الفهرس 
taxonomy and descriptionOnly 14 pages are availabe for public view
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Abstract
Invasive pulmonary aspergillosis (IPA) is the most common form of aspergillosis causing high morbidity and mortality in high risk patients. Patients at risk include neutropenic and less commonly non-neutropenic patients. Research is needed to elucidate pathogenesis of aspergillosis and develop sensitive tests for early diagnosis. Alternative therapeutics are also required to reduce mortality as survival rates have barely improved in the last 30 years. We developed models of aspergillosis in neutropenic and non-neutropenic hosts, as tools to facilitate studies of aspergillosis and development of improved diagnostics and therapeutics. Rats were chosen as primary hosts as they are less expensive, easy to handle and do not need specialized housing. Larger size allows collection of daily blood samples to monitor the animals longitudinally avoiding animal to animal variation. Infection by inhalation more closely recapitulates human disease. We used the models to assess clinically relevant diagnostic tools of IPA (CFU, RT-PCR, RT-rtPCR, GMI) and efficacy of antifungal drugs. Both models, showed progression of disease by lung histology, RT-PCR, RT-rtPCR and GMI, but burdens assessed by culture were poorly predictive. IPA pathogenesis varied between models which reflects observations in humans. In neutropenia, lung parenchyma was invaded by dense Aspergillus hyphae, with high burdens and few neutrophils but low burdens in bronchoalveolar lavage (BAL) indicating less airway localization but higher quantities of Aspergillus derived molecules transferring to the blood. In contrast, A. fumigatus in nonneutropenic lung was limited by overwhelming infiltration of inflammatory cells with airway localization, higher BAL burden and lower lung invasion, with little fungus derived material detected in blood. Diagnostics based on BAL samples had higher sensitivity in non-neutropenic compared to neutropenic models, with positive signals preceding clinical diagnosis. In contrast, blood was the best sample in neutropenic rats with positive GMI preceding clinical signs. All three non-culture methods reflected the progression of infection seen in lung histology, whilst culture did not reflect the changing in fungal burden highlighting the limitation of convention culture in A. fumigatus burden quantification. Posaconazole was effective in reducing the burden and improving survival in both models, caspofungin and amphotericin B had poor efficacy, whilst AmBisome improved animal survival in non-neutropenic model. Amphotericin B was also assessed in a mouse infected IV and by aerosol and was more effective at reducing kidney than lung burdens due to different pharmacokinetics at the target organ. In summary, the models will be useful in studying IPA as they closely recapitulate human infection providing data that is comparable to other models. The neutropenic and non neutropenic backgrounds reflect the human at risk groups. BAL is the best non-invasive sample for diagnosis in non-neutropenic hosts, whilst in neutropenic rats, GMI had high sensitivity. Posaconazole therapy was effective regardless of immune status in contrast to amphotericin B in which the outcome differed dependent on the target organ.