scholarly journals LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor

2012 ◽  
Vol 210 (1) ◽  
pp. 5-13 ◽  
Author(s):  
Xin-Jiang Lu ◽  
Jiong Chen ◽  
Chao-Hui Yu ◽  
Yu-Hong Shi ◽  
Yu-Qing He ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Polymorphonuclear Neutrophils ◽  
Bacterial Sepsis ◽  
Bacterial Killing ◽  
Improved Outcome ◽  
Multifunctional Cytokine

Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional cytokine and reduced plasma levels were found in patients with sepsis. However, precise functions and mechanisms of LECT2 remain unclear. The aim of the present study was to determine the role of LECT2 in modulating immune responses using mouse sepsis models. We found that LECT2 treatment improved outcome in mice with bacterial sepsis. Macrophages (MΦ), but not polymorphonuclear neutrophils, mediated the beneficial effect of LECT2 on bacterial sepsis. LECT2 treatment could alter gene expression and enhance phagocytosis and bacterial killing of MΦ in vitro. CD209a was identified to specifically interact with LECT2 and mediate LECT2-induced MΦ activation. CD209a-expressing MΦ was further confirmed to mediate the effect of LECT2 on sepsis in vivo. Our data demonstrate that LECT2 improves protective immunity in bacterial sepsis, possibly as a result of enhanced MΦ functions via the CD209a receptor. The modulation of MΦ functions by LECT2 may serve as a novel potential treatment for sepsis.

scholarly journals Role of Type I Interferons on Filovirus Pathogenesis

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 22 ◽  
Author(s):  
Beatriz Escudero-Pérez ◽  
César Muñoz-Fontela
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Marburg Virus ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune ◽  
Antigen Presenting

Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the ability of antigen-presenting cells to initiate adaptive immune responses. However, in recent years, a number of studies have underscored the conflicting data between in vitro studies and in vivo data obtained in animal models and clinical studies during outbreaks. This review aims to summarize these data and to discuss the relative contributions of IFN-α and IFN-β to filovirus pathogenesis in animal models and humans. Finally, we evaluate the putative utilization of IFN-I in post-exposure therapy and its implications as a biomarker of vaccine efficacy.

scholarly journals The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Shuang Wang ◽  
Xueyang Zou ◽  
Yi Zhang ◽  
Xiaoya Wang ◽  
Wei Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Immune Responses ◽  
Autoimmune Diseases ◽  
Hot Spot ◽  
Exploratory Stage ◽  
And Function

Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.

scholarly journals Analysis of the Role of TpUB05 Antigen from Theileria parva in Immune Responses to Malaria in Humans Compared to Its Homologue in Plasmodium falciparum the UB05 Antigen

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 271
Author(s):  
Jerome Nyhalah Dinga ◽  
Stephanie Numenyi Perimbie ◽  
Stanley Dobgima Gamua ◽  
Francis N. G. Chuma ◽  
Dieudonné Lemuh Njimoh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Theileria Parva ◽  
Peripheral Blood Mononuclear ◽  
Significant Difference ◽  
First Time

Despite the amount of resources deployed and the technological advancements in molecular biology, vaccinology, immunology, genetics, and biotechnology, there are still no effective vaccines against malaria. Immunity to malaria is usually seen to be species- and/or strain-specific. However, there is a growing body of evidence suggesting the possibility of the existence of cross-strain, cross-species, and cross-genus immune responses in apicomplexans. The principle of gene conservation indicates that homologues play a similar role in closely related organisms. The homologue of UB05 in Theileria parva is TpUB05 (XP_763711.1), which has been tested and shown to be associated with protective immunity in East Coast fever. In a bid to identify potent markers of protective immunity to aid malaria vaccine development, TpUB05 was tested in malaria caused by Plasmodium falciparum. It was observed that TpUB05 was better at detecting antigen-specific antibodies in plasma compared to UB05 when tested by ELISA. The total IgG raised against TpUB05 was able to block parasitic growth in vitro more effectively than that raised against UB05. However, there was no significant difference between the two study antigens in recalling peripheral blood mononuclear cell (PBMC) memory through IFN-γ production. This study suggests, for the first time, that TpUB05 from T. parva cross-reacts with UB05 from P. falciparum and is a marker of protective immunity in malaria. Hence, TpUB05 should be considered for possible development as a potential subunit vaccine candidate against malaria.

scholarly journals Downregulation of Microparticle Release and Pro-Inflammatory Properties of Activated Human Polymorphonuclear Neutrophils by LMW Fucoidan

2018 ◽  
Vol 11 (4) ◽  
pp. 330-346 ◽  
Author(s):  
João Alfredo Moraes ◽  
Ana Clara Frony ◽  
Pedro Barcellos-de-Souza ◽  
Marcel Menezes da Cunha ◽  
Thayanne Brasil Barbosa Calcia ◽  
...  
Keyword(s):  
Polymorphonuclear Neutrophils ◽  
In Vivo Experiments ◽  
Formyl Peptide ◽  
Human Pmns ◽  
Oxidative Effects ◽  
Species Production ◽  
Bacterial Products

Exposition of neutrophils (polymorphonuclear neutrophils, PMNs) to bacterial products triggers exacerbated activation of these cells, increasing their harmful effects on host tissues. We evaluated the possibility of interfering with the classic immune innate responses of human PMNs exposed to bacterial endotoxin (lipopolysaccharide, LPS), and further stimulated with bacterial formyl peptide (N-formyl-methionine-leucine-phenylalanine, fMLP). We showed that the low- molecular-weight fucoidan (LMW-Fuc), a polysaccharide extracted from brown algae, attenuated the exacerbated activation induced by fMLP on LPS-primed PMNs, in vitro, impairing chemotaxis, NET formation, and the pro-survival and pro-oxidative effects. LMW-Fuc also inhibited the activation of canonical signaling pathways, AKT, bad, p47phox and MLC, activated by the exposition of PMN to bacterial products. The activation of PMN by sequential exposure to LPS and fMLP induced the release of L-selectin+ microparticles, which were able to trigger extracellular reactive oxygen species production by fresh PMNs and macrophages. Furthermore, we observed that LMW-Fuc inhibited microparticle release from activated PMN. In vivo experiments showed that circulating PMN-derived microparticles could be detected in mice exposed to bacterial products (LPS/fMLP), being downregulated in animals treated with LMW-Fuc. The data highlight the autocrine and paracrine role of pro-inflammatory microparticles derived from activated PMN and demonstrate the anti-inflammatory effects of LMW-Fuc on these cells.

EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi167-vi168
Author(s):  
Manuela Silginer ◽  
Eleanna Papa ◽  
Emese Szabo ◽  
Flavio Vasella ◽  
Patrick Roth ◽  
...  
Keyword(s):  
Immune Responses ◽  
Synergistic Effects ◽  
Glioma Cells ◽  
Immunodeficient Mice ◽  
Glioma Growth ◽  
Pathway Inhibition ◽  
Murine Glioma

Abstract Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.

in vivo and in vitro analysis of the functional role of Epstein-Barr virus-induced gene 3 (EBI3) for regulation of Th2 mediated immune responses

2003 ◽  
Vol 124 (4) ◽  
pp. A335
Author(s):  
Stefan J. Wirtz ◽  
Christoph Becker ◽  
Edward E.S. Nieuwenhuis ◽  
Mark Birkenbach ◽  
Richard S. Blumberg ◽  
...  
Keyword(s):  
Immune Responses ◽  
Functional Role ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals A Francisella tularensis SCHU S4 mutant deficient in γ-glutamyltransferase activity induces protective immunity: characterization of an attenuated vaccine candidate

Microbiology ◽  
2011 ◽  
Vol 157 (11) ◽  
pp. 3172-3179 ◽  
Author(s):  
Philip M. Ireland ◽  
Helen LeButt ◽  
Rebecca M. Thomas ◽  
Petra C. F. Oyston
Keyword(s):  
Mutant Strain ◽  
Francisella Tularensis ◽  
Protective Immunity ◽  
Attenuated Vaccine ◽  
Schu S4 ◽  
Glutamyl Transpeptidase

Francisella tularensis is an intracellular pathogen which causes tularaemia. There is no licensed vaccine currently available for prophylaxis. The γ-glutamyl transpeptidase (GGT) encoded by the ggt gene has been shown to be important for the intracellular survival of F. tularensis. In this study we have constructed a ggt deletion mutant in the highly virulent F. tularensis strain SCHU S4. Characterization of the mutant strain confirmed the function of ggt, and confirmed the role of GGT in cysteine acquisition. The mutant strain was highly attenuated both in vitro and in vivo using murine models of infection. Moreover, we have demonstrated that the attenuated mutant is able to induce protective immunity against an F. tularensis SCHU S4 challenge, and thus may be a candidate for the development of an attenuated vaccine.

scholarly journals Febrile temperatures increase in vitro antibody affinity for malaria and dengue antigens

2018 ◽  
Author(s):  
Razvan C. Stan ◽  
Katia S. Françoso ◽  
Rubens P.S. Alves ◽  
Luís Carlos S. Ferreira ◽  
Irene S. Soares ◽  
...  
Keyword(s):  
Immune Responses ◽  
Binding Affinity ◽  
The Body ◽  
Antibody Affinity ◽  
Positive Role ◽  
Protein Partners ◽  
Adaptive Role

AbstractFever is a regulated elevation in the body setpoint temperature and may arise as a result of infectious and noninfectious causes. While beneficial in modulating immune responses to infection, the potential of febrile temperatures in regulating antigen binding affinity to antibodies has not been explored. We have investigated this process under in vitro conditions using selected malaria or dengue antigens and specific monoclonal antibodies, and observed a marked increase in the affinity of these antibody-antigen complexes at 40°C, compared to physiological (37°C) or pathophysiological temperatures (42°C). Induced thermal equilibration of the protein partners at these temperatures, prior to measurements, further increased their binding affinity. These results may indicate an unexpected beneficial and adaptive role for fever in vivo, and highlight the positive role of thermal priming in enhancing protein-protein affinity for samples of scarce availability.

Immunological and pathological responses in BALB/c mice induced by genetic administration ofTc13 Tul antigen ofTrypanosoma cruzi

Parasitology ◽  
2006 ◽  
Vol 132 (6) ◽  
pp. 855-866 ◽  
Author(s):  
G. A. GARCÍA ◽  
M. R. ARNAIZ ◽  
S. A. LAUCELLA ◽  
M. I. ESTEVA ◽  
N. AINCIART ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Encoding ◽  
Genetic Immunization ◽  
Humoral Immune ◽  
Specific Memory ◽  
Family Protein ◽  
Ifn Γ

Tc13 is atrans-sialidase family protein ofTrypanosoma cruzi, the aetiological agent of Chagas' disease. Recently,in vitrostudies had suggested thatTc13 might participate in the pathogenesis of the disease. In order to study the role ofTc13 antigens in anin vivomodel, we administered plasmid DNA encoding aTc13 antigen from the Tulahuén strain (Tc13 Tul) to BALB/c mice and evaluated the immunological and pathological manifestations as well as the capacity of this antigen to confer protection againstT. cruziinfection.Tc13 Tul immunization did not elicit a detectable humoral immune response but induced specific memory T-cells with no capacity to produce IFN-γ. Five months after DNA-immunization withTc13 Tul, signs of hepatotoxicity and reactive changes in the heart, liver and spleen were observed in 40–80% of mice. WhenTc13 Tul DNA-immunized animals were challenged with trypomastigotes, a significant decrease in parasitaemia in early and late acute phase was observed without modification in the survival rate. Surprisingly,Tc13 Tul-immunized mice chronically infected withT. cruzishowed a decrease in the severity of heart damage. We conclude that, in BALB/c mice, genetic immunization withTc13 Tul mainly induces immune responses associated with pathology.

scholarly journals New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation

2019 ◽  
Author(s):  
Jeannette L. Tenthorey ◽  
Roberto A. Chavez ◽  
Thornton W. Thompson ◽  
Katherine A. Deets ◽  
Russell E. Vance ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mutant Mouse ◽  
Adaptor Protein ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Biological Functions ◽  
Inflammasome Component

ABSTRACTThe NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.

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