scholarly journals Ceramide-1 Phosphate: Multi-targets Immune Adjuvant for Controlling Covid-19 infection ?

2020 ◽  
Author(s):  
Hridayesh Prakash ◽  
Dilip U padhyay ◽  
Obul Reddy Bandapalli ◽  
Aklank Jain ◽  
Burkhard Kleuser
Keyword(s):  
Pulmonary Fibrosis ◽  
Viral Entry ◽  
Effective Control ◽  
Mhc I ◽  
Adaptive Immune ◽  
Dual Specificity ◽  
Sphingosine 1 Phosphate ◽  
Membrane Bound ◽  
Interferon Responses ◽  
Ceramide 1

Sphingolipids are amphipathic molecules and critical for the progression of various respiratory diseases. The sphingolipids bears dual Specificity and can favor both host and pathogens Membrane bound Sphingolipids can influence viral entry by serving as co-receptors and modulate viral replication. In this context we have recently demonstrated that central Sphingolipid derivatives like Sphingosine 1 phosphate (S1P) is able to skews Interferon responses, inhibits IL-6 and pulmonary fibrosis and protect animals from M. tb infection. This led us to presume that this might control Covid 19 infection which exploits ACE-II receptor for its attachment and gain entry into the cells. Since activation of ACE-II receptor leads to the activation of S1P Receptor 1 signaling in the pulmonary compartment which promotes pulmonary fibrosis, cardio myopathy and Th17 responses which are the main reason of Covid19 mediated global deaths. In view of this paradox, S-1P cannot be used against Covid-19 infection. Therefore, in such conditions, other sphingolipids like Ceramide 1 phosphate (C1P) can solve the purpose of affording immunity against Covid-19 virus by enhancing autophagy, adaptive immune responses of macrophages, MHC-I dependent cytotoxic T lymphocytes (CTL) response for effective control of Covid-19 infection.

scholarly journals Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 617 ◽  
Author(s):  
Helen Freyberger ◽  
Yunxiu He ◽  
Amanda Roth ◽  
Mikeljon Nikolich ◽  
Andrey Filippov
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Adaptive Immune Response ◽  
Human Monocyte ◽  
Activation Markers ◽  
Mhc I ◽  
Adaptive Immune ◽  
Human Dendritic Cells

A potential concern with bacteriophage (phage) therapeutics is a host-versus-phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti-inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it.

scholarly journals Role for ribosome-associated quality control in sampling proteins for MHC class I-mediated antigen presentation

2020 ◽  
Vol 117 (8) ◽  
pp. 4099-4108 ◽  
Author(s):  
Débora Broch Trentini ◽  
Matteo Pecoraro ◽  
Shivani Tiwary ◽  
Jürgen Cox ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Quality Control ◽  
Antigen Presentation ◽  
Mammalian Cells ◽  
Adaptive Immune System ◽  
Messenger Rnas ◽  
Mhc I ◽  
Adaptive Immune ◽  
Ribosome Stalling ◽  
Endogenous Substrates ◽  
Insight Into

Mammalian cells present a fingerprint of their proteome to the adaptive immune system through the display of endogenous peptides on MHC-I complexes. MHC-I−bound peptides originate from protein degradation by the proteasome, suggesting that stably folded, long-lived proteins could evade monitoring. Here, we investigate the role in antigen presentation of the ribosome-associated quality control (RQC) pathway for the degradation of nascent polypeptides that are encoded by defective messenger RNAs and undergo stalling at the ribosome during translation. We find that degradation of model proteins by RQC results in efficient MHC-I presentation, independent of their intrinsic folding properties. Quantitative profiling of MHC-I peptides in wild-type and RQC-deficient cells by mass spectrometry showed that RQC substantially contributes to the composition of the immunopeptidome. Our results also identify endogenous substrates of the RQC pathway in human cells and provide insight into common principles causing ribosome stalling under physiological conditions.

scholarly journals The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Nitai C. Hait ◽  
Aparna Maiti
Keyword(s):  
Cell Growth ◽  
Cell Fate ◽  
Cancer Progression ◽  
Tissue Injury ◽  
Cell Types ◽  
Cancer Cell Growth ◽  
Ceramide Level ◽  
Cytokines And Chemokines ◽  
Sphingosine 1 Phosphate ◽  
Ceramide 1

Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

scholarly journals Phosphatidate Phosphohydrolase Catalyzes the Hydrolysis of Ceramide 1-Phosphate, Lysophosphatidate, and Sphingosine 1-Phosphate

1996 ◽  
Vol 271 (28) ◽  
pp. 16506-16509 ◽  
Author(s):  
David W. Waggoner ◽  
Antonio Gómez-Muñoz ◽  
Jay Dewald ◽  
David N. Brindley
Keyword(s):  
Phosphatidate Phosphohydrolase ◽  
Sphingosine 1 Phosphate ◽  
Ceramide 1 ◽  
Hydrolysis Of

scholarly journals The Expanding Family of Bone Marrow Homing Factors for Hematopoietic Stem Cells: Stromal Derived Factor 1 Is Not the Only Player in the Game

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Mariusz Z. Ratajczak ◽  
ChiHwa Kim ◽  
Anna Janowska-Wieczorek ◽  
Janina Ratajczak
Keyword(s):  
Bone Marrow ◽  
Extracellular Nucleotides ◽  
Bioactive Lipids ◽  
Hematopoietic Stem ◽  
Unique Role ◽  
Sphingosine 1 Phosphate ◽  
Complex Picture ◽  
Ceramide 1 ◽  
Cxcr4 Axis

Theα-chemokine stromal derived factor 1 (SDF-1), which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4-independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP) and adenosine triphosphate (ATP). Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 orβ2-defensin) as well as prostaglandin E2 (PGE2). Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis.

The Coordination of Prostaglandin E2 Production by Sphingosine-1-phosphate and Ceramide-1-phosphate

2005 ◽  
Vol 68 (2) ◽  
pp. 330-335 ◽  
Author(s):  
Benjamin J. Pettus ◽  
Kazuyuki Kitatani ◽  
Charles E. Chalfant ◽  
Tarek A. Taha ◽  
Toshihiko Kawamori ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Sphingosine 1 Phosphate ◽  
Ceramide 1

A Novel Paradigm In Stem Cell Trafficking: The Ratio of Peripheral Blood Sphingosine-1 Phosphate (S1P) to Bone Marrow Ceramide-1 Phosphate (C1P) Regulates Mobilization and Homing of Hematopoietic Stem Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 554-554 ◽  
Author(s):  
Chihwa Kim ◽  
Wu Wan ◽  
Rui Liu ◽  
Magdalena Kucia ◽  
Mary J. Laughlin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Chemotactic Activity ◽  
Bioactive Lipids ◽  
Myeloablative Conditioning ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Sphingosine 1 Phosphate ◽  
Ceramide 1

Abstract Abstract 554 The stromal derived factor-1 (SDF-1)–CXCR4 axis plays an unquestioned role in developmental migration of hematopoietic stem cells (HSPCs) and their retention in the bone marrow (BM). However, changes in the SDF-1 gradient between BM and peripheral blood (PB) do not always support its having a crucial role as chemoattractant for mobilization or homing of HSPCs. As demonstrated by others (e.g., Bone Marrow Transplantation 2003; 31:651–654, and Transfus Apher Sci 2009;40:159) and us (Leukemia 2010;24:976–985) the plasma SDF-1 level does not correlate with mobilization of HSPCs. On the other hand, there is increasing doubt about an exclusive role for SDF-1 in homing of HSPCs in BM. This is based on evidence that i) CXCR4−/− fetal liver HSPCs may home to BM in an SDF-1–independent manner (Immunity 1999;10:463-471), ii) homing of murine HSPCs made refractory to SDF-1 by incubation and co-injection with a CXCR4 receptor antagonist is normal or only mildly reduced (Science 2004;305:1000), and finally iii) HSPCs in which CXCR4 has been knocked down by means of an SDF-1 intrakine strategy also engraft in lethally irradiated recipients (Blood 2000;96:2074–,2080). All this strongly suggests the existence of other factors involved in the mobilization and homing of HSPCs. Moreover, while SDF-1 is a potent chemoattractant for HSPCs when employed at supraphysiological concentrations in vitro, as a peptide it is highly susceptible to degradation by proteases that are elevated, for example, in PB during stem cell mobilization or in the BM microenvironment after myeloablative conditioning for transplantation. Employing ELISA for detection in the present study, we observed insignificant changes in SDF-1 level both in PB during mobilization and in BM after myeloablative conditioning. We also found that mobilized PB (mPB) plasma as well as conditioned media (CM) from lethally irradiated mice chemoattract HSPCs in an SDF-1–independent manner as demonstrated by i) normal chemotaxis of AMD3100 pre-treated cells and ii) preservation of chemotactic activity of plasma and BM-derived CM following heat inactivation. However, the chemotactic activity of mPB plasma and BM CM was inhibited after stripping by activated charcoal. This suggested the involvement of small molecule bioactive lipids. It is known that sphingolipids, which are important components of cell membranes, give rise to two bioactive derivatives, sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P), with S1P already identified as a chemoattractant for HSPCs (Ann N Y Acad Sci. 200;1044:84–89). To our surprise, we found that C1P is also a strong chemoattractant for human and murine HSPCs. In addition, we observed that at physiological concentrations both these bioactive lipids i) activate phosphorylation of MAPKp42/44 and AKT in HSPCs, ii) induce expression of matrix metalloproteinases (MMPs), and iii) modulate adhesion to stroma and endothelium. Interestingly, by employing ELISA and/or mass spectophotometry we found that, while the S1P level increases in PB during mobilization, the C1P level increases in BM after myeloablative conditioning for transplantation. Based on these findings, we propose a new paradigm in which the S1P:C1P ratio plays a role in mobilization and homing of HSPCs. While S1P is a major chemoattractant that directs egress of HSPCs from BM into PB, C1P released from damaged cells in BM after myeloablative conditioning creates a homing gradient for circulating HSPCs. We also postulate that the S1P:C1P ratio plays a more universal role and is involved in regulating migration of other types of stem cells, such as circulating mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like (VSEL) stem cells. Accordingly, while S1P plays a role in egress of stem cells into PB, C1P released from damaged cells (e.g., in infarcted myocardium or brain tissue after stroke) chemoattracts circulating stem cells for potential repair. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutations in Tyr808 reveal a potential auto-inhibitory mechanism of guanylate cyclase-B regulation

2013 ◽  
Vol 33 (3) ◽  
Author(s):  
Takeshi Katafuchi
Keyword(s):  
Guanylate Cyclase ◽  
Sequence Similarity ◽  
Activation Mechanism ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Tyrosine Residues ◽  
Sphingosine 1 Phosphate ◽  
Membrane Bound ◽  
Partial Fragment ◽  
Insight Into

In this study, Tyr808 in GC-B (guanylate cyclase-B), a receptor of the CNP (C-type natriuretic peptide), has been shown to be a critical regulator of GC-B activity. In searching for phosphorylation sites that could account for suppression of GC-B activity by S1P (sphingosine-1-phosphate), mutations were introduced into several candidate serine/threonine and tyrosine residues. Although no novel phosphorylation sites that influenced the suppression of GC-B were identified, experiments revealed that mutations in Tyr808 markedly enhanced GC-B activity. CNP-stimulated activities of the Y808F and Y808A mutants were greater than 30-fold and 70-fold higher, respectively, than that of WT (wild-type) GC-B. The Y808E and Y808S mutants were constitutively active, expressing 270-fold higher activity without CNP stimulation than WT GC-B. Those mutations also influenced the sensitivity of GC-B to a variety of inhibitors, including S1P, Na3VO4 and PMA. Y808A, Y808E and Y808S mutations markedly weakened S1P- and Na3VO4-dependent suppression of GC-B activity, whereas Y808E and Y808S mutations rather elevated cGMP production. Tyr808 is conserved in all membrane-bound GCs and located in the niche domain showing sequence similarity to a partial fragment of the HNOBA (haem nitric oxide binding associated) domain, which is found in soluble GC and in bacterial haem-binding kinases. This finding provides new insight into the activation mechanism of GCs.

scholarly journals Deficiency of the NOD-Like Receptor NLRC5 Results in Decreased CD8+ T Cell Function and Impaired Viral Clearance

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Christopher R. Lupfer ◽  
Kate L. Stokes ◽  
Teneema Kuriakose ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Adaptive Immune Response ◽  
Influenza Virus Infection ◽  
Viral Clearance ◽  
Mhc I ◽  
Adaptive Immune ◽  
Pathogen Recognition Receptors

ABSTRACT Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response. The NLR family member NLRC5 regulates major histocompatibility complex class I (MHC-I) expression during various types of infections, but its role in immunity to influenza A virus (IAV) is not well studied. Here we show that Nlrc5 −/− mice exhibit an altered CD8+ T cell response during IAV infection compared to that of wild-type (WT) mice. Nlrc5 −/− mice have decreased MHC-I expression on hematopoietic cells and fewer CD8+ T cells prior to infection. NLRC5 deficiency does not affect the generation of antigen-specific CD8+ T cells following IAV infection; however, a change in epitope dominance is observed in Nlrc5 −/− mice. Moreover, IAV-specific CD8+ T cells from Nlrc5 −/− mice have impaired effector functions. This change in the adaptive immune response is associated with impaired viral clearance in Nlrc5 −/− mice. Collectively, our results demonstrate an important role for NLRC5 in regulation of antiviral immune responses and viral clearance during IAV infection. IMPORTANCE The NOD-like receptor family member NLRC5 is known to regulate expression of MHC-I as well as other genes required for antigen processing. In addition, NLRC5 also regulates various immune signaling pathways. In this study, we investigated the role of NLRC5 during influenza virus infection and found a major role for NLRC5 in restricting virus replication and promoting viral clearance. The observed increases in viral titers in NLRC5-deficient mice correlated with impaired effector CD8+ T cell responses. Although NLRC5-deficient mice were defective at clearing the virus, they did not show an increase in morbidity or mortality following influenza virus infection because of other compensatory immune mechanisms. Therefore, our study highlights how NLRC5 regulates multiple immune effector mechanisms to promote the host defense during influenza virus infection.

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