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This study investigated the possible mechanisms underlying the paradoxical caspofungin activityin vivo in preclinical aspergillosis. We evaluated the activity of escalating doses of caspofunginin 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 doses of 0.1 and 1 mg/kg of body weight depending on the experimental models. Paradoxical increase in pulmonary fungal burden as well as inflammatory pathology was observed at the highest dose of caspofungin (5 mg/kg), occurred independently of the so-called Eagle effect and susceptibility to caspofunginin vitro , and was contingent upon the presence of TLR2, Dectin-1, and TLR9. Increased expression of Dectin-1 and TLR9 were observed upon exposure to caspofunginin vitro andin vivo . Together, these findings suggest that the net activity of caspofunginin vivo is orchestrated by the activation, directly or indirectly, of multiple innate immune receptors.

Role of Innate Immune Receptors in Paradoxical Caspofungin ActivityIn Vivoin Preclinical Aspergillosis