCLUSIONS
IRAK-4 plays an important role in the production of type I IFN, as well as TNF-alpha, induced by all TLRs, including TLR3.


CONCLUSIONS
IRAK-4 may play a broader role in human innate antiviral immunity than previously appreciated.
McDonald
Douglas R
DR
Division of Immunology, Children's Hospital Boston, Boston, MA 02115, USA.
Brown
Daniel
D
Bonilla
Francisco A
FA
Geha
Raif S
RS
D002478:Cells, Cultured; D002648:Child; D015536:Down-Regulation; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D008297:Male; D009154:Mutation; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014777:Virus Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*
D016898:Interferon-alpha; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases