The main objective of the proposed study is to determine the mechanism of killing Ehrlichia chaffeensis in interferon gamma (IFN-gamma) activated human monocytes. E. chaffeensis is an obligate intracellular bacterium which infects monocytes and macrophages and is the etiologic agents of human ehrlichiosis. The clinical signs associated with this disease are; fever, headache, myalgia, nausea, vomiting, and a rash in some instances. The severity of human ehrlichiosis ranges from asymptomatic infection to severe morbidity and death in some cases. We found that ehrlichial species are extremely sensitive to cytoplasmic iron depletion and IFN-gamma-activated monocytes inhibit infection by Ehrlichia chaffeensis (39). our hypothesis for inhibitory mechanisms by IFN-gamma is that IFN-gamma causes the down-regulation of surface transferrin receptors which limits the availability of intracellular iron to the Ehrlichia which then induces acidification and lysosomal fusion of Ehrlichial inclusions. However, we also found that once infection is established, infected monocytes become refractory to IFN-gamma treatment (39). our hypothesis for this resistance is that ehrlichiae inhibit the signal transduction cascade induced by IFN-gamma. To test these two hypotheses the following aims will be examined.
| Barnewall, R E; Ohashi, N; Rikihisa, Y (1999) Ehrlichia chaffeensis and E. sennetsu, but not the human granulocytic ehrlichiosis agent, colocalize with transferrin receptor and up-regulate transferrin receptor mRNA by activating iron-responsive protein 1. Infect Immun 67:2258-65 |
