Tuberculosis, malaria, and invasive bacterial disease together account for more than 5 million deaths annually in the developing world. Although a significant proportion of interindividual variation in disease susceptibility can be attributed to environmental factors such as malnutrition and infection with the human immunodeficiency virus (HIV), a substantial portion is unexplained. Comparative studies involving twins and adopted persons suggest a genetic component,1 and genes that, when mutated, result in primary immunodeficiency states have been identified. Such immunodeficiencies are extremely rare, however, and the current understanding of common host genetic factors influencing susceptibility to major infectious diseases at the population level is limited.

A principal feature of the host immune response to infection by structurally diverse pathogens is the inflammatory cytokine response.2-4 The proinflammatory cytokine interleukin-2 determines the magnitude and duration of the T-cell response immediately after antigen encounter5 and assists in the maturation of macrophages and the proliferation of B cells and natural killer cells6 in the early stages of the adaptive immune response. Interleukin-2 also regulates the evolution of memory T cells after resolution of infection.7 An excessive cytokine-mediated inflammatory response can be harmful to the host, resulting in severe forms of malaria and sepsis.8-11

Control of cytokine signaling in humans is mediated in part by negative feedback from the suppressor of cytokine signaling (SOCS) family of proteins. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH) was the first member of the SOCS family to be described.12,13 CISH is the gene most consistently up-regulated by interleukin-2 stimulation in humans,14 and it appears to be critical for T-cell proliferation and survival15 in response to infection. CISH controls the signaling of a variety of cytokines, in particular interleukin-2. Unlike the other members of the SOCS family, CISH binds to the phosphorylated tyrosine residues of cytokine receptors and masks sites at which the signal transducer and activator of transcription 5 (STAT5) would otherwise dock.12,16-19 Thus, increased CISH activity blocks the cytoplasmic docking and activation of STAT5 and thereby inhibits downstream cytokine signaling. Given the central role of CISH in controlling interleukin-2 signaling, we hypothesized that variation in CISH influences susceptibility to common infectious diseases.