MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

A diagnostic signature for sepsis caused by Burkholderia pseudomallei infection was identified from transcriptional profiling of the blood of septicemia patients.

Septicemia is the most severe form of melioidosis caused by the Gram-negative bacterium, Burkholderia pseudomallei. Here, we showed that levels of IL-27p28 transcript and protein were both significantly elevated in patients with sepsis, particularly melioidosis and in patients with unfavorable disease outcome. Moreover, monocytes/macrophages and neutrophils were the major source of IL-27 during infection. Addition of exogenous IL-27 in vitro resulted in significantly increased bacterial survival, reduced B. pseudomallei-induced oxidative burst and enhanced IL-1beta and TNF-alpha production by purified neutrophils from healthy subjects. Finally, blockade of endogenous IL-27 in neutrophils using soluble IL-27 receptor antagonist prior to infection led to significantly reduced survival of bacteria and decreased IL-1beta, but not TNF-alpha production. These results indicate a potential role of IL-27 in suppression of antibacterial defense mechanisms that might contribute to disease severity in sepsis. The targeting of this cytokine may be beneficial in the management of human sepsis.

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