scholarly journals Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Suganya Viriyakosol ◽  
Maria del Pilar Jimenez ◽  
Michael A. Gurney ◽  
Mark E. Ashbaugh ◽  
Joshua Fierer
Keyword(s):  
Immune Response ◽  
Pathogenic Fungus ◽  
Lavage Fluid ◽  
Dependent Manner ◽  
Coccidioides Immitis ◽  
Necrosis Factor Alpha ◽  
Cell Immunity ◽  
Th17 Cytokines

ABSTRACTWe assessed the role of Dectin-1 in the immune response to the pathogenic fungusCoccidioides, bothin vitroandin vivo, using mice with a targeted mutation inClec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1−/−mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F2mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance toCoccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis.IMPORTANCECoccidioidomycosis is a fungal infection endemic in the southwestern United States and neighboring Mexico, causing ~150,000 lung infections in people and resulting in ~17,000 hospitalizations annually in California alone. Very little is known about innate immunity to this fungus. This paper shows that Dectin-1, the primary β-glucan receptor on myeloid cells, is required for resistance to this pathogen. Dectin-1 is part of the innate immune system, and it is needed to direct the acquired immune response toward into a pathway that will lead to macrophage activation. Lungs from infected mice lacking Dectin-1 had lower concentrations of Th1 and Th17 cytokines, two cytokine pathways that are very important for acquired T cell immunity toCoccidioidesspp. This is the first demonstration that Dectin-1 is required for host resistance to a dimorphic, primary pathogenic fungus.

scholarly journals The Antiinfective Effects of Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei) onStaphylococcus aureus-Infected Mice

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Ting-Yeu Dai ◽  
Chih-Hua Wang ◽  
Kun-Nan Chen ◽  
I-Nung Huang ◽  
Wei-Sheng Hong ◽  
...  
Keyword(s):  
Lipoteichoic Acid ◽  
Lavage Fluid ◽  
Dependent Manner ◽  
Protective Mechanisms ◽  
Velvet Antler ◽  
Sambar Deer ◽  
Dose Dependent ◽  
Cervus Unicolor

We assayed the effects of velvet antler (VA) of Formosan sambar deer (Cervus unicolor swinhoei) and its extracts on the anti-infective activity against pathogenicStaphylococcus aureus in vitroandin vivoin this study.In vitrodata indicated that the VA extracts stimulated the proliferation of resting splenocytes and macrophages in a dose-dependent manner up to the highest concentration used (150 μg mL−1). The production of proinflammatory cytokines (TNF-α, IL-6, IL-12) by lipoteichoic acid was significantly suppressed after being cocultured with the VA extracts in a dose-dependent manner. Animal test inS. aureus-infected mice demonstrated that the numbers of bacteria determined in the kidneys and peritoneal lavage fluid ofS. aureus-infected mice were significantly higher than those found in the same organs of mice pretreated with the VA samples. Moreover, the highly enhanced phagocytic activity of macrophages was further verified afterin vitrotreatment with the VA samples. The protective mechanisms of the VA samples might include an immune enhancer and an inflammatory cytokine suppressor.

scholarly journals Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

2001 ◽  
Vol 69 (4) ◽  
pp. 2025-2030 ◽  
Author(s):  
Shuhua Yang ◽  
Shunji Sugawara ◽  
Toshihiko Monodane ◽  
Masahiro Nishijima ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Lipid A ◽  
Micrococcus Luteus ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Monocytic Cells ◽  
Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

scholarly journals A Dairy Bacterium Displays InVitro Probiotic Properties for the Pharyngeal Mucosa by Antagonizing Group A Streptococci and Modulating the Immune Response

2010 ◽  
Vol 78 (11) ◽  
pp. 4734-4743 ◽  
Author(s):  
Simone Guglielmetti ◽  
Valentina Taverniti ◽  
Mario Minuzzo ◽  
Stefania Arioli ◽  
Ivan Zanoni ◽  
...  
Keyword(s):  
Immune Response ◽  
The Body ◽  
Lactobacillus Helveticus ◽  
Hypopharyngeal Carcinoma ◽  
Probiotic Properties ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α

ABSTRACT The probiotic approach represents an alternative strategy in the prevention and treatment of infectious diseases, not only at the intestinal level but also at other sites of the body where the microbiota plays a role in the maintenance of physiological homeostasis. In this context, we evaluated in vitro the potential abilities of probiotic and dairy bacteria in controlling Streptococcus pyogenes infections at the pharyngeal level. Initially, we analyzed bacterial adhesion to FaDu hypopharyngeal carcinoma cells and the ability to antagonize S. pyogenes on FaDu cell layers and HaCat keratinocytes. Due to its promising adhesive and antagonistic features, we studied the dairy strain Lactobacillus helveticus MIMLh5, also through in vitro immunological experiments. First, we performed quantification of several cytokines and measurement of NF-κB activation in FaDu cells. MIMLh5 efficiently reduced the induction of interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α), in a dose-dependent manner. After stimulation of cells with IL-1β, active NF-κB was still markedly lowered. Nevertheless, we observed an increased secretion of IL-6, gamma interferon (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) under these conditions. These effects were associated with the ability of MIMLh5 to enhance the expression of the heat shock protein coding gene hsp70. In addition, MIMLh5 increased the GM-CSF/G-CSF ratio. This is compatible with a switch of the immune response toward a TH1 pathway, as supported by our observation that MIMLh5, once in contact with bone marrow-derived dendritic cells, triggered the secretion of TNF-α and IL-2. In conclusion, we propose MIMLh5 as a potential probiotic bacterium for the human pharynx, with promising antagonistic and immunomodulatory properties.

scholarly journals Laser Capture Microdissection-Assisted Protein Biomarker Discovery from Coccidioides-Infected Lung Tissue

2020 ◽  
Vol 6 (4) ◽  
pp. 365
Author(s):  
Natalie M. Mitchell ◽  
Surendra Dasari ◽  
Thomas E. Grys ◽  
Douglas F. Lake
Keyword(s):  
Laser Capture Microdissection ◽  
Biomarker Discovery ◽  
Pathogenic Fungus ◽  
Dependent Manner ◽  
Label Free ◽  
Human Lungs ◽  
Human Proteins ◽  
Laser Capture

Laser capture microdissection (LCM) coupled to label-free quantitative mass spectrometry is a viable strategy to identify biomarkers from infected tissues. In this study, LCM was employed to take a “snapshot” of proteins produced in vivo during Coccidiodies spp. infection in human lungs. Proteomic analysis of LCM lung sections revealed hundreds of hosts and Coccidioidal proteins. Twenty-seven highly abundant Coccidioides spp. proteins were identified which do not share significant sequence orthology with human proteins. Three of the 27 Coccidioidal proteins are also potential Coccidoides-specific biomarkers, as they also do not share sequence homology to any other pathogenic fungus or microbe. Gene ontology analysis of the 27 biomarker candidate proteins revealed enriched hydrolase activity and increased purine and carbohydrate metabolism functions. Finally, we provide proteomic evidence that all 27 biomarker candidates are produced by the fungus when grown in vitro in a media- and growth-phase dependent manner.

scholarly journals Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs

2005 ◽  
Vol 202 (3) ◽  
pp. 425-435 ◽  
Author(s):  
Hiroyuki Yoneyama ◽  
Kenjiro Matsuno ◽  
Etsuko Toda ◽  
Tetsu Nishiwaki ◽  
Naoki Matsuo ◽  
...  
Keyword(s):  
Cluster Formation ◽  
Cell Mediated Immunity ◽  
Dependent Manner ◽  
Virus Eradication ◽  
Cell Immunity ◽  
Plasmacytoid Dcs ◽  
Simplex Virus ◽  
Ctl Induction

Antiviral cell–mediated immunity is initiated by the dendritic cell (DC) network in lymph nodes (LNs). Plasmacytoid DCs (pDCs) are known to migrate to inflamed LNs and produce interferon (IFN)-α, but their other roles in antiviral T cell immunity are unclear. We report that LN-recruited pDCs are activated to create local immune fields that generate antiviral cytotoxic T lymphocytes (CTLs) in association with LNDCs, in a model of cutaneous herpes simplex virus (HSV) infection. Although pDCs alone failed to induce CTLs, in vivo depletion of pDCs impaired CTL-mediated virus eradication. LNDCs from pDC-depleted mice showed impaired cluster formation with T cells and antigen presentation to prime CTLs. Transferring circulating pDC precursors from wild-type, but not CXCR3-deficient, mice to pDC-depleted mice restored CTL induction by impaired LNDCs. In vitro co-culture experiments revealed that pDCs provided help signals that recovered impaired LNDCs in a CD2- and CD40L-dependent manner. pDC-derived IFN-α further stimulated the recovered LNDCs to induce CTLs. Therefore, the help provided by pDCs for LNDCs in primary immune responses seems to be pivotal to optimally inducing anti-HSV CTLs.

scholarly journals Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3234-3244 ◽  
Author(s):  
Sanchita Bhatnagar ◽  
Kazuhiko Shinagawa ◽  
Francis J. Castellino ◽  
Jeffrey S. Schorey
Keyword(s):  
Immune Surveillance ◽  
Lavage Fluid ◽  
Intracellular Pathogens ◽  
Dependent Manner ◽  
Proinflammatory Response ◽  
Tnf Α ◽  
Molecular Patterns ◽  
Myeloid Differentiation Factor

Abstract Intracellular pathogens and the molecules they express have limited contact with the immune system. Here, we show that macrophages infected with intracellular pathogens Mycobacterium tuberculosis, M bovis BCG, Salmonella typhimurium, or Toxoplasma gondii release from cells small vesicles known as exosomes which contain pathogen-associated molecular patterns (PAMPs). These exosomes, when exposed to uninfected macrophages, stimulate a proinflammatory response in a Toll-like receptor– and myeloid differentiation factor 88–dependent manner. Further, exosomes isolated from the bronchoalveolar lavage fluid (BALF) of M bovis BCG–infected mice contain the mycobacteria components lipoarabinomannan and the 19-kDa lipoprotein and can stimulate TNF-α production in naive macrophages. Moreover, exosomes isolated from M bovis BCG– and M tuberculosis–infected macrophages, when injected intranasally into mice, stimulate TNF-α and IL-12 production as well as neutrophil and macrophage recruitment in the lung. These studies identify a previously unknown function for exosomes in promoting intercellular communication during an immune response to intracellular pathogens, and we hypothesize that extracellular release of exosomes containing PAMPs is an important mechanism of immune surveillance.

scholarly journals Suppression of Murine Endotoxin Response by E5531, a Novel Synthetic Lipid A Antagonist

1998 ◽  
Vol 42 (11) ◽  
pp. 2824-2829 ◽  
Author(s):  
Seiichi Kobayashi ◽  
Tsutomu Kawata ◽  
Akifumi Kimura ◽  
Kaname Miyamoto ◽  
Koichi Katayama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lipid A ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
In Vivo Models ◽  
Lps Challenge ◽  
Tnf Α

ABSTRACT As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A analogue, E5531, was designed and synthesized as an LPS antagonist, and its biological properties were examined in vitro and in vivo. In murine peritoneal macrophages, E5531 inhibited the release of tumor necrosis factor alpha (TNF-α) by Escherichia coli LPS with a 50% inhibitory concentration (IC50) of 2.2 nM, while E5531 elicited no significant increases in TNF-α on its own. In support of a mechanism consistent with antagonism of binding to a cell surface receptor for LPS, E5531 inhibited equilibrium binding of radioiodinated LPS ([125I]2-(r-azidosalicylamido)-1, 3′-dithiopropionate-LPS) to mouse macrophages with an IC50 of 0.50 μM. E5531 inhibited LPS-induced increases in TNF-α in vivo when it was coinjected with LPS into C57BL/6 mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this model, the efficacy of E5531 was inversely correlated to the LPS challenge dose, consistent with a competitive antagonist-like mechanism of action. Blockade of the inflammatory response by E5531 could further be demonstrated in other in vivo models: E5531 protected BCG-primed mice from LPS-induced lethality in a dose-dependent manner and suppressed LPS-induced hepatic injury in Propionibacterium acnes-primed or galactosamine-sensitized mice. These results argue that the novel synthetic lipid A analogue E5531 can antagonize the action of LPS in in vitro and suppress the pathological effects of LPS in vivo in mice.

scholarly journals Autoimmunity-Associated Gut Commensals Modulate Gut Permeability and Immunity in Humanized Mice

2019 ◽  
Vol 184 (Supplement_1) ◽  
pp. 529-536 ◽  
Author(s):  
Baskar Balakrishnan ◽  
David Luckey ◽  
Veena Taneja
Keyword(s):  
Immune Response ◽  
Type Ii Collagen ◽  
Gut Permeability ◽  
Associated Bacteria ◽  
Epithelial Integrity ◽  
Inflammatory Monocytes ◽  
Age Dependent ◽  
Th17 Cytokines

Abstract Objective Although the etiology of rheumatoid arthritis (RA) is unknown, recent studies have led to the concept that gut dysbiosis may be involved in onset. In this study, we aimed to determine if human gut commensals modulate the immune response and gut epithelial integrity in DQ8 mice. Methods DQ8 mice were orally gavaged with RA-associated (Eggerthella lenta or Collinsella aerofaciens) and non-associated (Prevotella histicola or Bifidobacterium sp.) on alternate days for 1 week in naïve mice. Some mice were immunized with type II collagen and oral gavage continued for 6 weeks and followed for arthritis. Epithelial integrity was done by FITC-Dextran assay. In addition, cytokines were measured in sera by ELISA and various immune cells were quantified using flow cytometry. Results Gut permeability was increased by the RA-associated bacteria and was sex and age-dependent. In vivo and in vitro observations showed that the RA-non-associated bacteria outgrow the RA-associated bacteria when gavaged or cultured together. Mice gavaged with the RA-non-associated bacteria produced lower levels of pro-inflammatory MCP-1 and MCP-3 and had lower numbers of Inflammatory monocytes CD11c+Ly6c+, when compared to controls. E. lenta treated naïve mice produce Th17 cytokines. Conclusions Our studies suggest that gut commensals influence immune response in and away from the gut by changing the gut permeability and immunity. Dysbiosis helps the growth of RA-associated bacteria and reduces the beneficial bacteria.

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

2005 ◽  
Vol 289 (2) ◽  
pp. L186-L195 ◽  
Author(s):  
Celine A. Beamer ◽  
Andrij Holian
Keyword(s):  
Scavenger Receptor ◽  
Lavage Fluid ◽  
Type I ◽  
Dependent Manner ◽  
Wild Type ◽  
Focal Lesions ◽  
Silica Exposure ◽  
Class A

Alveolar macrophages express the class A scavenger receptor (CD204) (Babaev VR, Gleaves LA, Carter KJ, Suzuki H, Kodama T, Fazio S, and Linton MF. Arterioscler Thromb Vasc Biol 20: 2593–2599, 2000); yet its role in vivo in lung defense against environmental particles has not been clearly defined. In the current study, CD204 null mice (129Sv background) were used to investigate the link between CD204 and downstream events of inflammation and fibrosis following silica exposure in vivo. CD204−/− macrophages were shown to recognize and uptake silica in vitro, although this response was attenuated compared with 129Sv wild-type mice. The production of tumor necrosis factor-α in lavage fluid was significantly enhanced in CD204 null mice compared with wild-type mice following silica exposure. Moreover, after exposure to environmental particles, CD204−/− macrophages exhibited improved cell viability in a dose-dependent manner compared with wild-type macrophages. Finally, histopathology from a murine model of chronic silicosis in 129Sv wild-type mice displayed typical focal lesions, interstitial thickening with increased connective tissue matrix, and cellular infiltrate into air space. In contrast, CD204−/− mice exhibited little to no deposition of collagen, yet they demonstrated enhanced accumulation of inflammatory cells largely composed of neutrophils. Our findings point to an important role of CD204 in mounting an efficient and appropriately regulated immune response against inhaled particles. Furthermore, these results indicate that the functions of CD204 are critical to the development of fibrosis and the resolution of inflammation.

scholarly journals HOXA9 Participates in the Transcriptional Activation of E-Selectin in Endothelial Cells

2007 ◽  
Vol 27 (12) ◽  
pp. 4207-4216 ◽  
Author(s):  
Smarajit Bandyopadhyay ◽  
Mohammad Z. Ashraf ◽  
Pamela Daher ◽  
Philip H. Howe ◽  
Paul E. DiCorleto
Keyword(s):  
Transcriptional Activation ◽  
Leukocyte Adhesion ◽  
Regulatory Element ◽  
Proximal Region ◽  
Binding Motif ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α

ABSTRACT The homeobox gene HOXA9 has recently been shown to be an important regulator of endothelial cell (EC) differentiation and activation in addition to its role in embryonic development and hematopoiesis. In this report, we have determined that the EC-leukocyte adhesion molecule E-selectin is a key target for HOXA9. The depletion of HOXA9 protein in ECs resulted in a significant and specific decrease in tumor necrosis factor alpha (TNF-α)-induced E-selectin gene expression. In addition, HOXA9 specifically activated the E-selectin gene promoter in ECs. Progressive deletional analyses together with site-specific mutagenesis of the E-selectin promoter indicated that the Abd-B-like HOX DNA-binding motif, CAATTTTATTAA, located in the proximal region spanning bp −210 to −221 upstream of the transcription start site was crucial for the promoter induction by HOXA9. Both HOXA9 in EC nuclear extract and recombinant HOXA9 protein bound to this sequence in vitro. Moreover, we showed that HOXA9 binds temporally, in a TNF-α-dependent manner, to the region containing this Abd-B-like element in vivo. We have thus identified a novel and functionally critical cis-regulatory element for TNF-α-mediated transient expression of the E-selectin gene. Further, we provide evidence that HOXA9 acts as an obligate proinflammatory factor by mediating cytokine induction of E-selectin.

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