Gamma interferon dominates the murine cytokine response to the agent of human granulocytic ehrlichiosis and helps to control the degree of early rickettsemia

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 intracell ular pathogens, was investigated by using IFN-gamma-deficient mice. The age nt of HGE (aoHGE) is an obligate intracellular bacterium that survives with in neutrophils: morulae (vacuoles containing HGE organisms) are evident in polymorphonuclear leukocytes of experimentally infected immunocompetent mic e 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 respo nse to aoHGE extracts or concanavalin A, splenocytes from ehrlichia-infecte d mice produced more IFN-gamma and less interleukin-4 than controls, sugges ting that aoHGE partially skewed the immune response towards a Th1 phenotyp e. Absolute concentration of morulae containing neutrophils in blood was 12 2 +/- 22 cells/mu l on day 8, The bacterial DNA burden was also highest on day 8 and then declined after IFN-gamma levels peaked. In contrast, IFN-gam ma-deficient mice had a markedly elevated HGE bacteria burden with morulae concentration of 282 +/- 48 cells/mu l on day 5 (P = 0.001) and 242 +/- 63 cells/mu l on day 8 (P = 0.005). Rickettsemia resolved in immunocompetent a nd IFN-gamma deficient mice after 2 weeks, while both the immunocompetent a nd the IFN-gamma-deficient mice had increased serum antibodies against aoHG E antigens at this time point. These data demonstrate that the HGE agent el icits a prominent IFN-gamma response in mice and that IFN-gamma is importan t in controlling the degree of rickettsemia during the early phase of infec tion, while IFN-gamma independent mechanisms play a role at later time poin ts.