Additive antifungal activity of anidulafungin and human neutrophils against Candida parapsilosis biofilms

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.

show abstract

“…albicans and C . parapsilosis , with biofilms exhibiting 5-fold increase in resistance to neutrophil killing 9,11,12,45 . For C .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms involved in the triggering of neutrophil extracellular traps (NETs) by Candida glabrata during planktonic and biofilm growth

Johnson

Kernien

Hoyer

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In addition to the well-described drug resistance, biofilm growth also appears to afford protection from the host immune response (55–58). Compared to planktonic cells, both neutrophils and mononuclear cells are less effective in killing Candida biofilm cells.…”

Section: Fungal Biofilm Traitsmentioning

confidence: 99%

“…Compared to planktonic cells, both neutrophils and mononuclear cells are less effective in killing Candida biofilm cells. Mononuclear cells become entrapped in biofilms, but do not efficiently activate or phagocytize fungal cells (57, 59) Neutrophils have impaired function against both C. albicans and C. parapsilosis biofilms (55, 56, 58). Although most studies involving the leukocyte response to fungal biofilms have been limited to in vitro studies, the phenotype appears clinically relevant.…”

Section: Fungal Biofilm Traitsmentioning

confidence: 99%

Fungal Biofilms: In Vivo Models for Discovery of Anti-Biofilm Drugs

Nett

Andes

2015

Microbiol Spectr

View full text Add to dashboard Cite

SUMMARY During infection, fungi frequently transition to a biofilm lifestyle, proliferating as communities of surface-adherent aggregates of cells. Phenotypically, cells in a biofilm are distinct from free-floating cells. Their high tolerance of antifungals and ability to withstand host defenses are two characteristics that foster resilience. Biofilm infections are particularly difficult to eradicate and most available antifungals have minimal activity. Therefore, the discovery of novel compounds and innovative strategies to treat fungal biofilms is of great interest. Although many fungi have been observed to form biofilms, the most well-studied is Candida albicans. Animal models have been developed to simulate common Candida device-associated infections, including those involving vascular catheters, dentures, urinary catheters, and subcutaneous implants. Models have also reproduced the most common mucosal biofilm infections, oropharyngeal and vaginal candidiasis. These models incorporate the anatomical site, immune components, and fluid dynamics of clinical niches and have been instrumental in the study of drug resistance and investigation of novel therapies. This chapter describes the significance of fungal biofilm infections, the animal models developed for biofilm study, and how these models have contributed to development of new strategies for eradication of fungal biofilm infections.

show abstract

“…Removal of Candida-infected devices is recommended, even for patients with intact immunity (9). In vitro studies corroborate a difference in immune responses to biofilm and planktonic Candida, but little is known about this mechanism (30,31,62,63). The present study identifies alarmin S100-A9 as a protein abundant among all three device-associated biofilms.…”

Section: Discussionmentioning

confidence: 50%

Host Contributions to Construction of Three Device-Associated Candida albicans Biofilms

et al. 2015

View full text Add to dashboard Cite

e Among the most fascinating virulence attributes of Candida is the ability to transition to a biofilm lifestyle. As a biofilm, Candida cells adhere to a surface, such as a vascular catheter, and become encased in an extracellular matrix. During this mode of growth, Candida resists the normal immune response, often causing devastating disease. Based on scanning electron microscopy images, we hypothesized that host cells and proteins become incorporated into clinical biofilms. As a means to gain an understanding of these host-biofilm interactions, we explored biofilm-associated host components by using microscopy and liquid chromatography-mass spectrometry. Here we characterize the host proteins associated with several in vivo rat Candida albicans biofilms, including those from vascular catheter, denture, and urinary catheter models as well as uninfected devices. A conserved group of 14 host proteins were found to be more abundant during infection at each of the niches. The host proteins were leukocyte and erythrocyte associated and included proteins involved in inflammation, such as C-reactive protein, myeloperoxidase, and alarmin S100-A9. A group of 59 proteins were associated with both infected and uninfected devices, and these included matricellular and inflammatory proteins. In addition, site-specific proteins were identified, such as amylase in association with the denture device. Cellular analysis revealed neutrophils as the predominant leukocytes associating with biofilms. These experiments demonstrate that host cells and proteins are key components of in vivo Candida biofilms, likely with one subset associating with the device and another being recruited by the proliferating biofilm.

show abstract

Additive antifungal activity of anidulafungin and human neutrophils against Candida parapsilosis biofilms

Abstract: Besides a lack of antagonistic interactions between newer antifungal agents and phagocytes, anidulafungin exerts additive immunopharmacological activity against C. parapsilosis biofilms.

Cited by 27 publications

References 12 publications

Mechanisms involved in the triggering of neutrophil extracellular traps (NETs) by Candida glabrata during planktonic and biofilm growth

Mechanisms involved in the triggering of neutrophil extracellular traps (NETs) by Candida glabrata during planktonic and biofilm growth

Fungal Biofilms: In Vivo Models for Discovery of Anti-Biofilm Drugs

Host Contributions to Construction of Three Device-Associated Candida albicans Biofilms

Contact Info

Product

Resources

About