This proposal seeks to continue identificstion and roles of factors responsible for the pathobiological events in Q fever. We have previously demonstrated several of these in guinea pigs or L-cells infected with Coxiella burnetii, the rickettsioid agent of Q fever (Fig. 1). Prominent in the pathobiology of infected guinea pig liver are: stimulated synythesis of RNA and protein, coincident with increased phosphorylation of non-histone chromatin protein (NHCP) and ribosomal protein, increased nuclear phosphoprotein kinase activity, and elevated levels of cortisol, cyclic AMP and polyamines. We propose a model (Fig. 2) in which levels of cAMP, polyamines, cortisol and glucagon increase in response to infection, triggering a series of interdependent reactions resulting in stimulated RNA and protein synthesis, and other previously demonstrated features of Q fever pathobiology. We plan to extend these findings: 1. to the identification and role of spermine-dependent and -independent, and cyclic mononucletide-dependent and -independent cytoplasmic and nuclear phoshoprotein kinases whose activities increase by infection; 2. to study interrelations of phosphatase and protein kinase mediated reactions as related to phosphorylation of NHCP and ribosmal protein in infection-stimulated synthesis of RNA and protein; 3. to determine what, if any, is the significance of ribosomal protein phosphorylation induced by infection and the role in stimulated translation; 4. to resume previous studies on the effects of C. burnetii lipopolysaccharide (LPS) on guinea pigs and cultured cells. (Our laboratory was first to isolate and characterize this LPS); 5. to see whether infection and/or LPSs imulates glucagon secretion, suggested by observed glycogenolysis, inhibited glucogen synthase, and stimulated phosphorylase and lipase activities. Elucidating the nature and regulation of pathobiological change induced by the Q fever models may aid in clarifying similar events in other types of infectious and non-infectious diseases.
| Picking, W D; Hackstadt, T; Paretsky, D (1990) The effect of rickettsial lipopolysaccharide and insulin on S6 phosphorylation in guinea pig liver and HepG2 cells. Ann N Y Acad Sci 590:118-26 |
| Picking, W D; Hackstadt, T; Paretsky, D (1989) Endotoxicosis induced by Coxiella burnetii lipopolysaccharide stimulates a ribosomal protein S6 kinase: some properties of the partially purified enzyme. Infect Immun 57:3683-8 |
| Hickey, M J; Gonzales, F R; Paretsky, D (1985) Ribosomal protein phosphorylation induced during Q fever or by lipopolysaccharide: in vitro translation is stimulated by infected liver ribosomes. Infect Immun 48:690-6 |
