Abstract
Candida spp. adhere to medical devices, such as catheters, forming drug-tolerant biofilms that resist killing by the immune system. Little is known about how C. glabrata, an emerging pathogen, resists attack by phagocytes. Here we show that upon encounter with planktonic (non-biofilm) C. glabrata, human neutrophils initially phagocytose the yeast and subsequently release neutrophil extracellular traps (NETs), complexes of DNA, histones, and proteins capable of inhibiting fungal growth and dissemination. When exposed to C. glabrata biofilms, neutrophils also release NETs, but significantly fewer than in response to planktonic cells. Impaired killing of biofilm parallels the decrease in NET production. Compared to biofilm, neutrophils generate higher levels of reactive oxygen species (ROS) when presented with planktonic organisms, and pharmacologic inhibition of NADPH-oxidase partially impairs NET production. In contrast, inhibition of phagocytosis nearly completely blocks NET release to both biofilm and planktonic organisms. Imaging of the host response to C. glabrata in a rat vascular model of infection supports a role for NET release in vivo. Taken together, these findings show that C. glabrata triggers NET release. The diminished NET response to C. glabrata biofilms likely contributes to the resilience of these structured communities to host defenses.
Highlights
The most common nosocomial fungal pathogen, Candida, causes disseminated, invasive disease with mortality near 35%1–3
We examined the neutrophil response to a variety of C. glabrata concentrations, representing E:T ranging from 2:5 to 1:30
neutrophil extracellular traps (NETs)-associated calprotectin has been shown to be critical for the killing of C. albicans in vitro and for the clearance of candidiasis in murine models of infection[22]
Summary
The most common nosocomial fungal pathogen, Candida, causes disseminated, invasive disease with mortality near 35%1–3. Non-biofilm C. albicans, they release neutrophil extracellular traps (NETs), which are webs of DNA, histones, and proteins with antifungal activity[19,20,21,22] These structures can prevent pathogen dissemination and kill organisms too large to be phagocytosed[19,20]. The impaired neutrophil function was linked to the biofilm matrix, the fungal-produced extracellular material that coheres cells within the biofilm and protects them from external insults[12,23] The composition of this material varies significantly among Candida spp. and it remains a mystery if other species employ this mechanism to resist killing by neutrophils[24,25,26,27]. We investigate the neutrophil response to C. glabrata during planktonic and biofilm growth and identify stark differences compared to C. albicans
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