title: Cunninghamella bertholletiae exhibits increased resistance to human neutrophils with or without antifungal agents as compared to Rhizopus spp.
abstract: Among Zygomycetes, Cunninghamella bertholletiae occurs less frequently as the etiologic agent of human disease but causes more aggressive, refractory, and fatal infections despite antifungal therapy. Little is known about the differential innate host response against Cunninghamella and other Zygomycetes in the presence of antifungal agents. We therefore studied the activity of human neutrophils (PMNs) alone or in combination with caspofungin, posaconazole (PSC), and voriconazole (VRC) against hyphae of Rhizopus oryzae, Rhizopus microsporus and C. bertholletiae. Hyphal damage was measured by XTT metabolic assay and release of IL-6, IL-8 and TNF-alpha from PMNs by ELISA. Cunninghamella bertholletiae was more resistant to PMN-induced hyphal damage than either Rhizopus spp. at effector:target (E:T) ratios of 1:1, 5:1 and 10:1 (P < 0.05). The hyphal damage caused by caspofungin at 0.1 microg/ml or PSC and VRC at 0.5 microg/ml with C. bertholletiae and R. oryzae and by caspofungin against R. microsporus ranged from 18-29%. The PMN-induced hyphal damage was not modulated by combination with antifungal agents. Cunninghamella bertholletiae induced significantly decreased IL-8 (P < 0.05), but increased TNF-alpha release from PMNs compared to both Rhizopus spp. (P < 0.01). No IL-6 was released from PMNs exposed to the three Zygomycetes. In comparison to R. oryzae and R. microsporus, C. bertholletiae is more resistant to PMN-induced hyphal damage with or without antifungal therapy and is more capable of suppressing release of IL-8.
authors.affiliation: Laboratory of Infectious Diseases, 3rd Department of Pediatrics, Aristotle University, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Simitsopoulou
authors.forename: Elpiniki
authors.initials: E
authors.lastname: Georgiadou
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roilides
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D000077336:Caspofungin; D002478:Cells, Cultured; D020093:Cunninghamella / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D054714:Echinocandins / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D055666:Lipopeptides; D050296:Microbial Viability / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology*; D011743:Pyrimidines / Q000494:pharmacology; D012233:Rhizopus / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D015850:Interleukin-6; D016209:Interleukin-8; D055666:Lipopeptides; D011743:Pyrimidines; D013778:Tetrazolium Salts; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; C101425:posaconazole; D000077336:Caspofungin; D065819:Voriconazole