Pharmacodynamic and immunomodulatory effects of micafungin on host responses against biofilms of Candida parapsilosis in comparison to those of Candida albicans
Antimicrobial Agents and Chemotherapy, Accepted manuscript posted online 4 June 2018, doi: 10.1128/AAC.00478-18
Yimin Fang, Cristal M. Hill, Justin Darcy, Adriana Reyes-Ordoñez, Edwin Arauz, Samuel McFadden, Chi Zhang, Jared Osland, John Gao, Tian Zhang, Stuart J. Frank, Martin A. Javors, Rong Yuan, John J. Kopchick, Liou Y. Sun, Jie Chen, and Andrzej Bartke
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Micafungin (MFG) demonstrates potent activity against biofilms of Candida albicans and Candida parapsilosis, the most frequent opportunistic fungal pathogens. Little is known about its immunopharmacological effect on antibiofilm activity of phagocytic cells following exposure to Candida biofilms. In this study, we investigated the effects of MFG on human neutrophil-mediated damage of C. albicans and C. parapsilosis biofilms by XTT and the potential mechanisms underlying the immunomodulatory MFG activities on cultured monocyte-derived THP-1 cells in response to these biofilms by RT-PCR, sandwich and multiplex ELISA. Pre-exposure of C. albicans to subinhibitory MFG concentrations significantly enhanced neutrophil-mediated biofilm damage, an effect that appears to be species-specific as a comparable effect was not observed with drug-pretreated C. parapsilosis biofilms. Human THP-1 cells responded to both Candida biofilms through TLR2 and TLR4 up-regulation, modest TLR6 involvement and enhanced NLRP3 activation, whereas the signal was relayed to the nucleus via NF-κB p65 activation. MFG caused 2- to 3-fold lower TLR2 and TLR4 mRNA levels compared to those caused by either organism. C. albicans biofilms induced a robust proinflammatory response, whereas C. parapsilosis biofilms either alone or in the presence of MFG caused increased IL-1β production, but low amounts of IL-8, IL-23 and TNF-α. In conclusion, MFG may condition THP-1 cells towards an inflammatory response through TLR2/TLR4 recruitment. Inflammatory signals observed with C. albicans biofilms, are considerably reduced upon exposure of THP-1 cells to C. parapsilosis biofilms possibly enhancing fungal survival and increasing biofilm pathogenicity.