Philippe Pouliot

Publications (20) View all

• Source

  Available from: Alexander Shkumatov

  Article: Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1.

  Jonathan Elegheert, Nathalie Bracke, Philippe Pouliot, Irina Gutsche, Alexander V Shkumatov, Nicolas Tarbouriech, Kenneth Verstraete, Anaïs Bekaert, Wim P Burmeister, Dmitri I Svergun, Bart N Lambrecht, Bjorn Vergauwen, Savvas N Savvides
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  ABSTRACT: Hematopoietic human colony-stimulating factor 1 (hCSF-1) is essential for innate and adaptive immunity against viral and microbial infections and cancer. The human pathogen Epstein-Barr virus secretes the lytic-cycle protein BARF1 that neutralizes hCSF-1 to achieve immunomodulation. Here we show that BARF1 binds the dimer interface of hCSF-1 with picomolar affinity, away from the cognate receptor-binding site, to establish a long-lived complex featuring three hCSF-1 at the periphery of the BARF1 toroid. BARF1 locks dimeric hCSF-1 into an inactive conformation, rendering it unable to signal via its cognate receptor on human monocytes. This reveals a new functional role for hCSF-1 cooperativity in signaling. We propose a new viral strategy paradigm featuring an allosteric decoy receptor of the competitive type, which couples efficient sequestration and inactivation of the host growth factor to abrogate cooperative assembly of the cognate signaling complex.
  Nature Structural &#38 Molecular Biology 08/2012; 19(9):938-47. · 12.71 Impact Factor
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  Available from: 211.144.68.84

  Article: Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33.

  Monique A M Willart, Kim Deswarte, Philippe Pouliot, Harald Braun, Rudi Beyaert, Bart N Lambrecht, Hamida Hammad
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  ABSTRACT: House dust mite (HDM) is one of the most common allergens worldwide. In this study, we have addressed the involvement of IL-1 in the interaction between HDM and the innate immune response driven by lung epithelial cells (ECs) and dendritic cells (DCs) that leads to asthma. Mice lacking IL-1R on radioresistant cells, but not hematopoietic cells, failed to mount a Th2 immune response and did not develop asthma to HDM. Experiments performed in vivo and in isolated air-liquid interface cultures of bronchial ECs showed that TLR4 signals induced the release of IL-1α, which then acted in an autocrine manner to trigger the release of DC-attracting chemokines, GM-CSF, and IL-33. Consequently, allergic sensitization to HDM was abolished in vivo when IL-1α, GM-CSF, or IL-33 was neutralized. Thymic stromal lymphopoietin (TSLP) became important only when high doses of allergen were administered. These findings put IL-1α upstream in the cytokine cascade leading to epithelial and DC activation in response to inhaled HDM allergen.
  Journal of Experimental Medicine 07/2012; 209(8):1505-17. · 13.85 Impact Factor
• Article: Generation and evaluation of A2-expressing Lactococcus lactis live vaccines against Leishmania donovani in BALB/c mice.

  Karen K Yam, Felix Hugentobler, Philippe Pouliot, Andrew M Stern, Jean-Daniel Lalande, Greg Matlashewski, Martin Olivier, Benoit Cousineau
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  ABSTRACT: Leishmaniasis is a parasitic disease affecting over 12 million individuals worldwide. As current treatments are insufficient, the development of an effective vaccine is a priority. This study generated and assessed the efficacy of Leishmania vaccines engineered from the non-colonizing, non-pathogenic Gram-positive bacterium Lactococcus lactis. A truncated, codon-optimized version of the A2 antigen from Leishmania donovani was engineered for expression in Lactococcus lactis in three different subcellular compartments: in the cytoplasm, secreted outside the cell or anchored to the cell wall. These three A2-expressing Lactococcus lactis strains were tested for their ability to generate A2-specific immune responses and as live vaccines against visceral Leishmania donovani infection in BALB/c mice. Subcutaneous immunization with live Lactococcus lactis expressing A2 anchored to the cell wall effectively induced high levels of antigen-specific serum antibodies. It was demonstrated that Lactococcus lactis-based vaccines are a feasible approach in the generation of live vaccines against leishmaniasis. The Lactococcus lactis strains generated in this study provide an excellent foundation for further studies on live bacterial vaccines against leishmaniasis and other pathogens.
  Journal of Medical Microbiology 04/2011; 60(Pt 9):1248-60. · 2.50 Impact Factor
• Article: An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma.

  Mirjam Kool, Monique A M Willart, Menno van Nimwegen, Ingrid Bergen, Philippe Pouliot, J Christian Virchow, Neil Rogers, Fabiola Osorio, Caetano Reis e Sousa, Hamida Hammad, Bart N Lambrecht
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  ABSTRACT: Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.
  Immunity 04/2011; 34(4):527-40. · 21.64 Impact Factor
• Source

  Available from: Philippe Pouliot

  Article: Involvement of endoplasmic reticulum stress in inflammatory bowel disease: a different implication for colonic and ileal disease?

  Sara Bogaert, Martine De Vos, Kim Olievier, Harald Peeters, Dirk Elewaut, Bart Lambrecht, Philippe Pouliot, Debby Laukens
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  ABSTRACT: Endoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously. Expression of UPR-related genes was investigated in colonic and ileal biopsies of 23 controls, 15 ulcerative colitis (UC) and 54 Crohn's disease (CD) patients. This expression was confirmed at protein level in colonic and ileal samples of five controls, UC and CD patients. HSPA5, PDIA4 and XBP1s were significantly increased in colonic IBD at mRNA and/or protein levels, indicating activation of the ATF6 and IRE1 branch. Colonic IBD was associated with increased phosphorylation of EIF2A suggesting the activation of the PERK branch, but subsequent induction of GADD34 was not observed. In ileal CD, no differential expression of the UPR-related genes was observed, but our data suggested a higher basal activation of the UPR in the ileal mucosa of controls. This was confirmed by the increased expression of 16 UPR-related genes as 12 of them were significantly more expressed in ileal controls compared to colonic controls. Tunicamycin stimulation of colonic and ileal samples of healthy individuals revealed that although the ileal mucosa is exhibiting this higher basal UPR activation, it is still responsive to ER stress, even more than colonic mucosa. Activation of the three UPR-related arms is seen in colonic IBD-associated inflammation. However, despite EIF2A activation, inflamed colonic tissue did not increase GADD34 expression, which is usually involved in re-establishment of ER homeostasis. This study also implies the presence of a constitutive UPR activation in healthy ileal mucosa, with no further activation during inflammation. Therefore, engagement of the UPR differs between colon and ileum and this could be a factor in the development of ileal or colonic disease.
  PLoS ONE 01/2011; 6(10):e25589. · 4.09 Impact Factor