scholarly journals Invasive Phenotype of Candida albicans Affects the Host Proinflammatory Response to Infection

2005 ◽  
Vol 73 (8) ◽  
pp. 4588-4595 ◽  
Author(s):  
C. C. Villar ◽  
H. Kashleva ◽  
A. P. Mitchell ◽  
A. Dongari-Bagtzoglou
Keyword(s):  
Endothelial Cells ◽  
Candida Albicans ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Inflammatory Responses ◽  
Gene Knockout ◽  
Critical Role ◽  
Host Cells ◽  
Proinflammatory Response ◽  
Cytokine Responses

ABSTRACT Candida albicans is a major opportunistic pathogen in immunocompromised patients. Production of proinflammatory cytokines by host cells in response to C. albicans plays a critical role in the activation of immune cells and final clearance of the organism. Invasion of host cells and tissues is considered one of the virulence attributes of this organism. The purpose of this study was to investigate whether the ability of C. albicans to invade host cells and tissues affects the proinflammatory cytokine responses by epithelial and endothelial cells. In this study we used the invasion-deficient RIM101 gene knockout strain DAY25, the highly invasive strain SC5314, and highly invasive RIM101-complemented strain DAY44 to compare the proinflammatory cytokine responses by oral epithelial or endothelial cells. Using a high-throughput approach, we found both qualitative and quantitative differences in the overall inflammatory responses to C. albicans strains with different invasive potentials. Overall, the highly invasive strains triggered higher levels of proinflammatory cytokines in host cells than the invasion-deficient mutant triggered. Significant differences compared to the attenuated mutant were noted in interleukin-1α (IL-1α), IL-6, IL-8, and tumor necrosis factor alpha in epithelial cells and in IL-6, growth-related oncogene, IL-8, monocyte chemoattractant protein 1 (MCP-1), MCP-2, and granulocyte colony-stimulating factor in endothelial cells. Our results indicate that invasion of host cells and tissues by C. albicans enhances the host proinflammatory response to infection.

scholarly journals Reversal of the Inflammatory Responses in Fabry Patient iPSC-Derived Cardiovascular Endothelial Cells by CRISPR/Cas9-Corrected Mutation

2021 ◽  
Vol 22 (5) ◽  
pp. 2381
Author(s):  
Hui-Yung Song ◽  
Yi-Ping Yang ◽  
Yueh Chien ◽  
Wei-Yi Lai ◽  
Yi-Ying Lin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Critical Role ◽  
Vascular Complications ◽  
Digital Pcr ◽  
Mapk Signaling ◽  
Autophagic Flux ◽  
Fabry Patient ◽  
Genomic Editing

The late-onset type of Fabry disease (FD) with GLA IVS4 + 919G > A mutation has been shown to lead to cardiovascular dysfunctions. In order to eliminate variations in other aspects of the genetic background, we established the isogenic control of induced pluripotent stem cells (iPSCs) for the identification of the pathogenetic factors for FD phenotypes through CRISPR/Cas9 genomic editing. We adopted droplet digital PCR (ddPCR) to efficiently capture mutational events, thus enabling isolation of the corrected FD from FD-iPSCs. Both of these exhibited the characteristics of pluripotency and phenotypic plasticity, and they can be differentiated into endothelial cells (ECs). We demonstrated the phenotypic abnormalities in FD iPSC-derived ECs (FD-ECs), including intracellular Gb3 accumulation, autophagic flux impairment, and reactive oxygen species (ROS) production, and these abnormalities were rescued in isogenic control iPSC-derived ECs (corrected FD-ECs). Microarray profiling revealed that corrected FD-derived endothelial cells reversed the enrichment of genes in the pro-inflammatory pathway and validated the downregulation of NF-κB and the MAPK signaling pathway. Our findings highlighted the critical role of ECs in FD-associated vascular dysfunctions by establishing a reliable isogenic control and providing information on potential cellular targets to reduce the morbidity and mortality of FD patients with vascular complications.

Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance

2021 ◽  
Author(s):  
Qiuhua Yang ◽  
Jiean Xu ◽  
Qian Ma ◽  
Zhiping Liu ◽  
Yaqi Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Endothelial Inflammation ◽  
Glucose Clearance ◽  
Deficient Mice

Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.

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 Riemerella anatipestifer infection in ducks induces IL-17A production, but not IL-23p19

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rochelle A. Flores ◽  
Cherry P. Fernandez-Colorado ◽  
Fahmida Afrin ◽  
Paula Leona T. Cammayo ◽  
Suk Kim ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Proinflammatory Cytokines ◽  
Post Infection ◽  
Proinflammatory Cytokine ◽  
Th17 Cells ◽  
Critical Role ◽  
Splenic Lymphocytes ◽  
Expression Levels ◽  
Time Points ◽  
Mrna Expression Analysis

Abstract R. anatipestifer (RA) is one of the most harmful bacterial pathogens affecting the duck industry, and infection is associated with the production of proinflammatory cytokines, including IL-17A. Another proinflammatory cytokine, IL-23, is critical for the development of Th17 cells, which produce IL-17. However, IL-23 roles have not been studied in this infection. Here, we describe the identification and mRNA expression analysis of duck IL-23p19 (duIL-23p19) in splenic lymphocytes and macrophages stimulated with killed RA and in spleens of RA-infected ducks. Expression of duIL-23p19 transcript identified in this study was relatively high in livers of healthy ducks and was upregulated in mitogen-activated splenic lymphocytes as well as in splenic lymphocytes and macrophages stimulated with killed RA. In spleens of RA-infected ducks, expression levels of duIL-23p19 transcript were unchanged at all time points except on days 4 and 7 post-infection; however, duIL-17A and IL-17F expression levels were upregulated in both spleens of RA-infected ducks and splenic lymphocytes and macrophages stimulated with killed RA. In sera collected at 24 h after this infection, duIL-23p19 expression levels were unchanged, whereas IL-17A significantly upregulated. These results suggest that IL-23p19 does not play a critical role in the IL-17A response in early stages of RA-infected ducks.

scholarly journals Campylobacter jejuni-Induced Cytokine Responses in Avian Cells

2005 ◽  
Vol 73 (4) ◽  
pp. 2094-2100 ◽  
Author(s):  
Chris K. Smith ◽  
Pete Kaiser ◽  
Lisa Rothwell ◽  
Tom Humphrey ◽  
Paul A. Barrow ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Proinflammatory Cytokines ◽  
Disease Process ◽  
Avian Host ◽  
Macrophage Cell ◽  
Proinflammatory Response ◽  
Cytokines And Chemokines ◽  
Cytokine Responses ◽  
Chick Kidney

ABSTRACT Campylobacter jejuni is a major cause of human inflammatory enteritis. During the course of human disease numerous proinflammatory cytokines are produced. Little is known, however, about the cytokine responses produced during the interaction of this bacterium with the avian host. Campylobacter has been considered a commensal of the avian host. Any differences in innate responses to this pathogen between the human and avian hosts should lead to a greater understanding of the disease process in humans. We have demonstrated expression of proinflammatory cytokines and chemokines in response to Campylobacter infection in avian primary chick kidney cells and the avian macrophage cell line HD11. The data indicate that Campylobacter can stimulate the avian host in a proinflammatory manner. The data strongly suggest that the lack of pathology in vivo is not due to an inability of Campylobacter to stimulate a proinflammatory response from avian cells.

scholarly journals Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4092-4103 ◽  
Author(s):  
Abinav Kumar Singh ◽  
Nagaraja R. Thirumalapura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Persistent Infection ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Interleukin 10 ◽  
Host Cells ◽  
Content Type ◽  
Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

scholarly journals Candida albicans Ecm33p Is Important for Normal Cell Wall Architecture and Interactions with Host Cells

2006 ◽  
Vol 5 (1) ◽  
pp. 140-147 ◽  
Author(s):  
Raquel Martinez-Lopez ◽  
Hyunsook Park ◽  
Carter L. Myers ◽  
Concha Gil ◽  
Scott G. Filler
Keyword(s):  
Endothelial Cells ◽  
Cell Wall ◽  
Candida Albicans ◽  
Epithelial Cells ◽  
Normal Cell ◽  
Cell Wall Integrity ◽  
Host Cells ◽  
Epithelial Cell Line ◽  
Oral Epithelial ◽  
Cell Wall Architecture

ABSTRACT Candida albicans ECM33 encodes a glycosylphosphatidylinositol-linked cell wall protein that is important for cell wall integrity. It is also critical for normal virulence in the mouse model of hematogenously disseminated candidiasis. To identify potential mechanisms through which Ecm33p contributes to virulence, we investigated the interactions of C. albicans ecm33Δ mutants with endothelial cells and the FaDu oral epithelial cell line in vitro. The growth rate of blastospores of strains containing either one or no intact copies of ECM33 was 50% slower than that of strains containing two intact copies of ECM33. However, all strains germinated at the same rate, forming similar-length hyphae on endothelial cells and oral epithelial cells. Strains containing either one or no intact copies of ECM33 had modestly reduced adherence to both types of host cells, and a markedly reduced capacity to invade and damage these cells. Saccharomyces cerevisiae expressing C. albicans ECM33 did not adhere to or invade epithelial cells, suggesting that Ecm33p by itself does not act as an adhesin or invasin. Examination of ecm33Δ mutants by transmission electron microscopy revealed that the cell wall of these strains had an abnormally electron-dense outer mannoprotein layer, which may represent a compensatory response to reduced cell wall integrity. The hyphae of these mutants also had aberrant surface localization of the adhesin Als1p. Collectively, these results suggest that Ecm33p is required for normal cell wall architecture as well as normal function and expression of cell surface proteins in C. albicans.

scholarly journals MicroRNA-155 Deficiency Results in Decreased Macrophage Inflammation and Attenuated Atherogenesis in Apolipoprotein E–Deficient Mice

2014 ◽  
Vol 34 (4) ◽  
pp. 759-767 ◽  
Author(s):  
Fen Du ◽  
Fang Yu ◽  
Yuzhen Wang ◽  
Yvonne Hui ◽  
Kevin Carnevale ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Apolipoprotein E ◽  
Knockout Mice ◽  
Proinflammatory Cytokine ◽  
Cholesterol Efflux ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cytokine Expression ◽  
Double Knockout ◽  
Proinflammatory Cytokine Expression

Objective— microRNA-155 (miR155) plays a critical role in immunity and macrophage inflammation. We aim to investigate the role of miR155 in atherogenesis. Approach and Results— Quantitative real-time polymerase chain reaction showed that miR155 was expressed in mouse and human atherosclerotic lesions. miR155 expression in macrophages was correlated positively with proinflammatory cytokine expression. Lentivirus-mediated overexpression of miR155 in macrophages enhanced their inflammatory response to lipopolysaccharide through targeting suppressor of cytokine signaling-1 and impaired cholesterol efflux from acetylated low-density lipoprotein–loaded macrophages, whereas deficiency of miR155 blunted macrophage inflammatory responses and enhanced cholesterol efflux possibly via enhancing lipid loading–induced macrophage autophagy. We next examined the atherogenesis in apolipoprotein E–deficient (apoE −/− ) and miR155 −/− /apoE −/− (double knockout) mice fed a Western diet. Compared with apoE −/− mice, the double knockout mice developed less atherosclerosis lesion in aortic root, with reduced neutral lipid content and macrophages. Flow cytometric analysis showed that there were increased number of regulatory T cells and reduced numbers of Th17 cells and CD11b+/Ly6C high cells in the spleen of double knockout mice. Peritoneal macrophages from the double knockout mice had significantly reduced proinflammatory cytokine expression and secretion both in the absence and presence of lipopolysaccharide stimulation. To determine whether miR155 in leukocytes contributes to atherosclerosis, we performed a bone marrow transplantation study. Deficiency of miR155 in bone marrow–derived cells suppressed atherogenesis in apoE −/− mice, demonstrating that hematopoietic cell–derived miR155 plays a critical role. Conclusions— miR155 deficiency attenuates atherogenesis in apoE −/− mice by reducing inflammatory responses of macrophages, enhancing macrophage cholesterol efflux and resulting in an antiatherogenic leukocyte profile. Targeting miR155 may be a promising strategy to halt atherogenesis.

scholarly journals Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6383-6391 ◽  
Author(s):  
Kristi L. Allen ◽  
Anne Hamik ◽  
Mukesh K. Jain ◽  
Keith R. McCrae
Keyword(s):  
Endothelial Cells ◽  
Antiphospholipid Antibodies ◽  
Transcriptional Activity ◽  
Cell Activation ◽  
Critical Role ◽  
Endothelial Activation ◽  
Dependent Manner ◽  
Endothelial Cell Activation ◽  
Proinflammatory Response ◽  
Endothelial Response

Abstract Antiphospholipid syndrome is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLAs). The majority of APLAs are directed against phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Anti-β2GPI antibodies activate endothelial cells in a β2GPI-dependent manner through a pathway that involves NF-κB. Krüppel-like factors (KLFs) play a critical role in regulating the endothelial response to inflammatory stimuli. We hypothesized that activation of endothelial cells by APLA/anti-β2GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-κB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-β2GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-κB transcriptional activity and blocked APLA/anti-β2GPI–mediated endothelial activation despite NF-κB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-κB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-κB. These findings suggest that the endothelial response to APLA/anti-β2GPI antibodies reflects competition between KLFs and NF-κB for their common cofactor, CBP/p300. Taken together, these observations are the first to implicate the KLFs as novel participants in the endothelial proinflammatory response to APLA/anti-β2GPI antibodies.

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