scholarly journals Echinocandin Treatment of Candida albicans Biofilms Enhances Neutrophil Extracellular Trap Formation

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Amanda R. Hoyer ◽  
Chad J. Johnson ◽  
Matthew R. Hoyer ◽  
John F. Kernien ◽  
Jeniel E. Nett
Keyword(s):  
Candida Albicans ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Host Defenses ◽  
Nosocomial Pathogen ◽  
Antimicrobial Proteins ◽  
Content Type ◽  
Extracellular Traps ◽  
The Face ◽  
Candida Albicans Biofilms

ABSTRACT The nosocomial pathogen Candida albicans forms biofilms on medical devices that persist in the face of antifungals and host defenses. Echinocandins, the most effective antibiofilm drugs, have recently been shown to augment the activity of neutrophils against biofilms through an unknown mechanism. Here, we show that treatment of C. albicans biofilms with subinhibitory concentrations of echinocandins promotes the formation of neutrophil extracellular traps (NETs), structures of DNA, histones, and antimicrobial proteins with antifungal activity.

scholarly journals Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 953-959 ◽  
Author(s):  
Kathleen D. Metzler ◽  
Tobias A. Fuchs ◽  
William M. Nauseef ◽  
Dominique Reumaux ◽  
Joachim Roesler ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Host Defense ◽  
Candida Species ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Extracellular Traps ◽  
Microbial Infections ◽  
Dependent Inhibition ◽  
Extracellular Trap

AbstractThe granule enzyme myeloperoxidase (MPO) plays an important role in neutrophil antimicrobial responses. However, the severity of immunodeficiency in patients carrying mutations in MPO is variable. Serious microbial infections, especially with Candida species, have been observed in a subset of completely MPO-deficient patients. Here we show that neutrophils from donors who are completely deficient in MPO fail to form neutrophil extracellular traps (NETs), indicating that MPO is required for NET formation. In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation. Extracellular products of MPO do not rescue NET formation, suggesting that MPO acts cell-autonomously. Finally, NET-dependent inhibition of Candida albicans growth is compromised in MPO-deficient neutrophils. The inability to form NETs may contribute in part to the host defense defects observed in completely MPO-deficient individuals.

scholarly journals The Extracellular Matrix of Candida albicans Biofilms Impairs Formation of Neutrophil Extracellular Traps

2016 ◽  
Vol 12 (9) ◽  
pp. e1005884 ◽  
Author(s):  
Chad J. Johnson ◽  
Jonathan Cabezas-Olcoz ◽  
John F. Kernien ◽  
Steven X. Wang ◽  
David J. Beebe ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Candida Albicans ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Candida Albicans Biofilms

scholarly journals Natural Variation in Clinical Isolates of Candida albicans Modulates Neutrophil Responses

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Madhu Shankar ◽  
Tricia L. Lo ◽  
Ana Traven
Keyword(s):  
Reactive Oxygen Species ◽  
Candida Albicans ◽  
Reactive Oxygen ◽  
Neutrophil Extracellular Traps ◽  
Prototype Strain ◽  
Human Neutrophils ◽  
Oxygen Species ◽  
Content Type ◽  
Extracellular Traps ◽  
Strain Sc5314

ABSTRACT Neutropenia predisposes patients to life-threatening infection with Candida albicans, a commensal and opportunistic fungal pathogen. How phenotypic variation in C. albicans isolates dictates neutrophil responses is poorly understood. By using a panel of clinical C. albicans strains, here we report that the prototype strain SC5314 induces the most potent accumulation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) by human neutrophils of all tested isolates. ROS and NET accumulation positively correlated with the degree of hyphal formation by the isolates, the hypha being the fungal morphotype that promotes pathogenesis. However, there was no correlation of ROS and NET accumulation with fungal killing by neutrophils. Fungal killing was also not correlated with phagocytosis levels or oxidative stress susceptibility of the isolates. The bloodstream isolate P94015 cannot make hyphae and was previously shown to be hyperfit in the murine gut commensalism model. Our results show that P94015 displays poor phagocytosis by neutrophils, the least ROS and NET accumulation of all tested isolates, and resistance to neutrophil-mediated killing. Our data suggest that reduced susceptibility to neutrophils is likely to be independent from a previously described genetic mutation in P94015 that promotes commensalism. Reduced clearance by neutrophils could benefit commensal fitness of C. albicans and could also have promoted the virulence of P94015 in the human patient in the absence of hyphal morphogenesis. Collectively, our study provides new insights into neutrophil interactions with C. albicans and suggests that studying diverse isolates informs knowledge of the relevant aspects of this key immune interaction. IMPORTANCE Neutrophils are the key immune cell type for host defenses against infections with Candida albicans. C. albicans strains isolated from patients display large phenotypic diversity, but how this diversity impacts host-pathogen interactions with neutrophils is incompletely defined. Here, we show that important neutrophil responses, such as accumulation of reactive oxygen species and neutrophil extracellular traps, as well as the levels of phagocytosis and killing of the pathogen, differ when comparing diverse C. albicans isolates. A bloodstream patient isolate previously described as more suited to commensalism than pathogenesis in animal models is relatively “silent” to neutrophils and resistant to killing. Our findings illuminate the relationships between fungal morphogenesis, neutrophil responses, and C. albicans survival. Our findings suggest that host phenotypes of a commensally adapted strain could be driven by resistance to immune clearance and indicate that we should extend our studies beyond the “prototype” strain SC5314 for deeper understanding of Candida-neutrophil interactions.

scholarly journals Neutrophil Extracellular Traps Exhibit Antibacterial Activity against Burkholderia pseudomallei and Are Influenced by Bacterial and Host Factors

2012 ◽  
Vol 80 (11) ◽  
pp. 3921-3929 ◽  
Author(s):  
Donporn Riyapa ◽  
Surachat Buddhisa ◽  
Sunee Korbsrisate ◽  
Jon Cuccui ◽  
Brendan W. Wren ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Capsular Polysaccharide ◽  
Neutrophil Extracellular Traps ◽  
Polymorphonuclear Neutrophils ◽  
Dependent Manner ◽  
Predisposing Factor ◽  
Bacterial Killing ◽  
Content Type ◽  
Extracellular Traps ◽  
Type Iii Protein Secretion

ABSTRACTBurkholderia pseudomalleiis the causative pathogen of melioidosis, of which a major predisposing factor is diabetes mellitus. Polymorphonuclear neutrophils (PMNs) kill microbes extracellularly by the release of neutrophil extracellular traps (NETs). PMNs play a key role in the control of melioidosis, but the involvement of NETs in killing ofB. pseudomalleiremains obscure. Here, we showed that bactericidal NETs were released from human PMNs in response toB. pseudomalleiin a dose- and time-dependent manner.B. pseudomallei-induced NET formation required NADPH oxidase activation but not phosphatidylinositol-3 kinase, mitogen-activated protein kinases, or Src family kinase signaling pathways.B. pseudomalleimutants defective in the virulence-associated Bsa type III protein secretion system (T3SS) or capsular polysaccharide I (CPS-I) induced elevated levels of NETs. NET induction by such mutants was associated with increased bacterial killing, phagocytosis, and oxidative burst by PMNs. Taken together the data imply that T3SS and the capsule may play a role in evading the induction of NETs. Importantly, PMNs from diabetic subjects released NETs at a lower level than PMNs from healthy subjects. Modulation of NET formation may therefore be associated with the pathogenesis and control of melioidosis.

scholarly journals Inactivation of α1-proteinase inhibitor by Candida albicans aspartic proteases favors the epithelial and endothelial cell colonization in the presence of neutrophil extracellular traps.

2015 ◽  
Vol 63 (1) ◽  
Author(s):  
Mariusz Gogol ◽  
Dominika Ostrowska ◽  
Kinga Klaga ◽  
Oliwia Bochenska ◽  
Natalia Wolak ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Proteinase Inhibitor ◽  
Proteolytic Enzymes ◽  
Fungal Infections ◽  
Critical Role ◽  
Neutrophil Extracellular Traps ◽  
Host Cells ◽  
Inhibition Mechanism ◽  
Aspartic Proteases ◽  
Extracellular Traps

Candida albicans, a causative agent of opportunistic fungal infections in immunocompromised patients, uses ten secreted aspartic proteases (SAPs) to deregulate the homeostasis of the host organism on many levels. One of these deregulation mechanisms involves a SAP-dependent disturbance of the control over proteolytic enzymes of the host by a system of dedicated proteinase inhibitors, with one important example being the neutrophil elastase and alpha1-proteinase inhibitor (A1PI). In this study, we found that soluble SAPs 1-4 and the cell membrane-anchored SAP9 efficiently cleaved A1PI, with the major cleavage points located at the C-terminal part of A1PI in a close vicinity to the reactive-site loop that plays a critical role in the inhibition mechanism. Elastase is released by neutrophils to the environment during fungal infection through two major processes, a degranulation or formation of neutrophil extracellular traps (NET). Both, free and NET-embedded elastase forms, were found to be controlled by A1PI. A local acidosis, resulting from the neutrophil activity at the infection sites, favors A1PI degradation by SAPs. The deregulation of NET-connected elastase affected a NET-dependent damage of epithelial and endothelial cells, resulting in the increased susceptibility of these host cells to candidal colonization. Moreover, the SAP-catalyzed cleavage of A1PI was found to decrease its binding affinity to a proinflammatory cytokine, interleukin-8. The findings presented here suggest a novel strategy used by C. albicans for the colonization of host tissues and overcoming the host defense.

scholarly journals Differential Use of Human Neutrophil FcγReceptors for Inducing Neutrophil Extracellular Trap Formation

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Omar Rafael Alemán ◽  
Nancy Mora ◽  
Ricarda Cortes-Vieyra ◽  
Eileen Uribe-Querol ◽  
Carlos Rosales
Keyword(s):  
Monoclonal Antibodies ◽  
Human Neutrophil ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Cross Linking ◽  
Erk Activation ◽  
Extracellular Traps ◽  
Extracellular Trap ◽  
Antigen Antibody ◽  
Insight Into

Neutrophils (PMN) are the most abundant leukocytes in the blood. PMN migrate from the circulation to sites of infection, where they are responsible for antimicrobial functions. PMN use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. NETs are fibers composed of chromatin and neutrophil-granule proteins. Several pathogens, including bacteria, fungi, and parasites, and also some pharmacological stimuli such as phorbol 12-myristate 13-acetate (PMA) are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. However the particular Fcγreceptor involved in triggering this function is a matter of controversy. In order to provide some insight into what Fcγreceptor is responsible for NET formation, each of the two human Fcγreceptors was stimulated individually by specific monoclonal antibodies and NET formation was evaluated. FcγRIIa cross-linking did not promote NET formation. Cross-linking other receptors such as integrins also did not promote NET formation. In contrast FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. NET formation was dependent on NADPH-oxidase, PKC, and ERK activation. These data show that cross-linking FcγRIIIb is responsible for NET formation by the human neutrophil.

scholarly journals Heparan Sulfate Modulates Neutrophil and Endothelial Function in Antibacterial Innate Immunity

2015 ◽  
Vol 83 (9) ◽  
pp. 3648-3656 ◽  
Author(s):  
Ding Xu ◽  
Joshua Olson ◽  
Jason N. Cole ◽  
Xander M. van Wijk ◽  
Volker Brinkmann ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Heparan Sulfate ◽  
Bactericidal Activity ◽  
Bacterial Pathogen ◽  
Systemic Infection ◽  
Neutrophil Extracellular Traps ◽  
Content Type ◽  
Extracellular Traps ◽  
The Central Nervous System ◽  
Group B

Recently, we showed that endothelial heparan sulfate facilitates entry of a bacterial pathogen into the central nervous system. Here, we show that normal bactericidal activity of neutrophils is influenced by the sulfation pattern of heparan sulfate. Inactivation of heparan sulfate uronyl 2-O-sulfotransferase (Hs2st) in neutrophils substantially reduced their bactericidal activity, and Hs2st deficiency rendered mice more susceptible to systemic infection with the pathogenic bacterium group BStreptococcus. Specifically, altered sulfation of heparan sulfate in mutant neutrophils affected formation of neutrophil extracellular traps while not influencing phagocytosis, production of reactive oxygen species, or secretion of granular proteases. Heparan sulfate proteoglycan(s) is present in neutrophil extracellular traps, modulates histone affinity, and modulates their microbial activity. Hs2st-deficient brain endothelial cells show enhanced binding to group BStreptococcusand are more susceptible to apoptosis, likely contributing to the observed increase in dissemination of group BStreptococcusinto the brain of Hs2st-deficient mice following intravenous challenge. Taken together, our data provide strong evidence that heparan sulfate from both neutrophils and the endothelium plays important roles in modulating innate immunity.

scholarly journals Extracellular Nucleic Acids Present in the Candida albicans Biofilm Trigger the Release of Neutrophil Extracellular Traps

2021 ◽  
Vol 11 ◽  
Author(s):  
Magdalena Smolarz ◽  
Marcin Zawrotniak ◽  
Dorota Satala ◽  
Maria Rapala-Kozik
Keyword(s):  
Candida Albicans ◽  
Nucleic Acids ◽  
Fungal Infection ◽  
Fungal Infections ◽  
Neutrophil Extracellular Traps ◽  
Human Neutrophils ◽  
High Concentration ◽  
First Line ◽  
Extracellular Traps ◽  
Biofilm Structure

Neutrophils, the first line of the host’s defense, use a variety of antimicrobial mechanisms to fight invading pathogens. One of the most crucial is the production of neutrophil extracellular traps (NETs) in the process called NETosis. The unique structure of NETs effectively inhibits the spread of pathogens and ensures their exposure to a high concentration of NET-embedded antimicrobial compounds. NETosis strategy is often used by the host to defend against fungal infection caused by Candida albicans. In immunocompromised patients, this microorganism is responsible for developing systemic fungal infections (candidiasis). This is correlated with the use of a vast array of virulence factors, leading to the acquisition of specific resistance to host defense factors and available drug therapies. One of the most important features favoring the development of drug resistance is a C. albicans ability to form biofilms that protect fungal cells mainly through the production of an extracellular matrix (ECM). Among the main ECM-building macromolecules extracellular nucleic acids have been identified and their role is probably associated with the stbilization of the biofilm structure. The complex interactions of immune cells with the thick ECM layer, comprising the first line of contact between these cells and the biofilm structure, are still poorly understood. Therefore, the current studies aimed to assess the release of extracellular nucleic acids by C. albicans strains at different stages of biofilm formation, and to determine the role of these molecules in triggering the NETosis. We showed for the first time that fungal nucleic acids, purified directly from mature C. albicans biofilm structure or obtained from the whole fungal cells, have the potential to induce NET release in vitro. In this study, we considered the involvement of TLR8 and TLR9 in NETosis activation. We showed that DNA and RNA molecules initiated the production of reactive oxygen species (ROS) by activation of the NADPH oxidase complex, essential for ROS-dependent NETosis. Furthermore, analysis of the cell migration showed that the nucleic acids located in the extracellular space surrounding the biofilm may be also effective chemotactic factors, driving the dynamic migration of human neutrophils to the site of ongoing fungal infection.

scholarly journals DNase I functional microgels for neutrophil extracellular trap disruption

2021 ◽  
Author(s):  
Aisa Hosseinnejad ◽  
Nadine Ludwig ◽  
Ann-Katrin Wienkamp ◽  
Rahul Rimal ◽  
Christian Bleilevens ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Neutrophil Extracellular Trap ◽  
Extracellular Traps ◽  
Extracellular Trap ◽  
Non Fouling

Non-fouling DNase I conjugated microgel provide a novel biohybrid platform to disrupt Neutrophil extracellular traps (NETs) and can be used as a non-thrombogenic coating for reduction of NET-mediated inflammation and microthrombi formation.

scholarly journals The emerging roles of neutrophil extracellular traps in wound healing

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Shuainan Zhu ◽  
Ying Yu ◽  
Yun Ren ◽  
Liying Xu ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Wound Healing Process ◽  
Loss Of Function ◽  
Delayed Wound Healing ◽  
Wound Site ◽  
Extracellular Traps ◽  
Extracellular Trap

AbstractDelayed wound healing causes problems for many patients both physically and psychologically, contributing to pain, economic burden, loss of function, and even amputation. Although many factors affect the wound healing process, abnormally prolonged or augmented inflammation in the wound site is a common cause of poor wound healing. Excessive neutrophil extracellular trap (NET) formation during this phase may amplify inflammation and hinder wound healing. However, the roles of NETs in wound healing are still unclear. Herein, we briefly introduce NET formation and discuss the possible NET-related mechanisms in wound healing. We conclude with a discussion of current studies, focusing on the roles of NETs in diabetic and normoglycemic wounds and the effectiveness of NET-targeting treatments in wound healing.

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