scholarly journals Lymphotoxin-αPlays Only a Minor Role in Host Resistance to Respiratory Infection with Virulent Type AFrancisella tularensisin Mice

2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Deng Zhang ◽  
Rhonda KuoLee ◽  
Greg Harris ◽  
Qinxian Zhang ◽  
J. Wayne Conlan ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Type A ◽  
Lavage Fluid ◽  
Host Responses ◽  
Mouse Strains ◽  
Minor Role ◽  
Histopathological Analysis ◽  
Time To Death ◽  
Virulent Type ◽  
Leukocyte Influx

This study examined the role of lymphotoxin (LT)-αin host defense against airborne infection withFrancisella tularensis, a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Following a low-dose aerosol infection with the highly virulent type A strain ofF. tularensis, mice deficient in LTα(LTα−/−) consistently harbored approximately 10-fold fewer bacteria in their spleens at day 2 and 10-fold more bacteria in their lungs at day 4 than LTα+/+ mice. However, the mortality and median time to death were indistinguishable between the two mouse strains. In addition, the inflammatory responses to the infection, as reflected by the cytokine levels and leukocyte influx in the bronchoalveolar lavage fluid and histopathological analysis, were generally similar between LTα−/− and LTα+/+ mice. These data suggest that although LTαdoes not contribute significantly to the resistance and host responses of mice to airborne type AF. tularensisinfection, it does play a subtle role in the multiplication/dissemination ofF. tularensis.

Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3455-3464 ◽  
Author(s):  
Richard A. Dean ◽  
Jennifer H. Cox ◽  
Caroline L. Bellac ◽  
Alain Doucet ◽  
Amanda E. Starr ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Binding Motif ◽  
Wild Type ◽  
Lps Challenge ◽  
Inflammatory Protein ◽  
Leukocyte Influx ◽  
Cc Chemokines ◽  
Intranasal Instillation

AbstractThrough the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)—thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR+ CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, -2, and -3 at E-LR. MMP-12-cleaved mCXCL2 (macrophage-inflammatory protein-2 [MIP-2]) and mCXCL3 (dendritic cell inflammatory protein-1 [DCIP-1]) lost chemotactic activity. Furthermore, MMP-12 processed and inactivated monocyte chemotactic proteins CCL2, -7, -8, and -13 at position 4-5 generating CCR antagonists. Indeed, PMNs and macrophages in bronchoalveolar lavage fluid were significantly increased 72 hours after intranasal instillation of LPS in Mmp12−/− mice compared with wild type. Specificity occurred at 2 levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR+CXC chemokines, mCXCL5 (LPS-induced CXC chemokine [LIX]) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine, promoting enhanced PMN early infiltration in wild-type mice compared with Mmp12−/− mice 8 hours after LPS challenge in air pouches. We propose that the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR+CXC and CC chemokines.

scholarly journals Live Attenuated Mutants of Francisella tularensis Protect Rabbits against Aerosol Challenge with a Virulent Type A Strain

2014 ◽  
Vol 82 (5) ◽  
pp. 2098-2105 ◽  
Author(s):  
Douglas S. Reed ◽  
Le'Kneitah P. Smith ◽  
Kelly Stefano Cole ◽  
Araceli E. Santiago ◽  
Barbara J. Mann ◽  
...  
Keyword(s):  
Weight Loss ◽  
Francisella Tularensis ◽  
Type A ◽  
Content Type ◽  
Time To Death ◽  
Virulent Type ◽  
No Weight Loss ◽  
The 1960S ◽  
Schu S4 ◽  
Derivatives Of

ABSTRACTFrancisella tularensis, a Gram-negative bacterium, is the causative agent of tularemia. No licensed vaccine is currently available for protection against tularemia, although an attenuated strain, dubbed the live vaccine strain (LVS), is given to at-risk laboratory personnel as an investigational new drug (IND). In an effort to develop a vaccine that offers better protection, recombinant attenuated derivatives of a virulent type A strain, SCHU S4, were evaluated in New Zealand White (NZW) rabbits. Rabbits vaccinated via scarification with the three attenuated derivatives (SCHU S4 ΔguaBA, ΔaroD, and ΔfipBstrains) or with LVS developed a mild fever, but no weight loss was detected. Twenty-one days after vaccination, all vaccinated rabbits were seropositive for IgG toF. tularensislipopolysaccharide (LPS). Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4 at doses ranging from 50 to 500 50% lethal doses (LD50). All rabbits developed fevers and weight loss after challenge, but the severity was greater for mock-vaccinated rabbits. The ΔguaBAand ΔaroDSCHU S4 derivatives provided partial protection against death (27 to 36%) and a prolonged time to death compared to results for the mock-vaccinated group. In contrast, LVS and the ΔfipBstrain both prolonged the time to death, but there were no survivors from the challenge. This is the first demonstration of vaccine efficacy against aerosol challenge with virulent type AF. tularensisin a species other than a rodent since the original work with LVS in the 1960s. The ΔguaBAand ΔaroDSCHU S4 derivatives warrant further evaluation and consideration as potential vaccines for tularemia and for identification of immunological correlates of protection.

scholarly journals Delayed Inflammatory Response to Primary Pneumonic Plague Occurs in Both Outbred and Inbred Mice

2006 ◽  
Vol 75 (2) ◽  
pp. 697-705 ◽  
Author(s):  
Sarah S. Bubeck ◽  
Angelene M. Cantwell ◽  
Peter H. Dube
Keyword(s):  
Bronchoalveolar Lavage ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Inbred Mice ◽  
Lavage Fluid ◽  
Mouse Strains ◽  
Necrosis Factor Alpha ◽  
Pneumonic Plague ◽  
Monocyte Chemoattractant Protein 1 ◽  
Cytokines And Chemokines

ABSTRACT Yersinia pestis is the causative agent of plague, a disease that can manifest as either bubonic or pneumonic plague. An interesting feature of plague is that it is a rapidly progressive disease, suggesting that Y. pestis either evades and/or suppresses the innate immune response to infection. Therefore, the early host response during the course of primary pneumonic plague was investigated in two mouse strains, the outbred strain CD1 and the inbred strain C57BL/6. A comparative analysis of the course of disease in these two strains of mice indicated that they are susceptible to intranasal Y. pestis CO92 infection and have similar 50% lethal doses and kinetics of infection with respect to colonization of the lung, liver, and spleen. Significantly, in both strains of mice, robust neutrophil recruitment to the lungs was not observed until 48 h after infection, suggesting that there was a delay in inflammatory cell recruitment to the site of infection. In addition, proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, gamma interferon, IL-12p70, monocyte chemoattractant protein 1) and chemokines (KC, MIP-2) in the bronchoalveolar lavage fluids were not readily detected until 48 h after infection, which coincided with the increase in polymorphonuclear leukocyte (PMN) recruitment to the lungs. In comparison, CD1 mice with gram-negative pneumonia caused by Klebsiella pneumoniae exhibited strong inflammatory responses early in infection, with PMNs comprising the majority of the cells in the bronchoalveolar lavage fluid 24 h postinfection, indicating that PMN recruitment to the lungs could occur earlier in this infection than in Y. pestis infection. Together, our results indicate that there is a delay in the recruitment of neutrophils to the lungs in the mouse model of primary plague pneumonia that correlates with delayed expression of proinflammatory cytokines and chemokines in both outbred and inbred mice.

scholarly journals The effect of Co-Q10 on allergic rhinitis and allergic asthma

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Qixue Du ◽  
Wei Meng ◽  
Seyyed Shamsadin Athari ◽  
Renzhong Wang
Keyword(s):  
Allergic Rhinitis ◽  
Animal Models ◽  
Allergic Asthma ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Inflammatory Factors ◽  
Stress Injury ◽  
Antioxidant Genes ◽  
Histamine Production ◽  
Nrf2 Expression

Abstract Background Allergic asthma is an inflammatory disease resulting from continued or intermittent allergen exposure, and allergic rhinitis can be trigger of asthma. The main mechanism of these disease is allergic reaction and immune response dysregulation. Co-Q10 is an enzyme cofactor in mitochondria can control asthma and allergic rhinitis symptoms. In the present study, we determined that the CoQ10-induced anti-allergic effects were mediated by up-regulation of Nrf2. Methods Animal models of allergic rhinitis and allergic asthma were produced and treated with Co-Q10, Co-Q10 and O-3, Co-Q10 and Mg-S. Bronchoalveolar lavage fluid was collected from animal models, and IL-4, 5, 13, INF-y, Eicosanoids, IgE, EPO, and histamine production were measured. Also, COX-2, CCL24, CCL11, Nrf2, Eotaxin, Cytb, COX1 and ND1 genes expressions and histopathology were studied. BALf's cells were collected by tracheostomy and used in slide producing by cytospine. Cytokines, Eicosanoids, IgE, EPO, and histamine were measured by ELISA method. Gene expression was done by Real-time PCR. Results Co-Q10 with two supplementation (Mg-S and O-3) modulate MRC, BALf eosinophils, eosinophilic inflammation related genes (eotaxin, CCL11 and CCL24), peribronchial and perivascular inflammation, EPO, type 2 cytokines (IL-4, 5 and 13), IgE, histamine, Cyc-LT and LTB4 as main allergic bio-factors. Importantly, Co-Q10 treatment increased Nrf2 expression and Nrf2 induced antioxidant genes, glutathione redox and inhibited inflammation, oxidative stress injury, Th2 cytokines production and attenuated allergic inflammatory responses. Conclusion Nrf2 is activated in response to allergen, induces resistance against the rhinitis and asthma development and plays an essential role in broncho-protection. Co-Q10 increases the Nrf2 expression and the Nrf2 over-expression has strong effect in control of type2 cytokines, allergic mediators and inflammatory factors that lead to harnessing of allergy and asthma. Graphic abstract

scholarly journals Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

2006 ◽  
Vol 74 (3) ◽  
pp. 1828-1836 ◽  
Author(s):  
Shayla West-Barnette ◽  
Andrea Rockel ◽  
W. Edward Swords
Keyword(s):  
Haemophilus Influenzae ◽  
Inflammatory Responses ◽  
Opportunistic Pathogen ◽  
Host Responses ◽  
Toll Like Receptor ◽  
Nontypeable Haemophilus Influenzae ◽  
Toll Like Receptor 4 ◽  
Biofilm Growth ◽  
Bacterial Endotoxins ◽  
Cell Layers

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses.

scholarly journals Gut Microbiota, Fusobacteria, and Colorectal Cancer

Diseases ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 109 ◽  
Author(s):  
Dervla Kelly ◽  
Liying Yang ◽  
Zhiheng Pei
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Host Responses ◽  
Future Research ◽  
Bacterial Microbiota ◽  
Promote Tumor Growth ◽  
Tumor Environment ◽  
Protective Strategies

The gut microbiota has emerged as an environmental contributor to colorectal cancer (CRC) in both animal models and human studies. It is now generally accepted that bacteria are ubiquitous colonizers of all exposed human body surfaces, including the entire alimentary tract (5). Recently, the concept that a normal bacterial microbiota is essential for the development of inflammation-induced carcinoma has emerged from studies of well-known colonic bacterial microbiota. This review explores the evidence for a role of fusobacteria, an anaerobic gram-negative bacterium that has repeatedly been detected at colorectal tumor sites in higher abundance than surrounding histologically normal tissue. Mechanistic studies provide insight on the interplay between fusobacteria, other gut microbiota, barrier functions, and host responses. Studies have shown that fusobacteria activate host inflammatory responses designed to protect against pathogens that promote tumor growth. We discuss how future research identifying the pathophysiology underlying fusobacteria colon colonization during colorectal cancer may lead to new therapeutic targets for cancer. Furthermore, disease-protective strategies suppressing tumor development by targeting the local tumor environment via bacteria represent another exciting avenue for researchers and are highlighted in this review.

scholarly journals TAK1 inhibition elicits mitochondrial ROS to block intracellular bacterial colonization

2021 ◽  
Vol 118 (25) ◽  
pp. e2023647118
Author(s):  
Wilfred López-Pérez ◽  
Kazuhito Sai ◽  
Yosuke Sakamachi ◽  
Cameron Parsons ◽  
Sophia Kathariou ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Defense Mechanism ◽  
Inflammatory Responses ◽  
Bacterial Colonization ◽  
Effector Proteins ◽  
Host Protein ◽  
Mitogen Activated Protein Kinase ◽  
Host Responses ◽  
Host Recognition ◽  
Intracellular Bacteria

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is an intracellular signaling intermediate of inflammatory responses. However, a series of mouse Tak1 gene deletion analyses have revealed that ablation of TAK1 does not prevent but rather elicits inflammation, which is accompanied by elevation of reactive oxygen species (ROS). This has been considered a consequence of impaired TAK1-dependent maintenance of tissue integrity. Contrary to this view, here we propose that TAK1 inhibition–induced ROS are an active cellular process that targets intracellular bacteria. Intracellular bacterial effector proteins such as Yersinia’s outer membrane protein YopJ are known to inhibit TAK1 to circumvent the inflammatory host responses. We found that such TAK1 inhibition induces mitochondrial-derived ROS, which effectively destroys intracellular bacteria. Two cell death–signaling molecules, caspase 8 and RIPK3, cooperatively participate in TAK1 inhibition–induced ROS and blockade of intracellular bacterial growth. Our results reveal a previously unrecognized host defense mechanism, which is initiated by host recognition of pathogen-induced impairment in a host protein, TAK1, but not directly of pathogens.

scholarly journals Intracellular survival ofBurkholderia cepaciacomplex in phagocytic cells

2015 ◽  
Vol 61 (9) ◽  
pp. 607-615 ◽  
Author(s):  
Miguel A. Valvano
Keyword(s):  
Burkholderia Cepacia ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Genetic Manipulation ◽  
Intracellular Survival ◽  
Burkholderia Cenocepacia ◽  
Burkholderia Cepacia Complex ◽  
Host Responses ◽  
Current View ◽  
Phagocytic Cells

Burkholderia cepacia complex (Bcc) species are a group of Gram-negative opportunistic pathogens that infect the airways of cystic fibrosis patients, and occasionally they infect other immunocompromised patients. Bcc bacteria display high-level multidrug resistance and chronically persist in the infected host while eliciting robust inflammatory responses. Studies using macrophages, neutrophils, and dendritic cells, combined with advances in the genetic manipulation of these bacteria, have increased our understanding of the molecular mechanisms of virulence in these pathogens and the molecular details of cell-host responses triggering inflammation. This article discusses our current view of the intracellular survival of Burkholderia cenocepacia within macrophages.

scholarly journals Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D.

1985 ◽  
Vol 162 (6) ◽  
pp. 2125-2141 ◽  
Author(s):  
R M Zinkernagel ◽  
T Leist ◽  
H Hengartner ◽  
A Althage
Keyword(s):  
T Cell ◽  
Virus Isolate ◽  
Cell Activity ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cytotoxic T Cell ◽  
Mouse Strains ◽  
Time To Death ◽  
Virus Isolates ◽  
Susceptibility Patterns

The lymphocytic choriomeningitis virus (LCMV) isolates Docile (D) and Aggressive (A) of Pfau et al. were studied in various strains of mice. Disease susceptibility, assessed as mortality and time to death to LCMV-D or -A varied greatly amongst mouse strains, and all four possible susceptibility patterns were observed: susceptibility to both (e.g. SWR/J), resistance to both (e.g. DBA/2), susceptibility to A but resistance to D (C57BL/6), or vice versa (CBA/J). Irrespective of the virus isolate or the mouse strain tested, susceptibility correlated with both early and high cytotoxic T cell activity found in spleens or leptomeningeal infiltrates, and with early and high primary footpad swelling reaction after local infection. C57BL/6 mice infected with A or SWR/J infected with A or with D showed, in both test systems, early and high activities; in contrast, DBA/2 mice infected with either D or A, and C57BL/6 infected with D showed no or only slow and low responses in both tests. Early and high LCMV-specific cytotoxic T cell activity, and the rapidity and extent of the primary footpad reaction directly correlated with susceptibility to LCM and all were dominantly regulated by H-2D.

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