Role of Toll-like Receptor Signalling Defects in Human Susceptibility to Invasive Infection by Streptococcus Pneumoniae

RATIONALE: Defective Toll-like receptor (TLR) signalling, due to IRAK4-deficiency and ectodermal dysplasia with immunodeficiency (EDA-ID), greatly enhances human susceptibility to pneumococcal infection. Nevertheless, the importance of TLR signalling defects in a larger population of children with invasive pneumococcal infections remains unclear. Should all children with invasive pneumococcal infection be assessed for abnormal TLR function? METHODS: We developed and optimized a peripheral blood TLR assay that readily identified patients with TLR defects resulting from IRAK4-deficiency and X-linked EDA-ID. We studied TLR function in population predicted to be enriched for TLR defects--healthy children who had developed invasive pneumococcal infection without classic risk factors for infection. RESULTS: By testing 36 healthy control neonates, children and adults we demonstrated that TNF-α and IL-6 most accurately report human TLR function and that TLR function was stable over the first six-decades of life. We tested 50 children with a history of invasive pneumococcal infection and although TLR defects were predicted to be over-represented in this population, we did not identify any TLR abnormalities. CONCLUSIONS: Although TLR signalling defects are associated with greatly enhanced susceptibility to invasive pneumococcal infection, our results suggest that routine clinical screening for TLR defects in healthy children who develop invasive pneumococcal infection is not justified.