scholarly journals Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

2013 ◽  
Vol 81 (7) ◽  
pp. 2309-2317 ◽  
Author(s):  
Stefanie Banik ◽  
Pablo Renner Viveros ◽  
Frank Seeber ◽  
Christian Klotz ◽  
Ralf Ignatius ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Giardia Duodenalis ◽  
Human Monocyte ◽  
Interleukin 10 ◽  
Arginine Deiminase ◽  
Infection Model ◽  
Reaction Products ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACTDepletion of arginine is a recognized strategy that pathogens use to evade immune effector mechanisms. Depletion depends on microbial enzymes such as arginases, which are considered virulence factors. The effect is mostly interpreted as being a consequence of successful competition with host enzymes for the substrate. However, both arginases and arginine deiminases (ADI) have been associated with pathogen virulence. Both deplete arginine, but their reaction products differ. An ADI has been implicated in the virulence ofGiardia duodenalis, an intestinal parasite that infects humans and animals, causing significant morbidity. Dendritic cells (DC) play a critical role in host defense and also in a murineG. duodenalisinfection model. The functional properties of these innate immune cells depend on the milieu in which they are activated. Here, the dependence of the response of these cells on arginine was studied by usingGiardiaADI and lipopolysaccharide-stimulated human monocyte-derived DC. Arginine depletion by ADI significantly increased tumor necrosis factor alpha and decreased interleukin-10 (IL-10) and IL-12p40 secretion. It also reduced the upregulation of surface CD83 and CD86 molecules, which are involved in cell-cell interactions. Arginine depletion also reduced the phosphorylation of S6 kinase in DC, suggesting the involvement of the mammalian target of rapamycin signaling pathway. The changes were due to arginine depletion and the formation of reaction products, in particular, ammonium ions. Comparison of NH4+and urea revealed distinct immunomodulatory activities of these products of deiminases and arginases, respectively. The data suggest that a better understanding of the role of arginine-depleting pathogen enzymes for immune evasion will have to take enzyme class and reaction products into consideration.

scholarly journals Infection of Human Dendritic Cells with a Mycobacterium tuberculosis sigE Mutant Stimulates Production of High Levels of Interleukin-10 but Low Levels of CXCL10: Impact on the T-Cell Response

2006 ◽  
Vol 74 (6) ◽  
pp. 3296-3304 ◽  
Author(s):  
Elena Giacomini ◽  
Ambar Sotolongo ◽  
Elisabetta Iona ◽  
Martina Severa ◽  
Maria Elena Remoli ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Human Monocyte ◽  
Interleukin 10 ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Effector Cells ◽  
Human Dendritic Cells

ABSTRACT The Mycobacterium tuberculosis genome encodes 13 sigma factors. We have previously shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and can attenuate the virulence phenotype. In this work, we focused on extracytoplasmic factor σE and studied the effects induced by the deletion of its structural gene (sigE) in the infection of human monocyte-derived dendritic cells (MDDC). We found that the wild-type M. tuberculosis strain (H37Rv), the sigE mutant (ST28), and the complemented strain (ST29) were able to infect dendritic cells (DC) to similar extents, although at 4 days postinfection a reduced ability to grow inside MDDC was observed for the sigE mutant ST28. After mycobacterium capture, the majority of MDDC underwent full maturation and expressed both inflammatory cytokines, such as tumor necrosis factor alpha, and the regulatory cytokines interleukin-12 (IL-12), IL-18, and beta interferon (IFN-β). Conversely, a higher level of production of IL-10 was observed in ST28-infected MDDC compared to H37Rv- or ST29-infected cell results. However, in spite of the presence of IL-10, supernatants from ST28-infected DC induced IFN-γ production by T cells similarly to those from H37Rv-infected DC culture. On the other hand, IL-10 impaired CXCL10 production in sigE mutant-infected DC and, indeed, its neutralization restored CXCL10 secretion. In line with these results, supernatants from ST28-infected cells showed a decreased capability to recruit CXCR3+ CD4+ T cells compared to those obtained from H37Rv-infected DC culture. Thus, our findings suggest that the sigE mutant-induced secretion of IL-10 inhibits CXCL10 expression and, in turn, the recruitment of activated-effector cells involved in the formation of granulomas.

scholarly journals Platelets Enhance Dendritic Cell Responses againstStaphylococcus aureusthrough CD40-CD40L

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Sharmeen Nishat ◽  
Leah M. Wuescher ◽  
Randall G. Worth
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Enhanced Production ◽  
Bacterial Uptake ◽  
Direct Killing

ABSTRACTStaphylococcus aureusis a major human pathogen that can cause mild to severe life-threatening infections in many tissues and organs. Platelets are known to participate in protection againstS. aureusby direct killing and by enhancing the activities of neutrophils and macrophages in clearingS. aureusinfection. Platelets have also been shown to induce monocyte differentiation into dendritic cells and to enhance activation of dendritic cells. Therefore, in the present study, we explored the role of platelets in enhancing bone marrow-derived dendritic cell (BMDC) function againstS. aureus. We observed a significant increase in dendritic cell phagocytosis and intracellular killing of a methicillin-resistantStaphylococcus aureus(MRSA) strain (USA300) by thrombin-activated platelets or their releasates. Enhancement of bacterial uptake and killing by DCs is mediated by platelet-derived CD40L. Coculture of USA300 and BMDCs in the presence of thrombin-activated platelet releasates invokes upregulation of the maturation marker CD80 on DCs and enhanced production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), and IL-6. Overall, these observations support our hypothesis that platelets play a critical role in the host defense againstS. aureusinfection. Platelets stimulate DCs, leading to direct killing ofS. aureusand enhanced DC maturation, potentially leading to adaptive immune responses againstS. aureus.

scholarly journals The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells

2013 ◽  
Vol 81 (9) ◽  
pp. 3300-3308 ◽  
Author(s):  
Edwin Garzón ◽  
Philippe Holzmuller ◽  
Rachel Bras-Gonçalves ◽  
Philippe Vincendeau ◽  
Gérard Cuny ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Trypanosoma Brucei ◽  
Cytokine Production ◽  
Interleukin 10 ◽  
Host Immune System ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Host Immune Responses ◽  
Trypanosoma Brucei Gambiense ◽  
Factor Alpha

ABSTRACTTrypanosoma brucei gambiense, a parasitic protozoan belonging to kinetoplastids, is the main etiological agent of human African trypanosomiasis (HAT), or sleeping sickness. One major characteristic of this disease is the dysregulation of the host immune system. The present study demonstrates that the secretome (excreted-secreted proteins) ofT. b. gambienseimpairs the lipopolysaccharide (LPS)-induced maturation of murine dendritic cells (DCs). The upregulation of major histocompatibility complex class II, CD40, CD80, and CD86 molecules, as well as the secretion of cytokines such as tumor necrosis factor alpha, interleukin-10 (IL-10), and IL-6, which are normally released at high levels by LPS-stimulated DCs, is significantly reduced when these cells are cultured in the presence of theT. b. gambiensesecretome. Moreover, the inhibition of DC maturation results in the loss of their allostimulatory capacity, leading to a dramatic decrease in Th1/Th2 cytokine production by cocultured lymphocytes. These results provide new insights into a novel efficient immunosuppressive mechanism directly involving the alteration of DC function which might be used byT. b. gambienseto interfere with the host immune responses in HAT and promote the infectious process.

scholarly journals CD4+ CD25+ Foxp3+ Regulatory T Cells, Dendritic Cells, and Circulating Cytokines in Uncomplicated Malaria: Do Different Parasite Species Elicit Similar Host Responses?

2010 ◽  
Vol 78 (11) ◽  
pp. 4763-4772 ◽  
Author(s):  
Raquel M. Gonçalves ◽  
Karina C. Salmazi ◽  
Bianca A. N. Santos ◽  
Melissa S. Bastos ◽  
Sandra C. Rocha ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Parasite Species ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Surface Expression ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Experimental Models ◽  
Necrosis Factor Alpha

ABSTRACT Clearing blood-stage malaria parasites without inducing major host pathology requires a finely tuned balance between pro- and anti-inflammatory responses. The interplay between regulatory T (Treg) cells and dendritic cells (DCs) is one of the key determinants of this balance. Although experimental models have revealed various patterns of Treg cell expansion, DC maturation, and cytokine production according to the infecting malaria parasite species, no studies have compared all of these parameters in human infections with Plasmodium falciparum and P. vivax in the same setting of endemicity. Here we show that during uncomplicated acute malaria, both species induced a significant expansion of CD4+ CD25+ Foxp3+ Treg cells expressing the key immunomodulatory molecule CTLA-4 and a significant increase in the proportion of DCs that were plasmacytoid (CD123+), with a decrease in the myeloid/plasmacytoid DC ratio. These changes were proportional to parasite loads but correlated neither with the intensity of clinical symptoms nor with circulating cytokine levels. One-third of P. vivax-infected patients, but no P. falciparum-infected subjects, showed impaired maturation of circulating DCs, with low surface expression of CD86. Although vivax malaria patients overall had a less inflammatory cytokine response, with a higher interleukin-10 (IL-10)/tumor necrosis factor alpha (TNF-α) ratio, this finding did not translate to milder clinical manifestations than those of falciparum malaria patients. We discuss the potential implications of these findings for species-specific pathogenesis and long-lasting protective immunity to malaria.

scholarly journals IN LABORATORY GENERATION AND MATURATION OF HUMAN MONOCYTE-DERIVED DENDRITIC CELLS FOR CANCER IMMUNOTHERAPY

2020 ◽  
pp. 46-52
Author(s):  
KANCHAN K. MISHRA ◽  
SUMIT BHARADVA ◽  
MEGHNAD G. JOSHI ◽  
ARVIND GULBAKE
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Gradient Centrifugation ◽  
Critical Role ◽  
Human Monocyte ◽  
Blood Monocytes ◽  
Adaptive Immune ◽  
Immunodeficiency Virus ◽  
Adaptive Immune Systems

Dendritic cells (DCs) play a critical role in the regulation of adaptive immune responses, furthermore they act as a bridge between the innate and the adaptive immune systems they have been ideal candidates for cell-based immunotherapy of cancers and infections in humans. The first reported trial using DCs in 1995, since they have been used in trials all over the world for several of indications, including cancer and human immunodeficiency virus infection. Generally, for in vitro experiments or for DCs vaccination monocyte-derived dendritic cells (moDCs) were generated from purified monocytes that isolated from peripheral blood by density gradient centrifugation. A variety of methods can be used for enrichment of monocytes for generation of clinical-grade DCs. Herein we summarized up to date understanding of systems and inputs used in procedures to differentiate DCs from blood monocytes in vitro.

scholarly journals Eyedrop Inoculation Causes Sublethal Leptospirosis in Mice

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Joseph Pierce Sullivan ◽  
Nisha Nair ◽  
Hari-Hara Potula ◽  
Maria Gomes-Solecki
Keyword(s):  
Periodic Acid ◽  
Interleukin 10 ◽  
Periodic Acid Schiff ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Infectious Dose ◽  
Inflammatory Protein ◽  
Mucosal Surfaces ◽  
Infected Urine ◽  
Mononuclear Cell Infiltrates

ABSTRACT Leptospirosis is potentially a fatal zoonosis acquired by contact of skin and mucosal surfaces with soil and water contaminated with infected urine. We analyzed the outcome of infection of C3H/HeJ mice with Leptospira interrogans serovar Copenhageni using an enzootic mode of transmission, the conjunctival route. Infection led to weight loss and L. interrogans dissemination from blood to urine, and spirochetes were detected in blood and urine simultaneously. The infectious dose that led to consistent dissemination to kidney after conjunctival infection was ∼108 leptospires. Interestingly, a lower number of spirochetes appeared to colonize the kidney, given that we quantified ∼105 and ∼10 leptospires per μl of urine and per μg of kidney, respectively. Leptospira-specific IgM and IgG were detected at 15 days postinfection, and isotyping of the Ig subclass showed that the total IgG response switched from an IgG1 response to an IgG3 response after infection with L. interrogans. Histological periodic acid-Schiff D staining of infected kidney showed interstitial nephritis, mononuclear cell infiltrates, and reduced size of glomeruli. Quantification of proinflammatory immunomediators in kidney showed that keratinocyte-derived chemokine, macrophage inflammatory protein 2, RANTES, tumor necrosis factor alpha, gamma interferon, and interleukin-10 were upregulated in infected mice. We show that the kinetics of disease progression after infection via the ocular conjunctiva is delayed compared with infection via the standard intraperitoneal route. Differences may be related to the number of L. interrogans spirochetes that succeed in overcoming the natural defenses of the ocular conjunctiva and transit through tissue.

scholarly journals The Host Antimicrobial Protein Calgranulin C Participates in the Control ofCampylobacter jejuniGrowth via Zinc Sequestration

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Janette M. Shank ◽  
Brittni R. Kelley ◽  
Joseph W. Jackson ◽  
Jessica L. Tweedie ◽  
Dana Franklin ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Serum Levels ◽  
Interleukin 10 ◽  
Poultry Meat ◽  
Antimicrobial Protein ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Full Resolution ◽  
Factor Alpha

ABSTRACTCampylobacter jejuniis a leading cause of bacterially derived gastroenteritis worldwide.Campylobacteris most commonly acquired through the consumption of undercooked poultry meat or through drinking contaminated water. Following ingestion,Campylobacteradheres to the intestinal epithelium and mucus layer, causing toxin-mediated inflammation and inhibition of fluid reabsorption. Currently, the human response to infection is relatively unknown, and animal hosts that model these responses are rare. As such, we examined patient fecal samples for the accumulation of the neutrophil protein calgranulin C during infection withCampylobacter jejuni. In response to infection, calgranulin C was significantly increased in the feces of humans. To determine whether calgranulin C accumulation occurs in an animal model, we examined disease in ferrets. Ferrets were effectively infected byC. jejuni, with peak fecal loads observed at day 3 postinfection and full resolution by day 12. Serum levels of interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α) significantly increased in response to infection, which resulted in leukocyte trafficking to the colon. As a result, calgranulin C increased in the feces of ferrets at the time whenC. jejuniloads decreased. Further, the addition of purified calgranulin C toC. jejunicultures was found to inhibit growth in a zinc-dependent manner. These results suggest that upon infection withC. jejuni, leukocytes trafficked to the intestine release calgranulin C as a mechanism for inhibitingC. jejunigrowth.

scholarly journals Staphylococcus aureusImpairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Evelien T. M. Berends ◽  
Xuhui Zheng ◽  
Erin E. Zwack ◽  
Mickaël M. Ménager ◽  
Michael Cammer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Adaptive Immunity ◽  
T Cell Activation ◽  
Antigen Presenting Cells ◽  
Infection Model ◽  
High Morbidity ◽  
Content Type ◽  
Human Dendritic Cells ◽  
Antigen Presenting

ABSTRACTStaphylococcus aureusis a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting thatS. aureusthwarts the development of sterilizing immunity.S. aureusstrains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense againstS. aureusinfections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using anex vivoinfection model of primary human monocyte-derived dendritic cells, we found thatS. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed thatS. aureustargets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy ofS. aureuswhereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs.IMPORTANCEAntigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect ofStaphylococcus aureustoxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability ofS. aureusto blunt the function of DCs could help explain the high frequency of recurrentS. aureusinfections. Taken together, the results from this study suggest that therapeutically targeting theS. aureusleukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.

scholarly journals Substrate Interaction with the EssC Coupling Protein of the Type VIIb Secretion System

2020 ◽  
Vol 202 (7) ◽  
Author(s):  
Nicole Mietrach ◽  
Diana Damián-Aparicio ◽  
Benjamin Mielich-Süss ◽  
Daniel Lopez ◽  
Sebastian Geibel
Keyword(s):  
Critical Role ◽  
Secretion System ◽  
Effector Proteins ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Atpase Domain ◽  
Bacterial Persistence ◽  
Substrate Transport ◽  
Content Type ◽  
Coupling Protein

ABSTRACT Staphylococcus aureus employs the type VIIb secretion system (T7SSb) to secrete effector proteins that either have antibacterial activities or promote bacterial persistence in mouse infection models. Here, we present the crystal structure of the ATPase domain D3 of the EssC coupling protein from S. aureus USA300_FPR3757, an integral component of the T7SSb complex, resolved at a 1.7-Å resolution. EssC-D3 shares structural homology with FtsK/SpoIII-like ATPase domains of T7SSa and T7SSb and exhibits a conserved pocket on the surface with differential amino acid composition. In T7SSa, substrate EsxB interacts with the D3 domain through this pocket. Here, we identify amino acids in this pocket that are essential for effector protein secretion in the T7SSb. Our results reveal that the adjacent ATPase domain D2 is a substrate binding site on EssC and that substrates bound to D2 require domain D3 for further transport. Point mutations in the Walker B motif of domain D3 have diametric effects on secretion activity, either abolishing or boosting it, pointing to a critical role of domain D3 in the substrate transport. Finally, we identify ATPase domain D3 as a virulence determinant of S. aureus USA300_FPR3757 using an invertebrate in vivo infection model. IMPORTANCE The emergence of antibiotic-resistant bacteria poses a rising problem in antibiotic treatment (S. Boyle-Vavra and R. S. Daum, Lab Invest 87:3–9, 2007, https://doi.org/10.1038/labinvest.3700501). We have used the multidrug-resistant S. aureus USA300_FPR3757 as a model organism to study the T7SSb. Effector proteins of this system have been associated with abscess formation and bacterial persistence in mouse models (M. L. Burts, A. C. DeDent, and D. M. Missiakas, Mol Microbiol 69:736–746, 2008, https://doi.org/10.1111/j.1365-2958.2008.06324.x; M. L. Burts, W. A. Williams, K. DeBord, and D. M. Missiakas, Proc Natl Acad Sci U S A 102:1169–1174, 2005, https://doi.org/10.1073/pnas.0405620102). We determined the structure of the essential ATPase domain D3 of the T7SSb at atomic resolution and validated a surface-exposed pocket as a potential drug target to block secretion. Furthermore, our study provides new mechanistic insights into the T7SSb substrate transport.

scholarly journals Chlamydia psittaci-Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Nadine Radomski ◽  
Axel Karger ◽  
Kati Franzke ◽  
Elisabeth Liebler-Tenorio ◽  
Rico Jahnke ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Early Response ◽  
Chlamydia Psittaci ◽  
Target Cells ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Host Cell Death ◽  
Ifn Γ

ABSTRACT Dendritic cells (DCs) and natural killer (NK) cells are critically involved in the early response against various bacterial microbes. Functional activation of infected DCs and NK cell-mediated gamma interferon (IFN-γ) secretion essentially contribute to the protective immunity against Chlamydia. How DCs and NK cells cooperate during the antichlamydial response is not fully understood. Therefore, in the present study, we investigated the functional interplay between Chlamydia-infected DCs and NK cells. Our biochemical and cell biological experiments show that Chlamydia psittaci-infected DCs display enhanced exosome release. We find that such extracellular vesicles (referred to as dexosomes) do not contain infectious bacterial material but strongly induce IFN-γ production by NK cells. This directly affects C. psittaci growth in infected target cells. Furthermore, NK cell-released IFN-γ in cooperation with tumor necrosis factor alpha (TNF-α) and/or dexosomes augments apoptosis of both noninfected and infected epithelial cells. Thus, the combined effect of dexosomes and proinflammatory cytokines restricts C. psittaci growth and attenuates bacterial subversion of apoptotic host cell death. In conclusion, this provides new insights into the functional cooperation between DCs, dexosomes, and NK cells in the early steps of antichlamydial defense.

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