This study investigated the possible mechanisms underlying the paradoxical caspofungin activity in vivo in preclinical aspergillosis. We evaluated the activity of escalating doses of caspofungin in vivo, in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. The therapeutic efficacy of caspofungin in experimental invasive aspergillosis was strictly dose-dependent, being observed at the doses of 0.1 and 1 mg/kg depending on the experimental models. Paradoxical increase in pulmonary fungal burden as well as inflammatory pathology was observed at the highest dose of caspofungin of 5 mg/kg, occurred independently from the 'Eagle effect' and susceptibility to caspofungin in vitro and was contingent upon the presence of TLR2, Dectin-1 and TLR9. Increased expression of Dectin-1 and TLR9 were observed upon the exposure to caspofungin in vitro and in vivo. Together, these findings suggest that the net activity of caspofungin in vivo is orchestrated by the activation, directly or indirectly, of multiple innate immune receptors.
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