scholarly journals Mice Lacking the Type I Interferon Receptor Are Resistant to Listeria monocytogenes

2004 ◽  
Vol 200 (4) ◽  
pp. 527-533 ◽  
Author(s):  
Victoria Auerbuch ◽  
Dirk G. Brockstedt ◽  
Nicole Meyer-Morse ◽  
Mary O'Riordan ◽  
Daniel A. Portnoy
Keyword(s):  
Listeria Monocytogenes ◽  
High Dose ◽  
Type I ◽  
Wild Type ◽  
Type I Ifns ◽  
Infection Resistance ◽  
Innate Antiviral Response ◽  
Factor Α

Listeria monocytogenes is a facultative intracellular pathogen that induces a cytosolic signaling cascade resulting in expression of interferon (IFN)-β. Although type I IFNs are critical in viral defense, their role in immunity to bacterial pathogens is much less clear. In this study, we addressed the role of type I IFNs by examining the infection of L. monocytogenes in BALB/c mice lacking the type I IFN receptor (IFN-α/βR−/−). During the first 24 h of infection in vivo, IFN-α/βR−/− and wild-type mice were similar in terms of L. monocytogenes survival. In addition, the intracellular fate of L. monocytogenes in macrophages cultured from IFN-α/βR−/− and wild-type mice was indistinguishable. However, by 72 h after inoculation in vivo, IFN-α/βR−/− mice were ∼1,000-fold more resistant to a high dose L. monocytogenes infection. Resistance was correlated with elevated levels of interleukin 12p70 in the blood and increased numbers of CD11b+ macrophages producing tumor necrosis factor α in the spleen of IFN-α/βR−/− mice. The results of this study suggest that L. monocytogenes might be exploiting an innate antiviral response to promote its pathogenesis.

scholarly journals Accelerated Neutrophil Apoptosis in Mice Lacking A1-a, a Subtype of the bcl-2–related A1 Gene

1998 ◽  
Vol 188 (11) ◽  
pp. 1985-1992 ◽  
Author(s):  
Azumi Hamasaki ◽  
Fujiro Sendo ◽  
Keiko Nakayama ◽  
Noriko Ishida ◽  
Izumi Negishi ◽  
...  
Keyword(s):  
Neutrophil Apoptosis ◽  
Spontaneous Apoptosis ◽  
Wild Type ◽  
Apoptosis Inhibition ◽  
Blood Neutrophils ◽  
Factor Α ◽  
Necrosis Factor

To elucidate the role of A1, a new member of the Bcl-2 family of apoptosis regulators active in hematopoietic cell apoptosis, we established mice lacking A1-a, a subtype of the A1 gene in mice (A1-a−/− mice). Spontaneous apoptosis of peripheral blood neutrophils of A1-a−/− mice was enhanced compared with that of either wild-type mice or heterozygous mutants (A1-a+/− mice). Neutrophil apoptosis inhibition induced by lipopolysaccharide treatment in vitro or transendothelial migration in vivo observed in wild-type mice was abolished in both A1-a−/− and A1-a+/− animals. On the other hand, the extent of tumor necrosis factor α–induced acceleration of neutrophil apoptosis did not differ among A1-a−/−, A1-a+/−, and wild-type mice. The descending order of A1 mRNA expression was wild-type, A1-a+/−, and A1-a−/−. Taken together, these results suggest that A1 is involved in inhibition of certain types of neutrophil apoptosis.

scholarly journals Recombinant Listeria monocytogenes Expressing a Cell Wall-Associated Listeriolysin O Is Weakly Virulent but Immunogenic

2009 ◽  
Vol 77 (10) ◽  
pp. 4371-4382 ◽  
Author(s):  
Javier A. Carrero ◽  
Boris Calderon ◽  
Hector Vivanco-Cid ◽  
Emil R. Unanue
Keyword(s):  
Listeria Monocytogenes ◽  
Listeriolysin O ◽  
Wild Type ◽  
Positive Bacterium ◽  
Cell Responses ◽  
A Cell ◽  
Weakly Virulent

ABSTRACT Listeriolysin O (LLO) is an essential virulence factor for the gram-positive bacterium Listeria monocytogenes. Our goal was to determine if altering the topology of LLO would alter the virulence and toxicity of L. monocytogenes in vivo. A recombinant strain was generated that expressed a surface-associated LLO (sLLO) variant secreted at 40-fold-lower levels than the wild type. In culture, the sLLO strain grew in macrophages, translocated to the cytosol, and induced cell death. However, the sLLO strain showed decreased infectivity, reduced lymphocyte apoptosis, and decreased virulence despite a normal in vitro phenotype. Thus, the topology of LLO in L. monocytogenes was a factor in the pathogenesis of the infection and points to a role of LLO secretion during in vivo infection. The sLLO strain was cleared by severe combined immunodeficient (SCID) mice. Despite the attenuation of virulence, the sLLO strain was immunogenic and capable of eliciting protective T-cell responses.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Defense Mechanism ◽  
Histopathological Examination ◽  
Bacterial Count ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR was performed to detect the expression of Type I IFNs and related genes. M. bovis induced lung lesions were assessed by histopathological examination and viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell recruitment and activation in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals Apparently Normal Tumor Necrosis Factor Receptor 1 Signaling in the Absence of the Silencer of Death Domains

2003 ◽  
Vol 23 (18) ◽  
pp. 6609-6617 ◽  
Author(s):  
Robert Endres ◽  
Georg Häcker ◽  
Inge Brosch ◽  
Klaus Pfeffer
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
High Dose ◽  
Wild Type ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand. Besides TNFR1, death receptor 3 (DR3), Hsp70/Hsc70, and Bcl-2 have been characterized as binding partners of SODD. In order to investigate the in vivo role of SODD, we generated mice congenitally deficient in expression of the sodd gene. No spontaneous inflammatory infiltrations were observed in any organ of these mice. Consistent with this finding, in the absence of SODD no alteration in the activation patterns of nuclear factor κB (NF-κB), stress kinases, or ERK1 or -2 was observed after stimulation with tumor necrosis factor (TNF). Activation of NF-κB by DR3 was also unchanged. The extents of DR3- and TNF-induced apoptosis were comparable in gene-deficient and wild-type cells. Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD. Furthermore, resistance to high-dose lipopolysaccharide (LPS) injections, LPS-d-GalN injections, and infection with listeriae was similar in wild-type and gene-deficient mice. In conclusion, our data do not support the concept of a unique, nonredundant role of SODD for the functions of TNFR1, Hsp70, and DR3.

scholarly journals Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes

2021 ◽  
Vol 17 (9) ◽  
pp. e1009493
Author(s):  
Courtney E. McDougal ◽  
Zachary T. Morrow ◽  
Tighe Christopher ◽  
Seonyoung Kim ◽  
Drake Carter ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
T Cell ◽  
T Cell Responses ◽  
Prostaglandin E ◽  
Type I ◽  
Wild Type ◽  
Cell Responses ◽  
T Cell Priming ◽  
Cox 2

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE2 production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE2 production early during infection whereas vacuole-constrained strains fail to induce PGE2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+ or CD11c+ cells produce less PGE2, suggesting these cell subsets contribute to PGE2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE2 production completely. Taken together, this work demonstrates that optimal PGE2 production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8+ T-cell responses may be to facilitate production of PGE2.

N-Linked Glycans within the A1A2A3 Domains of VWF Play a Critical Role in Modulating Macrophage-Mediated Clearance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 469-469
Author(s):  
Alain Chion ◽  
Jamie O'Sullivan ◽  
Gudmundur Bergsson ◽  
Sean Keyes ◽  
Orla Rawley ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Full Length ◽  
Type I ◽  
Dependent Manner ◽  
Wild Type ◽  
Macrophage Receptors ◽  
A2 Domain

Abstract Enhanced plasma clearance of von Willebrand factor (VWF) plays an important role in the etiology of both type 1 and type 2 VWD. Nevertheless, although significant progress has been achieved in understanding the structure and functional properties of VWF, the mechanism(s) responsible for modulating VWF clearance from the plasma remain poorly understood. Accumulating recent data suggests that hepatic and splenic macrophages play key roles in modulating VWF clearance. A number of putative macrophage receptors for VWF have been also been described, including LRP1, β2-integrins and Siglec-5. In addition, it is well recognised that variation in VWF glycan expression significantly influences its clearance rate. In particular, terminal ABO(H) blood group determinants which are predominantly expressed on the N-linked glycans of human VWF significantly modulate its rate of clearance. Critically however, the molecular mechanisms through which specific macrophage receptors interact with particular regions of the complex VWF glycoprotein have not been defined. To investigate the role of VWF glycans and specific VWF domains in regulating VWF clearance, we expressed and purified a series of recombinant VWF variants and truncations with/without specific glycan sites. In addition, VWF glycosylation was modified using specific exoglycosidase digestions. Subsequently, recombinant VWF variants and glycoforms thereof were injected into VWF-/-mice, and plasma VWF clearance rates determined by ELISA. VWF-macrophage interactions were also quantified in vitro using phorbol ester-differentiated monocytic THP-1 cells, and primary human monocytes, in a High Content Analysis Imaging system. In keeping with previous reports, we observed that clearance of a truncated VWFA1A2A3 fragment in VWF-/-mice was very similar to that of full-length wild type (WT-) VWF (VWFA1A2A3; t1/2 = 6.3 min versus rWT-VWF; t1/2 = 7.9 min). Furthermore, chemical depletion of macrophages using clodronate liposomes administration significantly inhibited A1A2A3 clearance in vivo (1.7-fold at 10 min time point) to a similar extent to that observed with full length VWF. In vitro binding experiments confirmed that A1A2A3 bound to differentiated THP-1 cells in a dose- and time- dependent manner. Interestingly, this binding was significantly enhanced in the presence of ristocetin. Cumulatively, these data demonstrate that the A1A2A3 domains of VWF contain a critical receptor-binding site for macrophage-mediated clearance. Interestingly, we observed that the half-life of infused human plasma-derived VWF and recombinant VWF expressed in HEK293T cells in VWF-/- mice were significantly different. Furthermore, treatment with PNGase F to completely remove N-linked glycan structures markedly enhanced the clearance of full length VWF (t1/2 2.1 min; p<0.05). Collectively, these findings highlight the essential roles played by N-glycans in regulating VWF survival. Two N-linked glycan sites are located within A1A2A3 at N1515 and N1574 respectively. Importantly, we found that PNGase digestion of A1A2A3 resulted in markedly enhanced macrophage binding in vitro. Consequently we hypothesized that the two N-glycans located within the A2 domain might be important in regulating VWF clearance by macrophages. Targeted disruption of these individual N-glycan sites by site-directed mutagenesis (A1A2A3-N1515Q and A1A2A3-N1574Q respectively) resulted in significantly enhanced macrophage binding in vitro compared to wild type A1A2A3. Furthermore, following tail vein infusion in VWF-/-mice, full length VWFN1515Q and VWFN1574Q both demonstrated markedly reduced half-lives compared to wild type VWF (VWFN1515Q; t1/2 = 3.7 min, VWFN1574Q; t1/2 = 5.5 min). Finally, introduction of the N1515Q point mutation into truncated A1A2A3 also served to significantly enhance plasma clearance, (A1A2A3N1515Q-VWF; t1/2 = 3.1 min versus A1A2A3-VWF; t1/2 = 6.3 min). In conclusion, our novel data identify a crucial role of the VWF A domains in regulating macrophage-mediated VWF clearance. In addition, we further demonstrate that the N-linked glycans structures located at N1515 and N1574 within the A2 domain play specific roles in protecting VWF against in vivo clearance by macrophages. Given the important role played by enhanced VWF clearance in the etiology of type I VWD, these findings are of direct clinical importance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Defense Mechanism ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination.Viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation

1999 ◽  
Vol 277 (3) ◽  
pp. G572-G576 ◽  
Author(s):  
Shigeyuki Kawachi ◽  
Adam Cockrell ◽  
F. Stephen Laroux ◽  
Laura Gray ◽  
D. Neil Granger ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Wild Type ◽  
Chronic Colitis ◽  
Antibody Technique ◽  
Tnf Α ◽  
Factor Α ◽  
Oxide Synthase

The objectives of this study were to assess the role of the inducible isoform of nitric oxide synthase (iNOS) on vascular cell adhesion molecule 1 (VCAM-1) expression in vivo in an acute model of inflammation induced in iNOS-deficient (iNOS−/−) mice and compare these data to those obtained by pharmacological inhibition of iNOS in a CD4+ T lymphocyte-dependent model of chronic colitis. VCAM-1 expression was quantified in vivo using the dual radiolabel monoclonal antibody technique. We found that intraperitoneal injection of 10 μg/kg tumor necrosis factor-α (TNF-α) enhanced VCAM-1 expression by approximately twofold in the colon, cecum, and stomach but not small intestine in iNOS−/−mice compared with TNF-α-injected wild-type mice. Injection of wild-type mice with 25 μg/kg TNF-α further enhanced VCAM-1 expression by approximately twofold compared with wild-type mice injected with 10 μg/kg TNF-α; however, VCAM-1 expression was not further enhanced in any gastrointestinal organ system in iNOS−/− mice. In a second series of experiments, we found that continuous inhibition of iNOS using oral administration of N G-iminoethyl-l-lysine did not alter the enhanced levels of VCAM-1 expression in the colon nor did it alter the severity of colonic inflammation in SCID mice reconstituted with CD4+, CD45RBhigh T cells. We conclude that iNOS may regulate VCAM-1 expression in acute inflammation; however, this effect is modest and tissue specific and occurs only when VCAM-1 expression is submaximal. iNOS does not appear to modulate VCAM-1 expression in an immune model of chronic colitis.

scholarly journals Prostaglandin E2 induction by cytosolic Listeria monocytogenes in phagocytes is necessary for optimal T-cell priming

2021 ◽  
Author(s):  
Courtney E McDougal ◽  
Zachary T Morrow ◽  
Seonyoung Kim ◽  
Drake Carter ◽  
David M Stevenson ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Type I ◽  
Wild Type ◽  
Cell Responses ◽  
T Cell Priming ◽  
Cox 2

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8 + T-cell responses. Despite the ongoing development of L. monocytogenes -based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8 + T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8 + T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Here, we describe a cytosol-dependent response that is critical for immunity to L. monocytogenes , namely production of prostaglandin E 2 (PGE 2 ) downstream of cyclooxygenase-2 (COX-2). Vacuole-constrained L. monocytogenes elicit reduced PGE 2 production compared to wild-type strains in macrophages and dendritic cells ex vivo . In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE 2 production early during infection whereas vacuole-constrained strains fail to induce PGE 2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2 + or CD11c + cells produce less PGE 2 , suggesting these cell subsets contribute to PGE 2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE 2 production completely . Taken together, this work identifies the first known cytosol-dependent innate immune response critical for generating CD8 + T-cell responses to L. monocytogenes, suggesting that one reason cytosolic access is required to prime CD8 + T-cell responses may be due to induction of PGE 2 .

scholarly journals Role of TLR4 in Persistent Leptospira interrogans Infection: A Comparative In Vivo Study in Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Nisha Nair ◽  
Mariana S. Guedes ◽  
Adeline M. Hajjar ◽  
Catherine Werts ◽  
Maria Gomes-Solecki
Keyword(s):  
Innate Immune ◽  
High Dose ◽  
Wild Type ◽  
Immune Markers ◽  
Lethal Infection ◽  
Tlr4 Gene ◽  
Kinetics Of ◽  
Overall Kinetics

Toll-Like Receptor (TLR) 4, the LPS receptor, plays a central role in the control of leptospirosis and absence of TLR4 results in lethal infection in mice. Because human TLR4 does not sense the atypical leptospiral-LPS, we hypothesized that TLR4/MD-2 humanized transgenic mice (huTLR4) may be more susceptible to leptospirosis than wild-type mice, and thus may constitute a model of acute human leptospirosis. We infected huTLR4 mice, which express human TLR4 but not murine TLR4, with a high dose of L. interrogans serovar Copenhageni FioCruz (Leptospira) in comparison to C57BL/6J wild-type (WT) and, as a control, a congenic strain in which the tlr4 coding sequences are deleted (muTLR4Lps-del). We show that the huTLR4 gene is fully functional in the murine background. We found that dissemination of Leptospira in blood, shedding in urine, colonization of the kidney and overall kinetics of leptospirosis progression is equivalent between WT and huTLR4 C57BL/6J mice. Furthermore, inflammation of the kidney appeared to be subdued in huTLR4 compared to WT mice in that we observed less infiltrates of mononuclear lymphocytes, less innate immune markers and no relevant differences in fibrosis markers. Thus, huTLR4 mice showed less inflammation and kidney pathology, and are not more susceptible to leptospirosis than WT mice. This study is significant as it indicates that one intact TLR4 gene, be it mouse or human, is necessary to control acute leptospirosis.

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