The two cosegregating mutations, Thr399Ile and Asp299Gly, which occur in the ectoplasmic leucine-rich repeat domain of TLR4, are significantly associated with a reduced cytokine response to lipopolysaccharide stimulation [32] and increased susceptibility to a variety of infections [33,34] by affecting the extracellular domain of TLR4 [35]. Here, TLR4 is linked to infection.