Acute Q fever is the disease manifestation of Coxiella burnetii infection. This obligate intracellular bacterium is phagocytosed by innate immune cells, where it replicates within the usually bactericidal environment of the phagolysosome. As the immune response is activated, the resultant pro-inflammatory cytokines aid in pathogen clearance but also trigger an acute sickness response in the host. This thesis describes the natural history of acute Q fever in a prospective cohort ??? the Dubbo Infection Outcomes Study (DIOS). In these subjects, the acute febrile illness was characterised by severe headache, drenching sweats and fatigue. In approximately 10% of subjects, symptomatic illness marked by fatigue remained present for months, or occasionally years, after the acute illness. Subjects with more severe acute illness were more likely to develop this post Q fever fatigue syndrome (QFS). The aim of this thesis was to determine whether ongoing infection or aberrant immune activation drive the prolonged symptoms of QFS. Sensitive real time PCR detection of Coxiella DNA revealed a significant minority of subjects had very low copy numbers in circulating monocytes, with an increased prevalence in those with QFS. However, the detection was not consistently found within individual subjects and the copy number was at the threshold of reliable detection. C. burnetii was shown here to stimulate cytokine production in monocytic cells via interaction with Toll-like receptor (TLR)-2 and not TLR-4. Functional polymorphisms in these TLRs were identified in subjects with Q fever, but were not associated with Q fever susceptibility, severity or duration. Phase I-specific responses are believed to be critical in the generation of protective immunity to C. burnetii, yet the phase II-specific responses of innate and adaptive immune components were consistently of higher magnitude. Whole C. burnetii organisms induced antigen-non-specific T cell activation, presumably via the indirect activation of monocytes by C. burnetii LPS. No significant differences were found in the magnitude or kinetics of the host response to infection, or in the carriage of genetic polymorphisms, when comparing subjects who developed QFS with subjects who had promptly resolving illness. It remains unclear what factors mediate the progression of acute Q fever to QFS.
| Identifer | oai:union.ndltd.org:ADTP/282061 |
| Date | January 2010 |
| Creators | Everett, Beth Jennifer, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Everett Beth Jennifer., http://unsworks.unsw.edu.au/copyright |
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