scholarly journals Priming programed Mucosal-Associated Invariant T cells protect against systemic or local bacterial infection

2020 ◽  
Author(s):  
Zhe Zhao ◽  
Mai Shi ◽  
Tianyuan Zhu ◽  
Huimeng Wang ◽  
Troi Pediongco ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Bacterial Load ◽  
Critical Role ◽  
Systemic Infection ◽  
Live Vaccine Strain ◽  
Protective Capacity ◽  
Mait Cells ◽  
Synthetic Ligand ◽  
Stable Memory

Abstract Mucosal-Associated Invariant T (MAIT) cells have potent antibacterial functions. Their protective capacity, in vivo, has been demonstrated in mouse models, particularly of respiratory infections. We now show that during systemic infection of mice with Francisella tularensis Live Vaccine Strain (LVS), MAIT cell expansion was evident in the liver, lungs, kidney, spleen and blood. MAIT cells manifested a polarised Th1-like (termed “MAIT-1”) phenotype and cytokine profile that conferred a critical role in controlling bacterial load. After resolution of the primary infection, the expanded MAIT cells developed to a stable memory-like MAIT-1 cell population, suggesting a basis for vaccination and protection against subsequent challenge. Indeed, a systemic vaccination with synthetic ligand (5-OP-RU) in combination with CpG adjuvant boosted MAIT-1 cells and resulted in enhanced protection against systemic and local infections with F. tularensis and Legionella longbeachae. Our study highlights the potential utility of targeting MAIT cells to combat multiple bacterial pathogens.

The novel iron chelator, DIBI, attenuates inflammation and improves outcome in colon ascendens stent peritonitis-induced experimental sepsis

2020 ◽  
Vol 76 (2) ◽  
pp. 241-261
Author(s):  
Danielle Fokam ◽  
Maral Aali ◽  
Kayle Dickson ◽  
Cassidy Scott ◽  
Bruce Holbein ◽  
...  
Keyword(s):  
Immune Response ◽  
Leukocyte Adhesion ◽  
Bacterial Load ◽  
Systemic Infection ◽  
Lavage Fluid ◽  
Experimental Sepsis ◽  
Capillary Perfusion ◽  
Term Survival ◽  
Colon Ascendens

BACKGROUND: Sepsis is the result of a dysregulated host immune response to an infection. An ideal therapy would target both the underlying infection and the dysregulated immune response. DIBI, a novel iron-binding polymer, was specifically developed as an antimicrobial agent and has also demonstrated in vivo anti-inflammatory properties. OBJECTIVE: This study aimed to further investigate the effects of DIBI with and without the antibiotic imipenem (IMI) in colon ascendens stent peritonitis (CASP)-induced experimental sepsis. METHODS: Vehicle, DIBI and/or IMI were administered in C57BL/6 mice after CASP surgery. Intestinal leukocyte activation and capillary perfusion was evaluated by intravital microscopy. Moreover, bacterial load in peritoneal lavage fluid and blood, and plasma cytokine levels were assessed. In a second series of experiments, surgery to repair the colon was performed at 5 hr and these mice were followed for long-term survival over 7 days. RESULTS: DIBI reduced leukocyte adhesion, improved capillary blood flow, and decreased key plasma cytokines levels. DIBI also improved survival of infected mice and greatly improved IMI efficacy. Survivors treated with IMI and DIBI were found to be free of systemic infection. CONCLUSIONS: DIBI has promising potential for sepsis treatment including its use as a sole or an adjunct therapeutic with antibiotics.

scholarly journals Activation of MAIT cells plays a critical role in viral vector vaccine immunogenicity

2019 ◽  
Author(s):  
Nicholas M. Provine ◽  
Ali Amini ◽  
Lucy C. Garner ◽  
Christina Dold ◽  
Claire Hutchings ◽  
...  
Keyword(s):  
Cell Activation ◽  
Viral Vector ◽  
Critical Role ◽  
Vector Vaccine ◽  
Future Design ◽  
Mait Cells ◽  
Lethal Infection ◽  
Mait Cell

AbstractMucosal-associated invariant T (MAIT) cells can be activated by viruses through a cytokine-dependent mechanism, and thereby protect from lethal infection. Given this, we reasoned MAIT cells may have a critical role in the immunogenicity of replication-incompetent adenovirus vectors, which are novel and highly potent vaccine platforms. In vitro, ChAdOx1 (Chimpanzee Adenovirus Ox1) induced potent activation of MAIT cells. Activation required transduction of monocytes and plasmacytoid dendritic cells to produce IL-18 and IFN-α, respectively. IFN-α-induced monocyte-derived TNF-α was identified as a novel intermediate in this activation pathway, and activation required combinatorial signaling of all three cytokines. Furthermore, ChAdOx1-induced in vivo MAIT cell activation in both mice and human volunteers. Strikingly, MAIT cell activation was necessary in vivo for development of ChAdOx1-induced HCV-specific CD8 T cell responses. These findings define a novel role for MAIT cells in the immunogenicity of viral vector vaccines, with potential implications for future design.One sentence summaryRobust immunogenicity of candidate adenovirus vaccine vectors requires the activation of unconventional T cells.

scholarly journals Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis

2015 ◽  
Vol 22 (9) ◽  
pp. 1060-1069 ◽  
Author(s):  
Mariateresa Coppola ◽  
Susan J. F. van den Eeden ◽  
Louis Wilson ◽  
Kees L. M. C. Franken ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Protective Efficacy ◽  
Bacterial Load ◽  
Effective Vaccine ◽  
Protective Capacity ◽  
Content Type ◽  
Ifn Γ ◽  
Vaccine Approach

ABSTRACTResponsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions.Mycobacterium bovisBCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity againstMycobacterium tuberculosislatency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a majorM. tuberculosislatency antigen which is highly expressed by “dormant”M. tuberculosisand well recognized by T cells from latentlyM. tuberculosis-infected individuals. In order to assess itsin vivoimmunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-γ+/TNF+) and IFN-γ+CD4+T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs ofM. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosischallenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential ofM. tuberculosislatency antigens to improve BCG efficacy. These data suggest a promising role forM. tuberculosislatency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting.

In Vivo Validation of Peptidoglycan Recycling as a Target to Disable AmpC-Mediated Resistance and Reduce Virulence Enhancing the Cell-Wall–Targeting Immunity

2019 ◽  
Vol 220 (11) ◽  
pp. 1729-1737 ◽  
Author(s):  
Gabriel Torrens ◽  
Irina Sánchez-Diener ◽  
Elena Jordana-Lluch ◽  
Isabel María Barceló ◽  
Laura Zamorano ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Respiratory Infections ◽  
Bacterial Load ◽  
Murine Models ◽  
Promising Therapeutic Target ◽  
One Step ◽  
First Time

Abstract Background Searching for new strategies to defeat Pseudomonas aeruginosa is of paramount importance. Previous works in vitro showed that peptidoglycan recycling blockade disables AmpC-dependent resistance and enhances susceptibility against cell-wall–targeting immunity. Our objective was to validate these findings in murine models. This study shows for the first time in different murine models of infection that blocking the peptidoglycan recycling in Pseudomonas aeruginosa causes an important virulence impairment and disables AmpC-mediated resistance, being hence validated as a promising therapeutic target. Methods Wildtype PAO1, recycling-defective AmpG and NagZ mutants, an AmpC hyperproducer dacB mutant, and their combinations were used to cause systemic/respiratory infections in mice. Their survival, bacterial burden, inflammation level, and effectiveness of ceftazidime or subtherapeutic colistin to treat the infections were assessed. Results Inactivation of AmpG or NagZ significantly attenuated the virulence in terms of mice mortality, bacterial load, and inflammation. When inactivating these genes in the dacB-defective background, the β-lactam resistance phenotype was abolished, disabling the emergence of ceftazidime-resistant mutants, and restoring ceftazidime for treatment. Subtherapeutic colistin was shown to efficiently clear the infection caused by the recycling-defective strains, likely due to the combined effect with the mice cell-wall– targeting immunity. Conclusions This study brings us one step closer to new therapies intended to disable P. aeruginosa AmpC-mediated resistance and dampen its virulence, and strongly support the interest in developing efficient AmpG and/or NagZ inhibitors.

scholarly journals Yersinia-induced Apoptosis In Vivo Aids in the Establishment of a Systemic Infection of Mice

1998 ◽  
Vol 188 (11) ◽  
pp. 2127-2137 ◽  
Author(s):  
Denise M. Monack ◽  
Joan Mecsas ◽  
Donna Bouley ◽  
Stanley Falkow
Keyword(s):  
Mutant Strain ◽  
Yersinia Pseudotuberculosis ◽  
Bacterial Load ◽  
Systemic Infection ◽  
Wild Type ◽  
Mesenteric Lymph Nodes ◽  
Induced Apoptosis ◽  
Factor Α

Pathogenic Yersinia cause a systemic infection in mice that is dependent on the presence of a large plasmid encoding a number of secreted virulence proteins called Yops. We previously demonstrated that a plasmid-encoded Yop, YopJ, was essential for inducing apoptosis in cultured macrophages. Here we report that YopJ is a virulence factor in mice and is important for the establishment of a systemic infection. The oral LD50 for a yopJ mutant Yersinia pseudotuberculosis increases 64-fold compared with wild-type. Although the yopJ mutant strain is able to reach the spleen of infected mice, the mutant strain seldom reaches the same high bacterial load that is seen with wild-type Yersinia strain and begins to be cleared from infected spleens on day 4 after infection. Furthermore, when in competition with wild-type Yersinia in a mixed infection, the yopJ mutant strain is deficient for spread from the Peyer's patches to other lymphoid tissue. We also show that wild-type Yersinia induces apoptosis in vivo of Mac-1+ cells from infected mesenteric lymph nodes or spleens, as measured by quantitative flow cytometry of TUNEL (Tdt-mediated dUTP–biotin nick-end labeling)-positive cells. The levels of Mac-1+, TUNEL+ cells from tissue infected with the yopJ mutant strain were equivalent to the levels detected in cells from uninfected tissue. YopJ is necessary for the suppression of TNF-α production seen in macrophages infected with wild-type Yersinia, based on previous in vitro studies (Palmer, L.E., S. Hobbie, J.E. Galan, and J.B. Bliska. 1998. Mol. Microbiol. 27:953–965). We conclude here that YopJ plays a role in the establishment of a systemic infection by inducing apoptosis and that this is consistent with the ability to suppress the production of the proinflammatory cytokine tumor necrosis factor α.

scholarly journals Vascular KATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia

2020 ◽  
Vol 98 (8) ◽  
pp. 1149-1160
Author(s):  
Qadeer Aziz ◽  
Jianmin Chen ◽  
Amie J Moyes ◽  
Yiwen Li ◽  
Naomi A Anderson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Ex Vivo ◽  
Critical Role ◽  
Lethal Dose ◽  
Systemic Infection ◽  
Cardiac Metabolism ◽  
Lipid Fatty Acid

Abstract KATP channels in the vasculature composed of Kir6.1 regulate vascular tone and may contribute to the pathogenesis of endotoxemia. We used mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO) to investigate this question. We found that smKO mice had a significant survival disadvantage compared with their littermate controls when treated with a sub-lethal dose of lipopolysaccharide (LPS). All cohorts of mice became hypotensive following bacterial LPS administration; however, mean arterial pressure in WT mice recovered to normal levels, whereas smKO struggled to overcome LPS-induced hypotension. In vivo and ex vivo investigations revealed pronounced cardiac dysfunction in LPS-treated smKO, but not in eKO mice. Similar results were observed in a cecal slurry injection model. Metabolomic profiling of hearts revealed significantly reduced levels of metabolites involved in redox/energetics, TCA cycle, lipid/fatty acid and amino acid metabolism. Vascular smooth muscle-localised KATP channels have a critical role in the response to systemic infection by normalising cardiac function and haemodynamics through metabolic homeostasis. Key messages • Mice lacking vascular KATP channels are more susceptible to death from infection. • Absence of smooth muscle KATP channels depresses cardiac function during infection. • Cardiac dysfunction is accompanied by profound changes in cellular metabolites. • Findings from this study suggest a protective role for vascular KATP channels in response to systemic infection.

The Natural Flavonoid Naringenin Inhibits the Cell Growth of WilmsTumorinChildren by Suppressing TLR4/NF-κB Signaling

2020 ◽  
Vol 20 ◽  
Author(s):  
Hongtao Li ◽  
Peng Chen ◽  
Lei Chen ◽  
Xinning Wang
Keyword(s):  
Cell Growth ◽  
Western Blot ◽  
Wilms Tumor ◽  
Critical Role ◽  
Time Dependent ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Tlr4 Expression ◽  
Protein Levels

Background: Nuclear factor kappa B (NF-κB) is usually activated in Wilms tumor (WT) cells and plays a critical role in WT development. Objective: The study purpose was to screen a NF-κB inhibitor from natural product library and explore its effects on WT development. Methods: Luciferase assay was employed to assess the effects of natural chemical son NF-κB activity. CCK-8 assay was conducted to assess cell growth in response to naringenin. WT xenograft model was established to analyze the effect of naringenin in vivo. Quantitative real-time PCR and Western blot were performed to examine the mRNA and protein levels of relative genes, respectively. Results: Naringenin displayed significant inhibitory effect on NF-κB activation in SK-NEP-1 cells. In SK-NEP-1 and G-401 cells, naringenin inhibited p65 phosphorylation. Moreover, naringenin suppressed TNF-α-induced p65 phosphorylation in WT cells. Naringenin inhibited TLR4 expression at both mRNA and protein levels in WT cells. CCK-8 staining showed that naringenin inhibited cell growth of the two above WT cells in dose-and time-dependent manner, whereas Toll-like receptor 4 (TLR4) over expression partially reversed the above phenomena. Besides, naringenin suppressed WT tumor growth in dose-and time-dependent manner in vivo. Western blot found that naringenin inhibited TLR4 expression and p65 phosphorylation in WT xenograft tumors. Conclusion: Naringenin inhibits WT development viasuppressing TLR4/NF-κB signaling

scholarly journals The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

2021 ◽  
Author(s):  
Valentin Sencio ◽  
Marina Gomes Machado ◽  
François Trottein
Keyword(s):  
Gut Microbiota ◽  
Bacterial Infections ◽  
Respiratory Infections ◽  
Critical Role ◽  
Good Health ◽  
Disease Outcomes ◽  
And Function ◽  
Viral Respiratory Infections ◽  
The Impact ◽  
Viral Respiratory

AbstractBacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host’s defense against viral respiratory infections. The gut microbiota’s composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota’s composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung–gut axis in coronavirus disease 2019.

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

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