title: Gamma interferon dominates the murine cytokine response to the agent of human granulocytic ehrlichiosis and helps to control the degree of early rickettsemia.
abstract: The cytokine response to the agent of human granulocytic ehrlichiosis (HGE) was assessed in a murine infection model and the role of gamma interferon (IFN-gamma), a cytokine that is crucial for host defenses against intracellular pathogens, was investigated by using IFN-gamma-deficient mice. The agent of HGE (aoHGE) is an obligate intracellular bacterium that survives within neutrophils: morulae (vacuoles containing HGE organisms) are evident in polymorphonuclear leukocytes of experimentally infected immunocompetent mice for 1 to 2 weeks. We now show that IFN-gamma levels increase during early infection of C3H/HeN or C57BL/6 mice with HGE bacteria. Moreover, in response to aoHGE extracts or concanavalin A, splenocytes from ehrlichia-infected mice produced more IFN-gamma and less interleukin-4 than controls, suggesting that aoHGE partially skewed the immune response towards a Th1 phenotype. Absolute concentration of morulae containing neutrophils in blood was 122 +/- 22 cells/microliter on day 8. The bacterial DNA burden was also highest on day 8 and then declined after IFN-gamma levels peaked. In contrast, IFN-gamma-deficient mice had a markedly elevated HGE bacteria burden with morulae concentration of 282 +/- 48 cells/microliter on day 5 (P = 0.004) and 242 +/- 63 cells/microliter on day 8 (P = 0.005). Rickettsemia resolved in immunocompetent and IFN-gamma deficient mice after 2 weeks, while both the immunocompetent and the IFN-gamma-deficient mice had increased serum antibodies against aoHGE antigens at this time point. These data demonstrate that the HGE agent elicits a prominent IFN-gamma response in mice and that IFN-gamma is important in controlling the degree of rickettsemia during the early phase of infection, while IFN-gamma independent mechanisms play a role at later time points.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
authors.forename: M
authors.initials: M
authors.lastname: Akkoyunlu
authors.forename: E
authors.initials: E
authors.lastname: Fikrig
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000276:immunology*; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D016873:Ehrlichiosis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D009504:Neutrophils / Q000382:microbiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012281:Rickettsia / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D013997:Time Factors
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D003208:Concanavalin A; D007371:Interferon-gamma