Our results suggest that neutrophils, rather than AM, play an indispensable role in host defense against A. fumigatus. Results Pathogenesis of invasive aspergillosis following different immunosuppression regimens Different immunosupression regimens were

used to study their impact on murine survival, the development of invasive aspergillosis (IA), and on fungal growth and dissemination, using the bioluminescent A. fumigatus strain C3 [16]. Immune MLN2238 mw competent mice manifested a transient weight loss on the day of infection (Figure 1A) and uniformly survived the infection (Figure 1B). As expected, mice treated with the alkylating agent cyclophosphamide or the glucocorticoid cortisone acetate died within five days after infection (Figure 1B) and progressive infection was accompanied by ongoing weight loss (Figure 1A). Both treatments are frequently used for testing the virulence of A. fumigatus and these results confirmed the virulence of bioluminescent strain C3 in different infection models. Figure 1 Clodrolip treated mice are not susceptible to A. fumigatus intranasal infection. In each experiment, groups of 5 mice were treated either with cortisone PLX4032 molecular weight acetate, cyclophosphamide, RB6-8C5 antibody, or

clodrolip prior to intranasal infection with 2 × 106 conidia of the luminescent A. fumigatus strain C3. Untreated infected mice are designated as immnocompetent (IC). Weight loss and survival were monitored for 8 days (A and B). (C): Time response study of luminescence emission from chest region 10 min after intraperitoneal injection of D-luciferin. Light emission from live animals was recorded for 5 min. Each point represents the average from 3 independent AZD1390 clinical trial experiments Thymidylate synthase of the total photon flux measured from a defined thoracic region from each individual animal of the respective cohort (5 mice). (D): Light emission from the lung of a dead animal immunosuppressed with cortisone acetate following direct injection of D-luciferin. A total photon flux/second of 3.744 × 106 has been measured using the living image software 3.1 after 1 min exposure. Neutrophils

were depleted by using the monoclonal antibody RB6-8C5, which binds the myeloid differentiation antigen Gr-1 and leads to neutropenia lasting for three to four days at the dose administered in our experiments [17]. In agreement with prior studies, transient neutropenia was sufficient to cause lethal pulmonary aspergillosis (Figure 1B) [17]. However, weight loss of mice treated with RB6-8C5 was less pronounced than observed with the other immunosuppressive regimens (Figure 1A). We also targeted resident alveolar macrophages by intranasal instillation of liposomes containing clodronate (clodrolip). Phagocytosis of clodrolip leads to an intracellular accumulation of clodronate and the induction of macrophage apoptosis [18].