Abstract
Invasive candidiasis frequently involves medical device placement. On the surfaces of these devices, Candida can form biofilms and proliferate in adherent layers of fungal cells surrounded by a protective extracellular matrix. Due in part to this extracellular matrix, biofilms resist host defenses and antifungal drugs. Previous work (using neutrophils from healthy donors) found that one mechanism employed to resist host defenses involves the inhibition of neutrophil extracellular traps (NET) formation. NETs contain nuclear DNA, as well as antimicrobial proteins that can ensnare pathogens too large or aggregated to be effectively killed by phagocytosis. Given that these neutrophil structures are anticipated to have activity against the large aggregates of C. albicans biofilms, understanding the role of this inhibition in patients could provide insight into new treatment strategies. However, prior work has not included patients. Here, we examine NET formation by neutrophils collected from patients with invasive candidiasis. When compared to neutrophils from healthy participants, we show that patient neutrophils exhibit a heightened background level of NET release and respond to a positive stimulus by producing 100% more NETs. However, despite these physiologic differences, patient neutrophil responses to C. albicans were similar to healthy neutrophils. For both groups, planktonic cells induce strong NET release and biofilms inhibit NET formation. These results show that a mechanism of immune evasion for fungal biofilms translates to the clinical setting.
Highlights
Candida albicans, a widespread nosocomial fungal pathogen, is an avid biofilm-former and a frequent cause of invasive fungal infection [1]
Neutrophils from patients with invasive candidiasis trended toward a higher background level of neutrophil extracellular traps (NET) release, but this did not reach statistical significance
We examined neutrophil responses to phorbol myristate acetate (PMA), a strong inducer of NETs
Summary
A widespread nosocomial fungal pathogen, is an avid biofilm-former and a frequent cause of invasive fungal infection [1]. Candida biofilms infections are notoriously difficult to treat, as they resist high levels of antifungal drugs and withstand host defenses [3,4,5,6,7,8,9,10]. Despite advancements in antifungal therapies and diagnostics, the mortality for Candida-associated bloodstream infection remains exceedingly high, near 30% [1, 11]. In the clinical setting, neutrophils are ineffective at controlling Candida device-associated biofilm infections. Eradication of infection most often requires device removal, even for patients with normal numbers of neutrophils [11]. Mortality rates increase for patients when biofilm-infected devices are retained [1, 11]
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