Martha Triantafilou

Publications (52)250.83 Total impact

• Article: The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation.

  Kathy Triantafilou, Timothy R Hughes, Martha Triantafilou, B Paul Morgan
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  ABSTRACT: The membrane attack complex of complement (MAC), apart from its classical role of lysing cells, can also trigger a range of non-lethal effects on cells, acting as a drive to inflammation. In this study we chose to investigate these non-lethal effects on inflammasome activation. We found that, following sublytic MAC attack, there is increased cytosolic Ca(2+) concentration, at least partly through Ca(2+) release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This increase in intracellular Ca(2+) concentration leads to Ca(2+) accumulation into the mitochondrial matrix via MICU1, the "mitochondrial calcium uniporter" (MCU), loss of mitochondrial transmembrane potential, triggering NLRP3 inflammasome activation and IL-1β release. NLRP3 co-localises with the mitochondria, likely sensing the increase in calcium and the resultant mitochondrial dysfunction, leading to caspase activation and apoptosis. This is the first study that links non-lethal effects of sublytic MAC attack with inflammasome activation and provides a mechanism by which sublytic MAC can drive inflammation and apoptosis.
  Journal of Cell Science 04/2013; · 6.11 Impact Factor
• Article: Human respiratory syncytial virus viroporin SH: a viral recognition pathway used by the host to signal inflammasome activation.

  Kathy Triantafilou, Satwik Kar, Emmanouil Vakakis, Sailesh Kotecha, Martha Triantafilou
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  ABSTRACT: Respiratory syncytial virus (RSV) remains the leading cause of serious viral bronchiolitis and pneumonia in infants and young children throughout the world. The burden of disease is significant, with 70% of all infants being infected with RSV within the first year of their life. 40% of those children discharged from hospital have recurrent, repeated respiratory symptoms and wheezing for at least 10 years. The infection is also an important illness in the elderly and immunocompromised individuals. Ongoing symptoms relate to continued lung inflammation. One cytokine that is associated with RSV infection is IL-1β, but the mechanism of activation remain unclear. In the current study, we set out to decipher the molecular mechanisms of RSV-induced inflammasome activation. Using deletion mutants of the virus and measuring IL-1β secretion, as well as caspase 1 expression via western blotting, we demonstrate that the NLRP3 inflammasome is activated through the small hydrophobic (SH) RSV viroporin which induces membrane permeability to ions or small molecules. Confocal microscopy revealed that during virus infection, SH seems to accumulate within lipid rafts in the Golgi compartments. Upon RSV infection, SH gets localised in the cell membranes and intracellular organelle membranes, and then induces permeability by disrupting membrane architecture, thus leading us to believe that formation of viral ion channels in lipid bilayers of cells is a viral recognition pathway used by the host to signal inflammasome activation.
  Thorax 01/2013; 68(1):66-75. · 6.84 Impact Factor
• Article: Synergic Activation of Toll-Like Receptor (TLR) 2/6 and 9 in Response to Ureaplasma parvum & urealyticum in Human Amniotic Epithelial Cells.

  Martha Triantafilou, Benjamin De Glanville, Ali F Aboklaish, O Brad Spiller, Sailesh Kotecha, Kathy Triantafilou
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  ABSTRACT: Ureaplasma species are the most frequently isolated microorganisms inside the amniotic cavity and have been associated with spontaneous abortion, chorioamnionitis, premature rupture of the membranes (PROM), preterm labour (PL) pneumonia in neonates and bronchopulmonary dysplasia in neonates. The mechanisms by which Ureaplasmas cause such diseases remain unclear, but it is believed that inappropriate induction of inflammatory responses is involved, triggered by the innate immune system. As part of its mechanism of activation, the innate immune system employs germ-lined encoded receptors, called pattern recognition receptors (PRRs) in order to "sense" pathogens. One such family of PRRs are the Toll like receptor family (TLR). In the current study we aimed to elucidate the role of TLRs in Ureaplasma-induced inflammation in human amniotic epithelial cells. Using silencing, as well as human embryonic kidney (HEK) transfected cell lines, we demonstrate that TLR2, TLR6 and TLR9 are involved in the inflammatory responses against Ureaplasma parvum and urealyticum serovars. Ureaplasma lipoproteins, such as Multiple Banded antigen (MBA), trigger responses via TLR2/TLR6, whereas the whole bacterium is required for TLR9 activation. No major differences were observed between the different serovars. Cell activation by Ureaplasma parvum and urealyticum seem to require lipid raft function and formation of heterotypic receptor complexes comprising of TLR2 and TLR6 on the cell surface and TLR9 intracellularly.
  PLoS ONE 01/2013; 8(4):e61199. · 4.09 Impact Factor
• Article: Visualisation of direct interaction of MDA5 and the dsRNA replicative intermediate form of positive strand RNA viruses.

  Kathy Triantafilou, Emmanouil Vakakis, Satwik Kar, Edward Richer, Gareth L Evans, Martha Triantafilou
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  ABSTRACT: The innate immune system is a vital part of the body's defences against viral pathogens. RIG-I and MDA5 function as cytoplasmic PRRs that are involved in the elimination of actively replicating RNA viruses. Their location and their differential responses to RNA viruses emphasises the complexity of the innate detection system. Despite the wealth of information on the types of RNA that trigger RIG-I, much less is known about the nature of the RNAs that act as agonists for MDA5. In order to identify which RNA species triggers MDA5 activation during infection, we isolated viral ssRNA and replicative intermediates of RNA from positive sense ssRNA viruses. We reveal that MDA5 recognises not the genomic ssRNA but the dsRNA generated by the replication of these viruses. Furthermore, using fluorescent imaging we present the first report of the visualization of dsRNA and MDA5, which provides unique evidence between the relationship of viral dsRNA and MDA5 and proves without a doubt that MDA5 is the key sensor for the dsRNA replicative intermediate form of positive sense ssRNA viruses.
  Journal of Cell Science 07/2012; · 6.11 Impact Factor
• Article: MARCKS as a negative regulator of lipopolysaccharide signaling.

  Mateja Mancek-Keber, Mojca Bencina, Bostjan Japelj, Gabriela Panter, Jörg Andrä, Klaus Brandenburg, Martha Triantafilou, Kathy Triantafilou, Roman Jerala
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  ABSTRACT: Myristoylated alanine-rich C kinase substrate (MARCKS) is an intrinsically unfolded protein with a conserved cationic effector domain, which mediates the cross-talk between several signal transduction pathways. Transcription of MARCKS is increased by stimulation with bacterial LPS. We determined that MARCKS and MARCKS-related protein specifically bind to LPS and that the addition of the MARCKS effector peptide inhibited LPS-induced production of TNF-α in mononuclear cells. The LPS binding site within the effector domain of MARCKS was narrowed down to a heptapeptide that binds to LPS in an extended conformation as determined by nuclear magnetic resonance spectroscopy. After LPS stimulation, MARCKS moved from the plasma membrane to FYVE-positive endosomes, where it colocalized with LPS. MARCKS-deficient mouse embryonic fibroblasts (MEFs) responded to LPS with increased IL-6 production compared with the matched wild-type MEFs. Similarly, small interfering RNA knockdown of MARCKS also increased LPS signaling, whereas overexpression of MARCKS inhibited LPS signaling. TLR4 signaling was enhanced by the ablation of MARCKS, which had no effect on stimulation by TLR2, TLR3, and TLR5 agonists. These findings demonstrate that MARCKS contributes to the negative regulation of the cellular response to LPS.
  The Journal of Immunology 03/2012; 188(8):3893-902. · 5.79 Impact Factor
• Article: Serum proteins modulate lipopolysaccharide and lipoteichoic acid-induced activation and contribute to the clinical outcome of sepsis.

  Martha Triantafilou, Marios-Angelos Mouratis, Philipp M Lepper, Rowenna Mitch Haston, Fiona Baldwin, Sarah Lowes, Mohamed Abd Elrahman Ahmed, Christian Schumann, Owen Boyd, Kathy Triantafilou
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  ABSTRACT: Bacterial cell wall components, such LPS and LTA, are potent initiators of an inflammatory response that can lead to septic shock. The advances in the past were centered around membrane-bound receptors and intracellular events, but our understanding of the initial interactions of these bacterial components with serum proteins as they enter the bloodstream remain unclear. In this study we identified several serum proteins, which are involved in the innate recognition of bacterial products. Using affinity chromatography and mass spectrometry we performed proteomic analysis of LPS- and LTA-binding serum proteins. We isolated proteins from normal serum that can interact with LPS and LTA. Fluorescent binding experiments and cytokine assays revealed that serum proteins, such as apolipoprotein, LDL, transferrin and holotransferrin could neutralize LPS/LTA binding as well as the subsequent inflammatory response, suggesting that serum proteins modulate LPS/LTA-induced responses. When compared with the proteomic profile of serum from septic patients it was shown that these proteins were in lower abundance. Investigation of serum proteins in 25 critically ill patients with a mortality rate of 40% showed statistically higher levels of these proteins in survivors. Patients surviving sepsis had statistically significant higher levels of apolipoprotein, albumin, LDL, transferrin and holotransferrin than individuals that succumbed, suggesting that these proteins have an inhibitory effect on LPS/LTA-induced inflammatory responses and in their absence there might be an augmented inflammatory response in sepsis.
  Virulence 03/2012; 3(2):136-45. · 2.26 Impact Factor
• Article: Visualising PAMP-PRR interactions using nanoscale imaging.

  Kathy Triantafilou, Martha Triantafilou
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  ABSTRACT: The innate immune system utilises a set of receptors, called pattern recognition receptors (PRRs), in order to recognise specific molecular patterns or motifs called pathogen-associated molecular patterns (PAMPs) on invading pathogens. The toll-like receptor (TLR) family of proteins is an integral part of the mammalian innate immune system. We are now beginning to decipher which TLRs are involved in the recognition of particular microbial patterns, but questions remain as to the homo- and heterotypic associations that TLRs form and how these associations affect their activation. Technical advances in fluorescence microscopy has enabled us to investigate the functional associations of TLRs and other PPRs in living cells in response to different pathogens using non-invasive fluorescence imaging methods. In this chapter, we will describe some of the fluorescent imaging techniques, such as FRET and FRAP, that we employ in order to study PAMP-PRR associations.
  Methods in molecular biology (Clifton, N.J.) 01/2012; 799:253-66.
• Article: Human rhinovirus recognition in non-immune cells is mediated by Toll-like receptors and MDA-5, which trigger a synergetic pro-inflammatory immune response.

  Kathy Triantafilou, Emmanouil Vakakis, Edward A J Richer, Gareth L Evans, Joseph P Villiers, Martha Triantafilou
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  ABSTRACT: The early detection of invading viruses by the host depends on their identification by pathogen sensors. These include Toll-like receptors (TLRs) as well as cytoplasmic RNA helicases such as retinoic acid inducible protein I (RIG-I) and melanoma differentiation associated gene 5 (MDA-5). These pathogen sensors recognize specific molecular patterns found in viruses and trigger inflammatory and antiviral responses that result in the eradication of invading pathogens. In this study we investigated the specific recognition of Human rhinovirus 6 (HRV6) the common cold pathogen by the innate immune response in lung epithelial cells. Our experiments established that in the first stages on infection the TLRs play a crucial role in HRV recognition and that different constituents of HRV6 are recognized by different TLRs, while upon viral replication and generation of dsRNA the type I IFN inflammatory response is mediated by MDA-5. The HRV6 capsid is recognized via TLR2, whereas upon HRV6 ssRNA internalization the virus genome is recognized by TLR7 and TLR8. Upon generation of dsRNA the type I IFN response is mediated by MDA-5. The combined recognition by different TLRs and MDA5 and their upregulation concurs with the huge inflammatory response seen in the common cold caused by human rhinoviruses.
  Virulence 01/2011; 2(1):22-9. · 2.26 Impact Factor
• Source

  Available from: Philipp M Lepper

  Article: Location, location, location: is membrane partitioning everything when it comes to innate immune activation?

  Martha Triantafilou, Philipp M Lepper, Robin Olden, Ivo de Seabra Rodrigues Dias, Kathy Triantafilou
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  ABSTRACT: In the last twenty years, the general view of the plasma membrane has changed from a homogeneous arrangement of lipids to a mosaic of microdomains. It is currently thought that islands of highly ordered saturated lipids and cholesterol, which are laterally mobile, exist in the plane of the plasma membrane. Lipid rafts are thought to provide a means to explain the spatial segregation of certain signalling pathways emanating from the cell surface. They seem to provide the necessary microenvironment in order for certain specialised signalling events to take place, such as the innate immune recognition. The innate immune system seems to employ germ-lined encoded receptors, called pattern recognition receptors (PRRs), in order to detect pathogens. One family of such receptors are the Toll-like receptors (TLRs), which are the central "sensing" apparatus of the innate immune system. In recent years, it has become apparent that TLRs are recruited into membrane microdomains in response to ligands. These nanoscale assemblies of sphingolipid, cholesterol, and TLRs stabilize and coalesce, forming signalling platforms, which transduce signals that lead to innate immune activation. In the current paper, we will investigate all past and current literature concerning recruitment of extracellular and intracellular TLRs into lipid rafts and how this membrane organization modulates innate immune responses.
  Mediators of Inflammation 01/2011; 2011:186093. · 3.26 Impact Factor
• Source

  Available from: Thomas Hartung

  Article: Internalization and coreceptor expression are critical for TLR2-mediated recognition of lipoteichoic acid in human peripheral blood.

  Sebastian Bunk, Stefanie Sigel, Daniela Metzdorf, Omar Sharif, Kathy Triantafilou, Martha Triantafilou, Thomas Hartung, Sylvia Knapp, Sonja von Aulock
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  ABSTRACT: Lipoteichoic acid (LTA), a ubiquitous cell wall component of Gram-positive bacteria, represents a potent immunostimulatory molecule. Because LTA of a mutant Staphylococcus aureus strain lacking lipoproteins (Deltalgt-LTA) has been described to be immunobiologically inactive despite a lack of ascertained structural differences to wild-type LTA (wt-LTA), we investigated the functional requirements for the recognition of Deltalgt-LTA by human peripheral blood cells. In this study, we demonstrate that Deltalgt-LTA-induced immune activation critically depends on the immobilization of LTA and the presence of human serum components, which, to a lesser degree, was also observed for wt-LTA. Under experimental conditions allowing LTA-mediated stimulation, we found no differences between the immunostimulatory capacity of Deltalgt-LTA and wt-LTA in human blood cells, arguing for a limited contribution of possible lipoprotein contaminants to wt-LTA-mediated immune activation. In contrast to human blood cells, TLR2-transfected human embryonic kidney 293 cells could be activated only by wt-LTA, whereas activation of these cells by Deltalgt-LTA required the additional expression of TLR6 and CD14, suggesting that activation of human embryonic kidney 293 cells expressing solely TLR2 is probably mediated by residual lipoproteins in wt-LTA. Notably, in human peripheral blood, LTA-specific IgG Abs are essential for Deltalgt-LTA-mediated immune activation and appear to induce the phagocytic uptake of Deltalgt-LTA via engagement of FcgammaRII. In this study, we have elucidated a novel mechanism of LTA-induced cytokine induction in human peripheral blood cells that involves uptake of LTA and subsequent intracellular recognition driven by TLR2, TLR6, and CD14.
  The Journal of Immunology 09/2010; 185(6):3708-17. · 5.79 Impact Factor
• Source

  Available from: Philipp M Lepper

  Article: Modulation of toll-like receptor signalling as a new therapeutic principle.

  Philipp M Lepper, Martha Triantafilou, Luke A O'Neill, Natalija Novak, Hermann Wagner, Andrew E Parker, Kathy Triantafilou
  Mediators of Inflammation 01/2010; 2010:705612. · 3.26 Impact Factor
• Article: Membrane partitioning: is location everything when it comes to endotoxin recognition?

  Martha Triantafilou, Kathy Triantafilou
  [show abstract] [hide abstract]
  ABSTRACT: Lipid rafts are envisaged as islands of highly ordered saturated lipids and cholesterol that are laterally mobile in the plane of the plasma membrane. Lipid rafts are thought to provide a means to explain the spatial segregation of certain signalling pathways emanating from the cell surface. They seem to provide the necessary microenvironment in order for certain specialised signalling events to take place- such as the innate immune recognition. The innate immune system seems to employ germ-lined encoded receptors, called pattern recognition receptors (PRRs) in order to "sense" pathogens. One family of such receptors are the Toll like receptors (TLRs), which are the central "sensing" apparatus of the innate immune system. In recent years, it has become apparent that TLRs are recruited into membrane microdomains in response to ligands and these constitute signalling platforms, which transducer singals that lead to innate immune activation. In this chapter will review all past and current literature concerning recruitment of TLRs into lipid rafts and how this membrane compartmentalization is crucial for innate immune responses.
  Sub-cellular biochemistry 01/2010; 53:173-84.
• Article: Microbial hijacking of complement-toll-like receptor crosstalk.

  Min Wang, Jennifer L Krauss, Hisanori Domon, Kavita B Hosur, Shuang Liang, Paola Magotti, Martha Triantafilou, Kathy Triantafilou, John D Lambris, George Hajishengallis
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  ABSTRACT: Crosstalk between complement and Toll-like receptors (TLRs) coordinates innate immunity. We report a previously unknown immune subversion mechanism involving microbial exploitation of communication between complement and TLRs. Porphyromonas gingivalis, a major oral and systemic pathogen with complement C5 convertase-like activity, synergizes with C5a (fragment of complement protein C5) to increase cyclic adenosine monophosphate (cAMP) concentrations, resulting in suppression of macrophage immune function and enhanced pathogen survival in vitro and in vivo. This synergy required TLR2 signaling, a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, with protein kinase A and glycogen synthase kinase-3beta as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications for periodontitis and atherosclerosis, diseases in which P. gingivalis is implicated. This first demonstration of complement-TLR crosstalk for immunosuppressive cAMP signaling indicates that pathogens may not simply undermine complement or TLRs (or both) as separate entities, but may also exploit their crosstalk pathways.
  Science Signaling 01/2010; 3(109):ra11. · 7.50 Impact Factor
• Article: Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis.

  Deanne L Pierce, So-ichiro Nishiyama, Shuang Liang, Min Wang, Martha Triantafilou, Kathy Triantafilou, Fuminobu Yoshimura, Donald R Demuth, George Hajishengallis
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  ABSTRACT: The fimbriae of Porphyromonas gingivalis mediate critical roles in host colonization and evasion of innate defenses and comprise polymerized fimbrilin (FimA) associated with quantitatively minor accessory proteins (FimCDE) of unknown function. We now show that P. gingivalis fimbriae lacking FimCDE fail to interact with the CXC-chemokine receptor 4 (CXCR4), and bacteria expressing FimCDE-deficient fimbriae cannot exploit CXCR4 in vivo for promoting their persistence, as the wild-type organism does. Consistent with these loss-of-function experiments, purified FimC and FimD (but not FimE) were shown to interact with CXCR4. However, significantly stronger binding was observed when a combination of all three proteins was allowed to interact with CXCR4. In addition, FimC and FimD bound to fibronectin and type 1 collagen, whereas FimE failed to interact with these matrix proteins. These data and the fact that FimE is required for the association of FimCDE with P. gingivalis fimbriae suggest that FimE may recruit FimC and FimD into a functional complex, rather than directly binding host proteins. Consistent with this notion, FimE was shown to bind both FimC and FimD. In summary, the FimCDE components cooperate and impart critical adhesive and virulence properties to P. gingivalis fimbriae.
  Infection and immunity 07/2009; 77(8):3294-301. · 4.21 Impact Factor
• Article: A phosphatidylserine species inhibits a range of TLR- but not IL-1beta-induced inflammatory responses by disruption of membrane microdomains.

  Lisa C Parker, Elizabeth C Prestwich, Jon R Ward, Elizabeth Smythe, Anthony Berry, Martha Triantafilou, Kathy Triantafilou, Ian Sabroe
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  ABSTRACT: TLRs detect conserved molecular patterns that are unique to microbes, enabling tailored responses to invading pathogens and modulating a multitude of immunopathological conditions. We investigated the ability of a naturally occurring stearoyl-arachidonoyl form of phosphatidylserine (SAPS) to inhibit the proinflammatory effects of TLR agonists in models of inflammation investigating the interaction of leukocytes with epithelial and endothelial cells. The responses to LPS of both epithelial and endothelial cells were highly amplified in the presence of PBMCs. Coincubation with SAPS markedly inhibited activation of cocultures by LPS, principally through inhibition of the TLR4 signaling pathway in PBMCs; however, this was not through downmodulation of TLR4 or coreceptor expression, nor was IL-1beta-induced cytokine release affected. SAPS also impaired Pam(3)CSK(4) (TLR2/1), Gardiquimod (TLR7/8), and Streptococcus pneumoniae-induced cytokine release, but had only modest effects on poly(I:C) (TLR3)-induced responses. Fluorescence resonance energy transfer analysis of molecular associations revealed that SAPS disrupted the association of both TLR4 and TLR2 with their respective membrane partners that are required for signaling. Thus, our data reinforce the existence and importance of cooperative networks of TLRs, tissue cells, and leukocytes in mediating innate immunity, and identify a novel disrupter of membrane microdomains, revealing the dependence of TLR signaling on localization within these domains.
  The Journal of Immunology 11/2008; 181(8):5606-17. · 5.79 Impact Factor
• Source

  Available from: pnas.org

  Article: Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function.

  George Hajishengallis, Min Wang, Shuang Liang, Martha Triantafilou, Kathy Triantafilou
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  ABSTRACT: We report a mechanism of microbial evasion of Toll-like receptor (TLR)-mediated immunity that depends on CXCR4 exploitation. Specifically, the oral/systemic pathogen Porphyromonas gingivalis induces cross-talk between CXCR4 and TLR2 in human monocytes or mouse macrophages and undermines host defense. This is accomplished through its surface fimbriae, which induce CXCR4/TLR2 co-association in lipid rafts and interact with both receptors: Binding to CXCR4 induces cAMP-dependent protein kinase A (PKA) signaling, which in turn inhibits TLR2-mediated proinflammatory and antimicrobial responses to the pathogen. This outcome enables P. gingivalis to resist clearance in vitro and in vivo and thus to promote its adaptive fitness. However, a specific CXCR4 antagonist abrogates this immune evasion mechanism and offers a promising counterstrategy for the control of P. gingivalis periodontal or systemic infections.
  Proceedings of the National Academy of Sciences 10/2008; 105(36):13532-7. · 9.68 Impact Factor
• Article: Cell surface molecular chaperones as endogenous modulators of the innate immune response.

  Martha Triantafilou, Daniel Sawyer, Abdiaziz Nor, Emmanouil Vakakis, Kathy Triantafilou
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  ABSTRACT: Mammalian responses to bacterial products can lead to an uncontrolled inflammatory response that can be deadly for the host. It has been shown that the innate immune system employs at least three cell surface receptors, TLR4, CD14 and MD2, in order to recognize bacterial products. We have previously shown that heat shock proteins (HSPs) are also involved in the innate immune recognition. HSPs are a family of highly conserved proteins that act as molecular chaperones and assist in proper folding, assembly and intracellular trafficking of proteins. How HSPs reach the cell surface and how they are involved in the innate immune response still remain unclear. In the present study we investigated their association with the TLR4/CD14/MD2 complex in response to bacterial products and provide evidence that the Hsp70 and Hsp90 associate with TLR4 on the cell surface in response to stimulation by bacterial products. These associations seem to take place within lipid rafts. The addition of exogenous recombinant Hsp70 to cells in vitro results in a dose-responsive inhibition of the inflammatory signal cascade and cytokine production. Our studies reveal that HSPs may play an important role as endogenous regulators of the innate immune response.
  Novartis Foundation symposium 02/2008; 291:74-9; discussion 79-85, 137-40.
• Article: Chemokine receptor 4 (CXCR4) is part of the lipopolysaccharide "sensing apparatus".

  Martha Triantafilou, Philipp M Lepper, Caspar David Briault, Mohamed Abd Elrahman Ahmed, Josh M Dmochowski, Christian Schumann, Kathy Triantafilou
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  ABSTRACT: Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system involves at least three receptor molecules: CD14, TLR4 and MD-2. Additional receptor components such as heat shock proteins, chemokine receptor 4 (CXCR4), or CD55 have been suggested to be part of this activation cluster; possibly acting as additional LPS transfer molecules. Our group has previously identified CXCR4 as a component of the "LPS-sensing apparatus". In this study we aimed to elucidate the role that CXCR4 plays in innate immune responses to LPS. Here we demonstrate that CXCR4 transfection results in responsiveness to LPS. Fluorescence correlation spectroscopy experiments further showed that LPS directly interacts with CXCR4. Our data suggest that CXCR4 is not only involved in LPS binding but is also responsible for triggering signalling, especially mitogen-activated protein kinases in response to LPS. Finally, co-clustering of CXCR4 with other LPS receptors seems to be crucial for LPS signalling, thus suggesting that CXCR4 is a functional part of the multimeric LPS "sensing apparatus".
  European Journal of Immunology 02/2008; 38(1):192-203. · 5.10 Impact Factor
• Article: Anthrax toxin evades Toll-like receptor recognition, whereas its cell wall components trigger activation via TLR2/6 heterodimers.

  Martha Triantafilou, Ahmed Uddin, Sebastien Maher, Nicholas Charalambous, Thomas S C Hamm, Ahmad Alsumaiti, Kathy Triantafilou
  [show abstract] [hide abstract]
  ABSTRACT: Bacillus anthracis is a Gram-positive bacillus that is the causative agent of anthrax. The virulence of the bacillus is partly due to the production of a tripartite virulence factor: protective antigen (PA), lethal factor (LF) and edema factor (EF). Recognition of the bacillus and its toxins by the innate immune system is likely to play a key role following infection. In this study we set out to investigate whether anthrax cell wall (ACW) components as well as the lethal toxin are sensed by Toll-like receptors (TLRs). Our data suggest that ACW components as well as PA are sensed by TLR2/6 heterodimers triggering an inflammatory response. This recognition takes place on the cell surface within specialized microdomains for ACW, whereas PA seems to trigger responses intracellularly. Interestingly, LF does not trigger a pro-inflammatory response, and when combined with PA, the complex is not sensed by the innate immune system. Overall our data suggest that TLR2/6 heterodimers are responsible for sensing the ACW and PA, whereas the formation of the subsequent toxin (LF + PA) seems to evade detection by the innate immune system contributing to the virulence of the toxin.
  Cellular Microbiology 01/2008; 9(12):2880-92. · 5.46 Impact Factor
• Source

  Available from: Marios Angelos Mouratis

  Article: Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells.

  Martha Triantafilou, Frederick G J Gamper, Philipp M Lepper, Marios Angelos Mouratis, Christian Schumann, Evlambia Harokopakis, Robert E Schifferle, George Hajishengallis, Kathy Triantafilou
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  ABSTRACT: Infection with bacteria such as Chlamydia pneumonia, Helicobacter pylori or Porphyromonas gingivalis may be triggering the secretion of inflammatory cytokines that leads to atherogenesis. The mechanisms by which the innate immune recognition of these pathogens could lead to atherosclerosis remain unclear. In this study, using human vascular endothelial cells or HEK-293 cells engineered to express pattern-recognition receptors (PRRs), we set out to determine Toll-like receptors (TLRs) and functionally associated PRRs involved in the innate recognition of and response to lipopolysaccharide (LPS) from H. pylori or P. gingivalis. Using siRNA interference or recombinant expression of cooperating PRRs, we show that H. pylori and P. gingivalis LPS-induced cell activation is mediated through TLR2. Human vascular endothelial cell activation was found to be lipid raft-dependent and to require the formation of heterotypic receptor complexes comprising of TLR2, TLR1, CD36 and CD11b/CD18. In addition, we report that LPS from these bacterial strains are able to antagonize TLR4. This antagonistic activity of H. pylori or P. gingivalis LPS, as well as their TLR2 activation capability may be associated with their ability to contribute to atherosclerosis.
  Cellular Microbiology 09/2007; 9(8):2030-9. · 5.46 Impact Factor