Improving survival after sepsis

2242 JEM Vol. 204, No. 10, 2007 Humans outgrow their need for a TLR-activated kinase, according to a new study by Ku et al. (page 2407). The kinase helps protect young children from specific pathogens but is expendable in adults. The TLRs are part of an early infection warning system that recognizes microbial intrusion. Many activated TLRs recruit a kinase called IRAK-4, which switches on immune-boosting transcription pathways. In mice, IRAK-4 is thought to be a crucial cog in innate defense, as mice of all ages lacking the kinase are vulnerable to many different viruses, bacteria, and fungi. But the human version now appears to be less comprehensive. The new study examined 28 patients with IRAK-4 mutations. Immune cells from these patients’ blood failed to produce inflammatory cytokines in response to TLR ligation. During infancy and childhood, these patients experienced repeated, sometimes lethal infections mainly with Streptococcus pneumoniae and Staphylococcus aureus. Resistance to other pathogens might stem from TLRs that bypass IRAK-4, including possibly TLR3 and TLR4, or from nonTLR pathways. About half of the young children succumbed to the bacterial infections. But the patients’ resistance improved with age, and older children consistently survived infections. The impact of IRAK-4 deficiency might fade as the adaptive immune network, particularly memory responses by T and B cells, kicks in later in life. It is unclear why IRAK-4 deficiency preferentially opens the door for some invasive bacteria but not other pathogens. The team has previously identified defects in other innate immunity factors that render patients susceptible to just one pathogen. A mechanistic explanation for this selectivity is yet to be found. Human dendritic cells that lack IRAK-4 (gray bars) do not produce inflammatory cytokines in response to most TLR signals.