Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1479-5876-8-6
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Funding
- Genome Prairie and Genome BC for the Pathogenomics of Innate Immunity research program
- Canadian Institutes for Health Research (CIHR)
- European Community's [FP7/2007-2013]
- Wellcome Trust
- Michael Smith Foundation for Health Research
- Canadian Bacterial Diseases Network
- Medical Research Council [G9900991B] Funding Source: researchfish
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Background: Activation of Toll-like receptors (TLRs) is widely accepted as an essential event for defence against infection. Many TLRs utilize a common signalling pathway that relies on activation of the kinase IRAK4 and the transcription factor NF kappa B for the rapid expression of immunity genes. Methods: 21 K DNA microarray technology was used to evaluate LPS-induced (TLR4) gene responses in blood monocytes from a child with an IRAK4-deficiency. In vitro responsiveness to LPS was confirmed by real-time PCR and ELISA and compared to the clinical predisposition of the child and IRAK4-deficient mice to Gram negative infection. Results: We demonstrated that the vast majority of LPS-responsive genes in IRAK4-deficient monocytes were greatly suppressed, an observation that is consistent with the described role for IRAK4 as an essential component of TLR4 signalling. The severely impaired response to LPS, however, is inconsistent with a remarkably low incidence of Gram negative infections observed in this child and other children with IRAK4-deficiency. This unpredicted clinical phenotype was validated by demonstrating that IRAK4-deficient mice had a similar resistance to infection with Gram negative S. typhimurium as wildtype mice. A number of immunity genes, such as chemokines, were expressed at normal levels in human IRAK4-deficient monocytes, indicating that particular IRAK4-independent elements within the repertoire of TLR4-induced responses are expressed. Conclusions: Sufficient defence to Gram negative immunity does not require IRAK4 or a robust, 'classic' inflammatory and immune response.
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