scholarly journals miR-181a regulates the host immune response against Schistosoma japonicum infection through the TLR4 receptor pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yixiao Tang ◽  
Yuanxi Shen ◽  
Yang Hong ◽  
Zuhang Zhang ◽  
Qi Zhai ◽  
...  
Keyword(s):  
Immune Response ◽  
Schistosoma Japonicum ◽  
Post Infection ◽  
Wild Type ◽  
Receptor Ligand ◽  
Susceptible Host ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Deficient Mice ◽  
Tlr4 Receptor

Abstract Background Schistosomiasis japonica is a serious zoonotic parasitic disease. Preliminary studies have shown that the expression of microRNA-181a (miR-181a) in the liver, lung and spleen tissues of susceptible host BALB/c mice and resistant host reed vole (Microtus fortis) 10 days post-infection (dpi) with Schistosoma japonicum was significantly different from pre-infection levels. This difference suggests the possibility that miR-181a expression may be related to the regulation of the hosts’ early immune response against S. japonicum infection and thereby affect the development and survival of parasites in their final hosts. Methods BALB/c mice, M. fortis, Toll-like receptor 4 (TLR4)-deficient mice and wild-type mice (C57BL/6) were infected with S. japonicum, and differences in miR-181a expression between BALB/c mice and M. fortis over different time points post-infection (0, 3, 7, 10 and 14 dpi) were compared. MiR-181a mimic, miR-181a inhibitor and irrelevant miRNA, as well as lipopolysaccharide (LPS), a TLR4 receptor ligand, were used to transfect mouse RAW264.7 macrophages. The expression levels of the TLR4 pathway-related cytokines interleukin (IL)-1β, tumor necrosis factor α (TNF-α) and IL-6 were detected by quantitative PCR analysis. Results The expression of miR-181a was significantly upregulated in the serum and liver of mice infected with S. japonicum and downregulated in the serum and liver of M. fortis. T-helper cell (Th1)-type cytokines, such as TNF-α, IL-6 and IL-1β, and Th2-type cytokines, such as IL-10 and IL-4, were differentially expressed in M. fortis and BALB/c mice in the early stage of infection. The expression level of miR-181a in the serum was threefold higher in TLR4-deficient mice than in wild-type mice 10 dpi with S. japonicum. The expression of IL-1β, TNF-α and IL-6 decreased in RAW264.7 cells transfected with miR-181a mimic and increased in cells transfected with miR-181a inhibitor. miR-181a expression was downregulated and the expressions of TLR4 and three TLR4 pathway-related cytokines (IL-1β, IL-6, and TNF-α) were upregulated in RAW264.7 macrophages stimulated with the TLR4 receptor ligand LPS. Conclusion These results suggest the possibility of mutual regulation between miR-181a and the TLR4 signaling pathway during S. japonicum infection. miR-181a may regulate the expression of pro-inflammatory factors through the TLR4 receptor pathway and participate in the immunomodulatory effect of anti-S. japonicum infection. Graphical abstract

scholarly journals Role of Nitric Oxide in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

2009 ◽  
Vol 83 (16) ◽  
pp. 8004-8011 ◽  
Author(s):  
Young-Sun Lee ◽  
Na Li ◽  
Seungjin Shin ◽  
Hee-Sook Jun
Keyword(s):  
Virus Infection ◽  
Encephalomyocarditis Virus ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Diabetes In Mice ◽  
Tnf Α ◽  
Deficient Mice

ABSTRACT The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic β cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in β-cell destruction by producing soluble mediators such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). To investigate the role of NO and inducible NO synthase (iNOS) in the development of diabetes in EMC-D virus-infected mice, we infected iNOS-deficient DBA/2 mice with EMC-D virus (2 × 102 PFU/mouse). Mean blood glucose levels in EMC-D virus-infected iNOS-deficient mice and wild-type mice were 205.5 and 466.7 mg/dl, respectively. Insulitis and macrophage infiltration were reduced in islets of iNOS-deficient mice compared with wild-type mice at 3 days after EMC-D virus infection. Apoptosis of β cells was decreased in iNOS-deficient mice, as evidenced by reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. There were no differences in mRNA expression of antiapoptotic molecules Bcl-2, Bcl-xL, Bcl-w, Mcl-1, cIAP-1, and cIAP-2 between wild-type and iNOS-deficient mice, whereas expression of proapoptotic Bax and Bak mRNAs was significantly decreased in iNOS-deficient mice. Expression of IL-1β and TNF-α mRNAs was significantly decreased in both islets and macrophages of iNOS-deficient mice compared with wild-type mice after EMC-D virus infection. Nuclear factor κB was less activated in macrophages of iNOS-deficient mice after virus infection. We conclude that NO plays an important role in the activation of macrophages and apoptosis of pancreatic β cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and β-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.

scholarly journals Antibody Is Critical for the Clearance of Murine Norovirus Infection

2008 ◽  
Vol 82 (13) ◽  
pp. 6610-6617 ◽  
Author(s):  
Karen A. Chachu ◽  
David W. Strong ◽  
Anna D. LoBue ◽  
Christiane E. Wobus ◽  
Ralph S. Baric ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Murine Norovirus ◽  
Wild Type ◽  
Human Norovirus ◽  
Mucosal Infection ◽  
Antibody Levels ◽  
Deficient Mice ◽  
Immune Antibody

ABSTRACT Human noroviruses cause more than 90% of epidemic nonbacterial gastroenteritis. However, the role of B cells and antibody in the immune response to noroviruses is unclear. Previous studies have demonstrated that human norovirus specific antibody levels increase upon infection, but they may not be protective against infection. In this report, we used murine norovirus (MNV), an enteric norovirus, as a model to determine the importance of norovirus specific B cells and immune antibody in clearance of norovirus infection. We show here that mice genetically deficient in B cells failed to clear primary MNV infection as effectively as wild-type mice. In addition, adoptively transferred immune splenocytes derived from B-cell-deficient mice or antibody production-deficient mice were unable to efficiently clear persistent MNV infection in RAG1−/− mice. Further, adoptive transfer of either polyclonal anti-MNV serum or neutralizing anti-MNV monoclonal antibodies was sufficient to reduce the level of MNV infection both systemically and in the intestine. Together, these data demonstrate that antibody plays an important role in the clearance of MNV and that immunoglobulin G anti-norovirus antibody can play an important role in clearing mucosal infection.

The functionality of cell mediated immunity in the pathogenesis of Schistosoma japonicum

2015 ◽  
Vol 3 (4) ◽  
pp. 350-364
Author(s):  
Wen-jian Chen ◽  
Xuefeng Xie
Keyword(s):  
Immune Response ◽  
Schistosoma Japonicum ◽  
Schistosomiasis Japonica ◽  
Cell Mediated Immunity ◽  
Tissue Destruction ◽  
Mesenteric Lymph Nodes ◽  
Tnf Α ◽  
Ifn Γ ◽  
Serious Disease ◽  
Α Level

Schistosomiasis japonica is a serious disease caused by the parasitic worm Schistosoma japonicum. The induction of granulomas that form around the eggs in the liver around which are reported to be positively depends upon cell mediated immunity, and there is evidence that increased production of proinflammatory cytokine is associated with strong tissue destruction observed in Schistosomiasis japonica. We investigate the role of regulatory cytokines and cytokine antagonists in the downregulation of immune response in Schistosoma japonicum infection. Male wild type C57BL/6 mice were used, each mouse was infected with 10 cercariae of S. japonicum through the abdominal skin. Single cell suspensions of splenocytes and lymphocytes were prepared by mincing the mouse spleens and mesenteric lymph nodes. IL-10 and TGF-β downmodulate TNF-α and IL-17 production, Neutralization of TNF-α decreased IFN-γ level and the neutralization of IFN-γ decreased TNF-α level and increased IL-10 production. Our study is report that IL-10 and TGF-β are cytokines that appear to be more involved in modulation of immune response in Schistosomiasis japonica.

scholarly journals SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

2017 ◽  
Vol 42 (4) ◽  
pp. 1358-1365 ◽  
Author(s):  
Piyush Sharma ◽  
Vishal Khairnar ◽  
Ivana Vrhovac Madunić ◽  
Yogesh Singh ◽  
Aleksandra Pandyra ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Glucose Uptake ◽  
Bacterial Load ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Hepatic Expression ◽  
Cell Functions ◽  
Tnf Α ◽  
Listeria Infection ◽  
Deficient Mice

Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na+-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose concentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x104 CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1–/– mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.

scholarly journals Neutralization or Absence of the Interleukin-23 Pathway Does Not Compromise Immunity to Mycobacterial Infection

2006 ◽  
Vol 74 (11) ◽  
pp. 6092-6099 ◽  
Author(s):  
Alissa A. Chackerian ◽  
Shi-Juan Chen ◽  
Scott J. Brodie ◽  
Jeanine D. Mattson ◽  
Terrill K. McClanahan ◽  
...  
Keyword(s):  
Immune Response ◽  
Secondary Infection ◽  
Mycobacterial Infection ◽  
Effective Control ◽  
Bacterial Burden ◽  
Wild Type ◽  
Interleukin 23 ◽  
Deficient Mice ◽  
Stimulation Of

ABSTRACT Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection.

scholarly journals Genome assembly and transcriptome analysis provide insights into the anti-schistosome mechanism of Microtus fortis

2020 ◽  
Author(s):  
Hong Li ◽  
Zhen Wang ◽  
Shumei Chai ◽  
Xiong Bai ◽  
Guohui Ding ◽  
...  
Keyword(s):  
Immune Response ◽  
Genome Assembly ◽  
Post Infection ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Inflammatory Responses ◽  
Gene Annotation ◽  
Intrinsic Resistance ◽  
Schistosome Infection ◽  
Susceptible Host

ABSTRACTMicrotus fortis (M. fortis) so far is the only mammal host that exhibits intrinsic resistance against Schistosoma japonicum infection. However, the underlying molecular mechanisms of this intrinsic resistance are not yet known. Here we performed the first de novo genome assembly of M. fortis, comprehensive gene annotation and evolution analysis. Furthermore, we compared the recovery rate of schistosome, pathological change and liver transcriptome between non-permissive host M. fortis and susceptible host mouse at different time points after Schistosome infection. We reveal that Immune response of M. fortis and mouse is different in time and type. M. fortis activates immune and inflammatory responses on the 10th days post infection, involving in multiple pathways, such as leukocyte extravasation, antibody activation (especially IgG3), Fc-gamma receptor mediated phagocytosis, and interferon signaling cascade. The strong immune responses of M. fortis in early stages of infection play important roles in preventing the development of schistosome. On the contrary, intense immune response occurred in mouse in late stages of infection (28~42 days post infection), and cannot eliminate schistosome. Infected mouse suffers severe pathological injury and continuous decrease of important functions such as cell cycle and lipid metabolism. Our findings offer new insights to the intrinsic resistance mechanism of M. fortis against schistosome infection. The genome sequence also provides bases for future studies of other important traits in M. fortis.

scholarly journals Thymic Tolerance to Only One Viral Protein Reduces Lymphocytic Choriomeningitis Virus-Induced Immunopathology and Increases Survival in Perforin-Deficient Mice

1999 ◽  
Vol 73 (7) ◽  
pp. 5918-5925 ◽  
Author(s):  
Matthias von Herrath ◽  
Bryan Coon ◽  
Dirk Homann ◽  
Tom Wolfe ◽  
Luca G. Guidotti
Keyword(s):  
Immune Response ◽  
Viral Protein ◽  
Selective Reduction ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Term Survival ◽  
Tnf Α ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Lcmv Infection

ABSTRACT The outcome of viral infections is dependent on the amount of tissue destruction caused either by direct lysis of infected cells and/or by immunopathology resulting from the immune response to the virus. We investigated whether induction of tolerance to only one viral protein could reduce immunopathology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perforin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associated with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL) that secrete inflammatory cytokines. We report here that perforin-deficient mice exhibit severe immunopathology in multiple organs that is characterized by infiltration of anti-LCMV CTL that secrete large amounts of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Importantly, this immunopathology is significantly reduced and long-term survival of LCMV infection is increased in perforin-deficient mice expressing LCMV nucleoprotein (NP) in the thymus (and therefore deleting most of their LCMV-NP CTL) compared to the situation in thymus nonexpressors. This is due to the selective reduction of NP-specific CTL responses and their inflammatory-cytokine (IFN-γ and TNF-α) secretion and to a lack of pathogenetically relevant compensatory responses to other viral proteins. Thus, “selective reduction” of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeutic possibility for certain nonlytic infections.

scholarly journals CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models

2015 ◽  
Vol 93 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Alonso G.P. Guedes ◽  
Deepak A. Deshpande ◽  
Mythili Dileepan ◽  
Timothy F. Walseth ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Map Kinases ◽  
Surface Protein ◽  
Airway Smooth Muscle Cells ◽  
Wild Type ◽  
Partial Restoration ◽  
Cd38 Expression ◽  
Tnf Α ◽  
Deficient Mice

Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3′ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

IL-6 is essential in TNF-α-induced fever

1998 ◽  
Vol 275 (6) ◽  
pp. R2028-R2034 ◽  
Author(s):  
Anna K. Sundgren-Andersson ◽  
Pernilla Östlund ◽  
Tamas Bartfai
Keyword(s):  
Tumor Necrosis ◽  
Prostaglandin E ◽  
High Dose ◽  
Central Administration ◽  
Wild Type ◽  
Febrile Response ◽  
Tnf Α ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-α results in septic shock and fever. We have used interleukin-1β (IL-1β)- and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-α in fever. Briefly, the mice produced prostaglandin E2-dependent fevers in response to recombinant murine TNF-α (rmTNF-α). Furthermore, rmTNF-α (12 μg/mouse ip) triggered a febrile response in IL-1β-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-α (4.5 μg/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-α could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF-α can trigger fever independent of IL-1β but dependent on IL-6. We also suggest that central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h after pyrogenic challenge) is essential in TNF-α-induced fever.

scholarly journals Endothelial cell adhesion molecule expression in gene-targeted mice

1997 ◽  
Vol 273 (4) ◽  
pp. H1903-H1908 ◽  
Author(s):  
Michael J. Eppihimer ◽  
Janice Russell ◽  
Donald C. Anderson ◽  
Barry A. Wolitzky ◽  
D. Neil Granger
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Wild Type ◽  
Tnf Α ◽  
Endothelial Cell Adhesion Molecules ◽  
Vascular Beds ◽  
Deficient Mice ◽  
Endothelial Cell Adhesion

Gene-targeted mice are now routinely employed as tools for defining the contribution of different leukocyte and endothelial cell adhesion molecules to the leukocyte recruitment and tissue injury associated with acute and chronic inflammation. The objective of this study was to determine whether gene-targeted mice that are deficient in CD11/CD18, intracellular adhesion molecule-1 (ICAM-1), or P-selectin exhibit an altered constitutive or induced expression of the endothelial cell adhesion molecules E- and P-selectin. The gene-targeted mice were all developed in the 129Sv mouse strain and backcrossed into C57Bl/6J mice. The number of backcrosses ranged between 8 (P-selectin) and 10 (CD18 and ICAM-1) generations. The dual-radiolabeled monoclonal antibody technique was used to quantify E- and P-selectin expression in different vascular beds. In the unstimulated state, E-selectin expression was significantly elevated (relative to wild-type mice) in the stomach, large intestine, and brain of mutants deficient in ICAM-1. In general, constitutive expression of P-selectin did not differ between wild-type, ICAM-1-deficient, and CD11/CD18-deficient mutants. In CD11/CD18-deficient mice, tumor necrosis factor-α (TNF-α) administration elicited a more profound upregulation of P-selectin in several vascular beds, compared with wild-type and ICAM-1-deficient mice. E-selectin expression in brain of TNF-α-stimulated, ICAM-1-deficient, and P-selectin-deficient mice was attenuated compared with wild-type mice. These findings indicate that chronic deficiency of some of the adhesion glycoproteins that mediate leukocyte recruitment alters basal and induced surface expression of other adhesion molecules on endothelial cells.

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