Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis

Genetically determined responsiveness to microbial stimuli such as lipopolysaccharide (LPS) may affect the pathophysiology of human sepsis. The D299G mutation in human Toll-like receptor-4 (TLR4) impairs LPS signalling in homozygous and heterozygous individuals. To investigate whether the presence of the TLR4(D299G) mutation may correlate with the development or outcome of sepsis following major visceral surgery the presence of TLR4(D299G)mutation was analysed in 307 Caucasian patients (154 without and 153 with sepsis). Sepsis was caused in 84% of patients by polymicrobial infection. The presence of the mutant TLR4 did not significantly correlate with development or outcome of sepsis. Serum levels of tumour necrosis factor, interleukin (IL)-10, and IL-6 at sepsis onset did not significantly differ between patients carrying wild-type and mutant TLR4. Moreover, studies in a murine model of polymicrobial septic peritonitis demonstrated that TLR4-deficiency did neither influence the systemic cytokine response nor the development of organ injury. The results suggest that the signalling capacity of TLR4 as affected by loss-of-function mutations does not influence human or experimental sepsis caused by polymicrobial infection. Thus in polymicrobial infection, other innate immune receptors may compensate for TLR4 defects.