scholarly journals Poxvirus-encoded TNF receptor homolog dampens inflammation and protects the host from uncontrolled lung pathology and death during respiratory infection

2020 ◽  
Author(s):  
Zahrah Al Rumaih ◽  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Pratikshya Pandey ◽  
Sergio M. Pontejo ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Lung Pathology ◽  
Tnf Receptor ◽  
Response Modifier ◽  
Inflammatory Cytokine Production ◽  
Lethal Infection ◽  
Ifn Γ ◽  
Necrosis Factor

AbstractEctromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both viruses encode tumor necrosis factor receptor (TNFR) homologs termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain termed smallpox virus-encoded chemokine receptor (SECRET) domain. Infection of ECTV-resistant C57BL/6 mice with an ECTV CrmD deletion mutant resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production but viral load was not affected. CrmD dampened lung pathology, leukocyte recruitment and inflammatory cytokines including TNF, IL-6, IL-10 and IFN-γ. Blockade of IL-6, IL-10R or TNF function with monoclonal antibodies reduced lung pathology and provided 60-100% protection from an otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were deleted but it was neither necessary nor sufficient to cause pathology when only the CrmD SECRET domain was expressed by virus.

scholarly journals Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection

2020 ◽  
Vol 117 (43) ◽  
pp. 26885-26894
Author(s):  
Zahrah Al Rumaih ◽  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Pratikshya Pandey ◽  
Sergio M. Pontejo ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Lung Pathology ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Reverse Signaling ◽  
Ifn Γ

Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1β, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti–IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.

scholarly journals TNF deficiency dysregulates inflammatory cytokine production leading to lung pathology and death during respiratory poxvirus infection

2019 ◽  
Author(s):  
Ma. Junaliah Tuazon Kels ◽  
Esther Ng ◽  
Zahrah Al Rumaih ◽  
Pratikshya Pandey ◽  
Sigrid R. Ruuls ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Cytokine Signaling ◽  
Lung Pathology ◽  
Suppressor Of Cytokine Signaling ◽  
Inflammatory Cytokine Production ◽  
Significant Pathology ◽  
Ifn Γ ◽  
Necrosis Factor ◽  
Severe Lung

AbstractExcessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused significant pathology during respiratory ectromelia virus (ECTV) infection, a surrogate mouse model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those expressing only transmembrane TNF, recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines IL-6, IL-10, TGF-β, and IFN-γ. Blockade of these cytokines reduced lung pathology concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Short-term inhibition of STAT3 activation in ECTV-infected TNF-/- mice with an inhibitor reduced lung pathology. TNF is essential for regulating inflammation and its deficiency exacerbates ECTV infection as a consequence of significant lung pathology caused by dysregulation of inflammatory cytokine production, in part via overactivation of STAT3.

scholarly journals A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of  T Cells

1997 ◽  
Vol 185 (10) ◽  
pp. 1777-1783 ◽  
Author(s):  
Daniel E. Speiser ◽  
Soo Young Lee ◽  
Brian Wong ◽  
Joseph Arron ◽  
Angela Santana ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Cytokine Production ◽  
Biological Effects ◽  
Tumor Necrosis Factor Receptor ◽  
Tnf Receptor ◽  
Cell Type ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Necrosis Factor

Tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) and TRAF1 were found as components of the TNFR2 signaling complex, which exerts multiple biological effects on cells such as cell proliferation, cytokine production, and cell death. In the TNFR2-mediated signaling pathways, TRAF2 works as a mediator for activation signals such as NF-κB, but the role of TRAF1 has not been previously determined. Here we show in transgenic mice that TRAF1 overexpression inhibits antigen-induced apoptosis of CD8+ T lymphocytes. Our results demonstrate a biological role for TRAF1 as a regulator of apoptotic signals and also support the hypothesis that the combination of TRAF proteins in a given cell type determines distinct biological effects triggered by members of the TNF receptor superfamily.

scholarly journals Increased Mortality and Dysregulated Cytokine Production in Tumor Necrosis Factor Receptor 1-Deficient Mice following Systemic Klebsiella pneumoniae Infection

2003 ◽  
Vol 71 (9) ◽  
pp. 4891-4900 ◽  
Author(s):  
Thomas A. Moore ◽  
Michelle L. Perry ◽  
Andrew G. Getsoian ◽  
Christine L. Monteleon ◽  
Anna L. Cogen ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Klebsiella Pneumoniae ◽  
Tumor Necrosis ◽  
Cytokine Production ◽  
Lymphocyte Subsets ◽  
Tumor Necrosis Factor Receptor ◽  
Tnf Α ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT A significant clinical complication of pulmonary infections with Klebsiella pneumoniae is peripheral blood dissemination, resulting in a systemic infection concurrent with the localized pulmonary infection. In this context, little is known about the role of tumor necrosis factor receptor 1 (TNFR1)-mediated innate immune responses during systemic Klebsiella infections. Mice lacking TNFR1 were significantly more susceptible to Klebsiella-induced mortality following intravenous inoculation. Bacterial clearance was impaired in TNFR1-deficient mice at early times following infection. Unexpectedly, bacterial burdens at the onset of mortality (days 2 to 3 postinfection) were not higher in mice lacking TNFR1. However, elevated production of liver-associated proinflammatory cytokines (interleukin-12, tumor necrosis factor alpha [TNF-α[, and gamma interferon [IFN-γ]) and chemokines (MIP-1α, MIP-2, and MCP-1) was observed within the first 24 h of infection. Additionally, excessive plasma-associated IFN-γ was also observed late in the course of infection (day 3). Spleen cells from day-3 infected TNFR1-deficient mice secreted markedly enhanced levels of IFN-γ when cultured in vitro. Additionally, there was a marked increase in the total number of activated lymphocyte subsets as indicated by CD69 upregulation. A notable exception was the sharp decrease in the frequency of splenic NK T cells in infected TNFR1 knockout (KO) mice. Anti-TNF-α therapy in TNFR1 KO mice significantly reduced chemokine production and liver injury. Combined, these data indicate a dysregulated antibacterial host response following intravenous Klebsiella infection in the absence of TNFR1 signaling, resulting in heightened cytokine production and hyperactivation of specific splenic lymphocyte subsets.

scholarly journals Mapping of Equine Lentivirus Receptor 1 Residues Critical for Equine Infectious Anemia Virus Envelope Binding

2007 ◽  
Vol 82 (3) ◽  
pp. 1204-1213 ◽  
Author(s):  
Baoshan Zhang ◽  
Chengqun Sun ◽  
Sha Jin ◽  
Michael Cascio ◽  
Ronald C. Montelaro
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Functional Receptor ◽  
Herpesvirus Entry Mediator ◽  
Necrosis Factor

ABSTRACT The equine lentivirus receptor 1 (ELR1), a member of the tumor necrosis factor receptor (TNFR) protein family, has been identified as a functional receptor for equine infectious anemia virus (EIAV). Toward defining the functional interactions between the EIAV SU protein (gp90) and its ELR1 receptor, we mapped the gp90 binding domain of ELR1 by a combination of binding and functional assays using the EIAV SU gp90 protein and various chimeric receptor proteins derived from exchanges between the functional ELR1 and the nonbinding homolog, mouse herpesvirus entry mediator (murine HveA). Complementary exchanges of the respective cysteine-rich domains (CRD) between the ELR1 and murine HveA proteins revealed CRD1 as the predominant determinant of functional gp90 binding to ELR1 and also to a chimeric murine HveA protein expressed on the surface of transfected Cf2Th cells. Mutations of individual amino acids in the CRD1 segment of ELR1 and murine HveA indicated the Leu70 in CRD1 as essential for functional binding of EIAV gp90 and for virus infection of transduced Cf2Th cells. The specificity of the EIAV SU binding domain identified for the ELR1 receptor is fundamentally identical to that reported previously for functional binding of feline immunodeficiency virus SU to its coreceptor CD134, another TNFR protein. These results indicate unexpected common features of the specific mechanisms by which diverse lentiviruses can employ TNFR proteins as functional receptors.

Polymorphism A36G of the tumor necrosis factor receptor 1 gene is associated with PAI-1 levels in obese women

2007 ◽  
Vol 97 (01) ◽  
pp. 62-66 ◽  
Author(s):  
Alenka Mavri ◽  
Delphine Bastelica ◽  
Marjorie Poggi ◽  
Pierre Morange ◽  
Franck Peiretti ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Plasma Concentrations ◽  
Tumor Necrosis Factor Receptor ◽  
Tnf Receptor ◽  
Obese Women ◽  
The Metabolic Syndrome ◽  
Necrosis Factor ◽  
Pai 1

SummaryThe tumor necrosis factor (TNF) pathway may be implicated in etiopathogenesis of PAI-1 overexpression during obesity. The aim of this study was to investigate the influence of polymorphismA36G of the TNF receptor 1 (TNFRSF1A +36A/G) on plasma concentrations of PAI-1 in 163 obese (31 with the metabolic syndrome, MetS) and 150 lean, healthy women. Genotypic and allele frequencies did not significantly differ between obese and lean subjects. TNFRSF1A genotypes were significantly associated with sTNFR1 plasma levels in obese women only (p<0.01); TNFRSF1A +36G/G obese carriers exhibited higher sTNFR1 and PAI-1 levels than A carriers (p<0.01 and p<0.05, respectively). In obese women, the presence of the MetS significantly potentiated the elevation of sTNFR1 and PAI-1 levels observed in the TNFRSF1A+36G/G carriers. Our results suggest that association between TNFRSF1A +36G/G genotype and the MetS renders obese women more prone to activation of the TNF pathway reflected by high circulating sTNFR1 and PAI-1 levels.

Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL)

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3617-3623 ◽  
Author(s):  
Shino Hanabuchi ◽  
Norihiko Watanabe ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Tomoki Ito ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Necrosis Factor Receptor ◽  
Type I ◽  
Cell Cytotoxicity ◽  
Cpg Odn ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity ◽  
Necrosis Factor

Plasmacytoid dendritic cell precursors (pDCs) are professional type I interferon-producing cells, a critical cell type in regulating innate and adaptive immune responses. By microarray gene expression analysis, we found that pDCs activated by virus or CpG-ODN preferentially express the ligand for the glucocorticoid-induced tumor necrosis factor receptor (GITRL), which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analysis. Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells. We show that pDCs activated by CpG-ODN promote NK cell cytotoxicity and interferon (IFN)-γ production through type I IFNs and GITRL. Using a GITRL-transfected cell line, we further demonstrate that GITRL promotes NK cell cytotoxicity and IFN-γ production in synergy with interleukin-2 (IL-2), IFN-α, and NKG2D triggering. We also demonstrated that pDCs localized in close contact to NK cells in T-cell areas of the tonsils, and a subpopulation of the pDCs expressed GITRL. This study reveals a novel function of GITR/GITRL in pDC-mediated coactivation of NK cells.

scholarly journals A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus

2006 ◽  
Vol 103 (15) ◽  
pp. 5995-6000 ◽  
Author(s):  
A. Alejo ◽  
M. B. Ruiz-Arguello ◽  
Y. Ho ◽  
V. P. Smith ◽  
M. Saraiva ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Smallpox Virus ◽  
Necrosis Factor

scholarly journals Aspergeillus Fumigatus: The Effects of Adiponectin on Inflammatory Cytokine Production

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Rick Foust ◽  
Robert Templeton
Keyword(s):  
Cytokine Production ◽  
Cytokine Secretion ◽  
Rt Pcr ◽  
Macrophage Cell ◽  
Experimental Conditions ◽  
Inflammatory Cytokine Production ◽  
Cytokine Tumor Necrosis Factor ◽  
Immune Pathology ◽  
Necrosis Factor ◽  
Wild Type Control

Background and Hypothesis: Although inflammatory cytokines are important for antifungal defenses, excessive production significantly increases host immune pathology. It is therefore important to identify host pathways that limit detrimental inflammation in invasive fungal infection. Our prior results showed that mice with invasive aspergillosis (IA) that were deficient in the metabolic cytokine production produced more of the cytokine Tumor Necrosis Factor (TNF) than alveolar in wild-type control mice.  Therefore, we hypothesize that adiponectin inhibits antifungal cytokine secretion in alveolar macrophages.   Experimental Design or Project Methods: To test this hypothesis, the commonly used A. fumigatus strain Af293 was purchased from the Fungal Genetics Stock Center and grown on and harvested from agar. The alveolar macrophage cell line MH-S and cytokine ELISA kits was obtained from MilliporeSigma and ThermoFisher, respectively. MH-S cells were stimulated with swollen, fixed Af293 conidia for 24 hours in the presence or absence of recombinant mouse adiponectin. After 24 hours, supernatants and cells was were collected and assayed for ILs 1a, 6, and TNF protein and mRNA , by ELISA and quantitative RT-PCR, respectively.  Results: Although our preliminary results suggest possible inhibition of cytokine secretion by adiponectin in response to A. fumigatus, significant differences have thus far not been observed.   Conclusion and Potential Impact: We are therefore currently optimizing our experimental conditions to improve antifungal cytokine secretion. These studies may ultimately assist in the discovery of novel therapeutic targets and improve the prognosis of A. fumigatus infections 

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