- none, +/- minimal, + mild, ++ moderate, +++ marked, ++++ severe Cortisone acetate treatment versus the combination of cortisone acetate and clodrolip As shown in Figure 1C, 2 (inlet) and 6, mice treated with cortisone acetate (Figure 6A-B) or the combination of cortisone acetate and clodrolip (Figure 6C-D) displayed the highest peak of lung luminescence between day one and day two post infection. Both treatment groups experienced 100% mortality five to six days after infection. In addition to the thoracic region, a significant luminescence was observed from the abdomen of all infected Smoothened Agonist research buy mice. However, the abdominal signal declined rapidly and therefore was unlikely to result from

fungal dissemination. This was confirmed in histology, by the absence of fungal CFU from the liver, spleen, stomach, and kidneys (data not shown). Therefore, it is likely that some conidia were swallowed and maintained for some

time within the RAD001 nmr intestinal tract without manifestation of an infection. In contrast, a luminescence signal from the sinus regions has been observed in 20% of infected mice. This signal steadily increased and peaked during the terminal survival phase of illness (Figure 6E). In parallel with the bioluminescence increase from the sinus region, these infected mice became ataxic and displayed a disturbance in equilibrium. These data demonstrate that bioluminescence imaging can detect signals from extrathoracic sites. Figure 6 Bioluminescence enables detection of thoracic and extra thoracic signals in cortisone acetate treated mice. (A): Time Histidine ammonia-lyase response study of luminescence DZNeP emission from mice immunosuppressed either with cortisone acetate (A, B) or with a combination of cortisone acetate and clodrolip (C-E). Mice were intranasally infected with 2 × 106 conidia. A cohort of 10 mice received liposomes as a control prior to infection (F). Images of day one (D1) and two (D2) post-infection are shown. Luminescence was monitored 10 min after intraperitoneal injection of D-luciferin. Images from ventral (V) and dorsal (D) views of the sinus region, six

days after infection (D6) of mice treated with both, cortisone acetate and clodrolip, are shown (E). The graph in (G) represents the average of the total photon flux measured from a defined thoracic region from each individual animal of the respective cohort. (H): Time course of total luminescence from chest, abdomen and head regions from animals receiving the combination of cortisone acetate and clodrolip. Neutrophils encircle A. fumigatus conidia and limit their infiltrative potential, but fail to prevent their germination under corticosteroid-treatment For histopathological analysis, five mice were sacrificed one day post-infection to visualise fungal outgrowth and the immune response in the early phase of infection.