Role of innate immune receptors in paradoxical caspofungin activity in vivo in preclinical aspergillosis.
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 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 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 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.
Department of Experimental Medicine and Biochemical Science, University of Perugia, Perugia, Italy.
Silvia
S
Moretti
Silvia
S
Bozza
Carmen
C
D'Angelo
Andrea
A
Casagrande
Maria Agnese
MA
Della Fazia
Lucia
L
Pitzurra
Luigina
L
Romani
Franco
F
Aversa
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects; D000077336:Caspofungin; D054714:Echinocandins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D055666:Lipopeptides; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D011971:Receptors, Immunologic / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D000099181:Dectin-1
D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D037181:Lectins, C-Type; D055666:Lipopeptides; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D000099181:Dectin-1; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse