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Cytokine Signaling and Susceptibility to Infectious Diseases
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: In a case-control study, an association between several cytokine-inducible SRC homology 2 (CISH) polymorphisms and susceptibility to bacteremia, severe malaria, and tuberculosis was observed. The overall risk of one of these infectious diseases was increased by > 18% among persons carrying CISH alleles.
Source: Khor CC, et al. CISH and susceptibility to infectious diseases. N Engl J Med. 2010;362:2092-2101.
In this study, 8,402 patients from seven case-control series were examined in this trial. The series included Kenyan children with bacteremia, patients with tuberculosis (TB) in Malawi, Hong Kong, and Gambia, and patients with severe malaria in Gambia, Kenya, and Vietnam. Standard methods for genotyping selected genes in PBMCs were employed. Gene expression following IL-2 and IL-3 stimulation was also done with extracted RNA, then quantified using real-time PCR of complementary DNA. Five single nucleotide polymorphisms (SNPs) were identified within the CISH-associated locus, which, considered together in a multiple-SNP score, were highly associated (p = 3.8x10 e-11) with susceptibility to bacteremia, severe malaria, and TB. The SNP at -292 accounted for most of the association (p = 4.58x10e-7). PBMC stimulation of cells containing the -292 SNP, as compared to wild type cells, showed a muted response to IL-2, with 25%-40% less CISH expression.
The complex and overlapping components of the human immune system (encompassing humoral and cellular immunity, cytokines and chemokines, the complement system, and the innate immune system) generally functions as a beautiful machine, protecting our bodies from most pathogens. While individual pathogens are relatively easily shown to vary in degree of pathogenicity (and pathogenic factors identified), differences in individual response of the host to specific pathogens are much more difficult to tease out.
The IL-2-mediated immune response is critical for host defense against many infectious agents. CISH domain protein is a suppressor of cytokine signaling (SOCS), and specifically controls IL-2 signaling. CISH is encoded on chromosome 3. Khor et al have taken advantage of the huge dataset (8402 patients) available from seven case-control studies of three diseases of huge global health importance.
While far from the definitive word on host factors affecting clinical outcome in bacteremia, severe malaria, and TB, this large, strongly powered study sheds some light on at least one plausible mechanism responsible for adverse outcomes of these three diseases in at least some patients. One of the paradoxes of the human immune response to many pathogens is the fine line that the host must walk in promptly recognizing and controlling infectious diseases vs. an overly vigorous immune response, which can lead to more severe illness and death.
In the conclusion of the paper, the authors speculate that pharmacologic manipulation of the SOCS pathway may have an effect on the treatment of multiple diverse infectious diseases. While only a few pharmacologic interventions targeting the host in the setting of infection have actually panned out, (and I am generally skeptical of targeting the host rather than the pathogen), the study represents some good basic science and sheds light on one mechanism contributing to adverse outcomes in a broad spectrum of infectious diseases.