Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection.

BACKGROUND Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored. METHODS We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus. RESULTS We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes. CONCLUSIONS These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.

[1]  S. Miller,et al.  Glial toll-like receptor signaling in central nervous system infection and autoimmunity , 2008, Brain, Behavior, and Immunity.

[2]  I. Hickie,et al.  Postinfective fatigue syndrome is not associated with altered cytokine production. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  M. Jacobson,et al.  Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects. , 2007, European cytokine network.

[4]  F. Crews,et al.  Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration , 2007, Glia.

[5]  L. Teyton,et al.  Interleukin-10 determines viral clearance or persistence in vivo , 2006, Nature Medicine.

[6]  Jenefer M Blackwell,et al.  Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better? , 2006, The Lancet Infectious Diseases.

[7]  I. Hickie,et al.  Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study , 2006, BMJ : British Medical Journal.

[8]  Man Wai Ng,et al.  The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome , 2006, BMC infectious diseases.

[9]  I. Hickie,et al.  Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. , 2006, The Journal of infectious diseases.

[10]  G. E. Etokebe,et al.  Interferon‐γ Gene (T874A and G2109A) Polymorphisms Are Associated With Microscopy‐positive Tuberculosis , 2006, Scandinavian journal of immunology.

[11]  E. Abraham,et al.  GENETIC POLYMORPHISMS AND SEPSIS , 2005, Shock.

[12]  A. Randolph,et al.  Genetic polymorphisms in sepsis , 2005, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[13]  D. Posthuma,et al.  Heritability estimates of innate immunity: an extended twin study , 2005, Genes and Immunity.

[14]  I. Hickie,et al.  Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans , 2004, Psychological Medicine.

[15]  M. Ebell.  Epstein-Barr virus infectious mononucleosis. , 2004, American family physician.

[16]  S. Opdal,et al.  IL-10 gene polymorphisms in infectious disease and SIDS. , 2004, FEMS immunology and medical microbiology.

[17]  K. Schroder,et al.  Interferon‐γ: an overview of signals, mechanisms and functions , 2004 .

[18]  G. Raghu,et al.  A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. , 2004, The New England journal of medicine.

[19]  T. Murakami,et al.  Simultaneous measurement of T-helper 1 cytokines in tuberculous pleural effusion. , 2003, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[20]  N. Hunt,et al.  Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. , 2003, Trends in immunology.

[21]  S. Maier.  Bi-directional immune–brain communication: Implications for understanding stress, pain, and cognition , 2003, Brain, Behavior, and Immunity.

[22]  W. Doyle,et al.  Cytokine gene polymorphisms moderate illness severity in infants with respiratory syncytial virus infection. , 2003, Human immunology.

[23]  N. Webster,et al.  Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients* , 2003, Critical care medicine.

[24]  M. O’Donovan,et al.  DNA Pooling: a tool for large-scale association studies , 2002, Nature Reviews Genetics.

[25]  R. Dantzer,et al.  Cytokine-induced sickness behaviour: mechanisms and implications , 2002, Trends in Neurosciences.

[26]  D. Harlan,et al.  ASSOCIATION OF CYTOKINE POLYMORPHIC INHERITANCE AND IN VITRO CYTOKINE PRODUCTION IN ANTI-CD3/CD28-STIMULATED PERIPHERAL BLOOD LYMPHOCYTES1 , 2001, Transplantation.

[27]  U. Vollmer-Conna.  Acute sickness behaviour: an immune system-to-brain communication? , 2001, Psychological Medicine.

[28]  I. Hickie,et al.  Development of a simple screening tool for common mental disorders in general practice , 2001, The Medical journal of Australia.

[29]  G. Marks,et al.  Asthma and hayfever in Aboriginal and non‐Aboriginal children living in non‐remote rural towns , 2001, The Medical journal of Australia.

[30]  A. Stevens,et al.  A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. , 2000, Human immunology.

[31]  S. D'alfonso,et al.  New polymorphisms in the IL-10 promoter region , 2000, Genes and Immunity.

[32]  Ching Li,et al.  A Defect in Interleukin-10 Leads to Enhanced Malarial Disease in Plasmodium chabaudi chabaudi Infection in Mice , 1999, Infection and Immunity.

[33]  M. Hurme,et al.  Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein-Barr virus infection. , 1999, The Journal of infectious diseases.

[34]  C. Hunter,et al.  Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii , 1997, Infection and immunity.

[35]  A. Sher,et al.  In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. , 1996, Journal of immunology.

[36]  F. Sisay-Joof,et al.  Genetic regulation of fever in Plasmodium falciparum malaria in Gambian twin children. , 1995, The Journal of infectious diseases.

[37]  N. Rothwell,et al.  Cytokines and the nervous system II: actions and mechanisms of action , 1995, Trends in Neurosciences.

[38]  Steven F. Maier,et al.  Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication , 1995, Neuroscience Letters.

[39]  T. Mosmann,et al.  IL-10 inhibits cytokine production by activated macrophages. , 1991, Journal of immunology.

[40]  C G Figdor,et al.  Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes , 1991, The Journal of experimental medicine.

[41]  B. Hart.  Biological basis of the behavior of sick animals , 1988, Neuroscience & Biobehavioral Reviews.

[42]  P. Andersen,et al.  Genetic and environmental influences on premature death in adult adoptees. , 1988, The New England journal of medicine.

[43]  L. García,et al.  Cytokine gene polymorphisms in Colombian patients with different clinical presentations of tuberculosis. , 2006, Tuberculosis.

[44]  Dean T. Jamison,et al.  Measuring the Global Burden of Disease and Risk Factors, 1990–2001 , 2006 .

[45]  W. Doyle,et al.  Cytokine gene polymorphisms moderate responses to respiratory syncytial virus in adults. , 2003, Human immunology.

[46]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[47]  J. Andersson.  Clinical and immunological considerations in Epstein-Barr virus-associated diseases. , 1996, Scandinavian journal of infectious diseases. Supplementum.

[48]  T. Bártfai,et al.  Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. , 1993, Brain research.

[49]  John E. Bennett,et al.  Principles and practice of infectious diseases. Vols 1 and 2. , 1979 .