The Extracellular Matrix of Candida albicans Biofilms Impairs Formation of Neutrophil Extracellular Traps.
Neutrophils release extracellular traps (NETs) in response to planktonic C. albicans. These complexes composed of DNA, histones, and proteins inhibit Candida growth and dissemination. Considering the resilience of Candida biofilms to host defenses, we examined the neutrophil response to C. albicans during biofilm growth. In contrast to planktonic C. albicans, biofilms triggered negligible release of NETs. Time lapse imaging confirmed the impairment in NET release and revealed neutrophils adhering to hyphae and migrating on the biofilm. NET inhibition depended on an intact extracellular biofilm matrix as physical or genetic disruption of this component resulted in NET release. Biofilm inhibition of NETosis could not be overcome by protein kinase C activation via phorbol myristate acetate (PMA) and was associated with suppression of neutrophil reactive oxygen species (ROS) production. The degree of impaired NET release correlated with resistance to neutrophil attack. The clinical relevance of the role for extracellular matrix in diminishing NET production was corroborated in vivo using a rat catheter model. The C. albicans pmr1Δ/Δ, defective in production of matrix mannan, appeared to elicit a greater abundance of NETs by scanning electron microscopy imaging, which correlated with a decreased fungal burden. Together, these findings show that C. albicans biofilms impair neutrophil response through an inhibitory pathway induced by the extracellular matrix.
Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Chad J
0000-0002-0017-4284
CJ
Johnson
Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Jonathan
J
Cabezas-Olcoz
Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
John F
0000-0002-4424-7713
JF
Kernien
Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, United States of America.
Steven X
SX
Wang
Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, United States of America.
David J
0000-0002-0415-9006
DJ
Beebe
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, United States of America.
Anna
A
Huttenlocher
Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Hamayail
H
Ansari
Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America.
Jeniel E
JE
Nett
D000818:Animals; D018441:Biofilms / Q000254:growth & development*; D002176:Candida albicans / Q000502:physiology* / Q000648:ultrastructure; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D006801:Humans; D025301:Hyphae / Q000276:immunology* / Q000648:ultrastructure; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000648:ultrastructure; D051381:Rats