Stoyan Ivanov

Publications (7)33.47 Total impact

• Article: Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection.

  Stoyan Ivanov, Joelle Renneson, Josette Fontaine, Adeline Barthelemy, Christophe Paget, Elodie Macho Fernandez, Fany Blanc, Carl De Trez, Laurye Van Maele, Laure Dumoutier, Michel-René Huerre, Gérard Eberl, Mustapha Si-Tahar, Pierre Gosset, Jean Christophe Renauld, Jean Claude Sirard, Christelle Faveeuw, François Trottein
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  ABSTRACT: Interleukin (IL)-22 has redundant, protective or pathogenic functions during auto-immune, inflammatory and infectious diseases. Here, we addressed the potential role of IL-22 in host defence and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that RORγt-positive αβ and γδ T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as two days post-infection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22 deficient animals had an enhanced lung injury and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection where it limits lung inflammation and subsequent bacterial superinfections.
  Journal of Virology 04/2013; · 5.40 Impact Factor
• Article: Key role for respiratory CD103(+) dendritic cells, IFN-γ, and IL-17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide.

  Stoyan Ivanov, Josette Fontaine, Christophe Paget, Elodie Macho Fernandez, Laurye Van Maele, Joelle Renneson, Isabelle Maillet, Natalia Muñoz Wolf, Analia Rial, Hélène Léger, Bernard Ryffel, Benoit Frisch, José A Chabalgoity, Jean Claude Sirard, Arndt Benecke, Christelle Faveeuw, François Trottein
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  ABSTRACT: Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive αβ T lymphocytes, with use of mucosal α-galactosylceramide (α-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to α-GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans. α-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103(+) subset, play a major role in the activation (IFN-γ and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-γ and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis. These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-γ and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae.
  The Journal of Infectious Diseases 06/2012; 206(5):723-34. · 6.41 Impact Factor
• Article: Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages.

  Christophe Paget, Stoyan Ivanov, Josette Fontaine, Joelle Renneson, Fany Blanc, Muriel Pichavant, Laure Dumoutier, Bernhard Ryffel, Jean Christophe Renauld, Philippe Gosset, Pierre Gosset, Mustapha Si-Tahar, Christelle Faveeuw, François Trottein
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  ABSTRACT: Invariant natural killer T (iNKT) cells are non-conventional lipid-reactive αβ T lymphocytes that play a key role in host responses during viral infections, in particular through the swift production of cytokines. Their beneficial role during experimental influenza A virus (IAV) infection has recently been proposed, although the mechanisms involved remain elusive. Here we show that during in vivo IAV infection, mouse pulmonary iNKT cells produce IFN-γ and IL-22, a Th17-related cytokine critical in mucosal immunity. Although permissive to viral replication, IL-22 production by iNKT cells is not due to IAV infection per se of these cells but is indirectly mediated by IAV-infected dendritic cells (DCs). We show that activation of the viral RNA sensors TLR7 and RIG-I in DCs is important for triggering IL-22 secretion by iNKT cells, whereas the NOD-like receptors NOD2 and NLRP3 are dispensable. Invariant NKT cells respond to IL-1β and IL-23 provided by infected DCs independently of the CD1d molecule to release IL-22. In vitro, IL-22 protects IAV-infected airway epithelial cells against mortality but has no role on viral replication. Finally, during early IAV infection, IL-22 plays a positive role in the control of lung epithelial damages. Overall, IAV infection of DCs activates iNKT cells, providing a rapid source of IL-22 that might be beneficial to preserve the lung epithelium integrity.
  Journal of Biological Chemistry 01/2012; 287(12):8816-29. · 4.77 Impact Factor
• Article: A detrimental role for invariant natural killer T cells in the pathogenesis of experimental dengue virus infection.

  Joelle Renneson, Rodrigo Guabiraba, Isabelle Maillet, Rafael E Marques, Stoyan Ivanov, Josette Fontaine, Christophe Paget, Valérie Quesniaux, Christelle Faveeuw, Bernhard Ryffel, Mauro M Teixeira, François Trottein
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  ABSTRACT: Dengue virus (DENV), a member of the mosquito-borne flaviviruses, is a serious public health problem in many tropical countries. We assessed the in vivo physiologic contribution of invariant natural killer T (iNKT) cells, a population of nonconventional lipid-reactive αβ T lymphocytes, to the host response during experimental DENV infection. We used a mouse-adapted DENV serotype 2 strain that causes a disease that resembles severe dengue in humans. On DENV challenge, splenic and hepatic iNKT cells became activated insofar as CD69 and Fas ligand up-regulation and interferon-γ production. C57BL/6 mice deficient in iNKT cells (Jα18(-/-)) were more resistant to lethal infection than were wild-type animals, and the phenotype was reversed by adoptive transfer of iNKT cells to Jα18(-/-) animals. The absence of iNKT cells in Jα18(-/-) mice was associated with decreased systemic and local inflammatory responses, less liver injury, diminished vascular leak syndrome, and reduced activation of natural killer cells and neutrophils. iNKT cell functions were not necessary for control of primary DENV infection, after either natural endogenous activation or exogenous activation with the canonical iNKT cell agonist α-galactosylceramide. Together, these data reveal a novel and critical role for iNKT cells in the pathogenesis of severe experimental dengue disease.
  American Journal Of Pathology 08/2011; 179(4):1872-83. · 4.89 Impact Factor
• Article: Potential role of invariant NKT cells in the control of pulmonary inflammation and CD8+ T cell response during acute influenza A virus H3N2 pneumonia.

  Christophe Paget, Stoyan Ivanov, Josette Fontaine, Fany Blanc, Muriel Pichavant, Joelle Renneson, Emilie Bialecki, Julien Pothlichet, Catherine Vendeville, Giovanna Barba-Spaeth, Giovanna Barba-Speath, Michel-René Huerre, Christelle Faveeuw, Mustapha Si-Tahar, François Trottein
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  ABSTRACT: Influenza A virus (IAV) infection results in a highly contagious respiratory illness leading to substantial morbidity and occasionally death. In this report, we assessed the in vivo physiological contribution of invariant NKT (iNKT) lymphocytes, a subset of lipid-reactive αβ T lymphocytes, on the host response and viral pathogenesis using a virulent, mouse-adapted, IAV H3N2 strain. Upon infection with a lethal dose of IAV, iNKT cells become activated in the lungs and bronchoalveolar space to become rapidly anergic to further restimulation. Relative to wild-type animals, C57BL/6 mice deficient in iNKT cells (Jα18(-/-) mice) developed a more severe bronchopneumonia and had an accelerated fatal outcome, a phenomenon reversed by the adoptive transfer of NKT cells prior to infection. The enhanced pathology in Jα18(-/-) animals was not associated with either reduced or delayed viral clearance in the lungs or with a defective local NK cell response. In marked contrast, Jα18(-/-) mice displayed a dramatically reduced IAV-specific CD8(+) T cell response in the lungs and in lung-draining mediastinal lymph nodes. We further show that this defective CD8(+) T cell response correlates with an altered accumulation and maturation of pulmonary CD103(+), but not CD11b(high), dendritic cells in the mediastinal lymph nodes. Taken together, these findings point to a role for iNKT cells in the control of pneumonia as well as in the development of the CD8(+) T cell response during the early stage of acute IAV H3N2 infection.
  The Journal of Immunology 05/2011; 186(10):5590-602. · 5.79 Impact Factor
• Source

  Available from: Luc Lebeau

  Article: Spleen-resident CD4+ and CD4- CD8α- dendritic cell subsets differ in their ability to prime invariant natural killer T lymphocytes.

  Emilie Bialecki, Elodie Macho Fernandez, Stoyan Ivanov, Christophe Paget, Josette Fontaine, Fabien Rodriguez, Luc Lebeau, Christophe Ehret, Benoit Frisch, François Trottein, Christelle Faveeuw
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  ABSTRACT: One important function of conventional dendritic cells (cDC) is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α(+) and CD8α(-) cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4(-) and CD4(+) CD8α(-) cDC subsets. We show that, when loaded in vitro with OVA peptide or whole protein, and in steady-state conditions, splenic CD4(-) and CD4(+) cDC are equivalent in their capacity to prime and direct CD4(+) and CD8(+) T cell differentiation. In contrast, in response to α-galactosylceramide (α-GalCer), CD4(-) and CD4(+) cDC differentially activate invariant Natural Killer T (iNKT) cells, a population of lipid-reactive non-conventional T lymphocytes. Both cDC subsets equally take up α-GalCer in vitro and in vivo to stimulate the iNKT hybridoma DN32.D3, the activation of which depends solely on TCR triggering. On the other hand, and relative to their CD4(+) counterparts, CD4(-) cDC more efficiently stimulate primary iNKT cells, a phenomenon likely due to differential production of co-factors (including IL-12) by cDC. Our data reveal a novel functional difference between splenic CD4(+) and CD4(-) cDC subsets that may be important in immune responses.
  PLoS ONE 01/2011; 6(10):e26919. · 4.09 Impact Factor
• Article: Glycosyltransferase and sulfotransferase gene expression profiles in human monocytes, dendritic cells and macrophages.

  François Trottein, Lana Schaffer, Stoyan Ivanov, Christophe Paget, Catherine Vendeville, Aurélie Cazet, Sophie Groux-Degroote, Suzanna Lee, Marie-Ange Krzewinski-Recchi, Christelle Faveeuw, Steven R Head, Philippe Gosset, Philippe Delannoy
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  ABSTRACT: Using a focused glycan-gene microarray, we compared the glycosyltransferase (GT) and sulfotransferase gene expression profiles of human monocytes, dendritic cells (DCs) and macrophages (Mphis), isolated or differentiated from the same donors. Microarray analysis indicated that monocytes express transcripts for a full set of enzymes involved in the biosynthesis of multi-multiantennary branched N-glycans, potentially elongated by poly-N-acetyl-lactosamine chains, and of mucin-type Core 1 and Core 2 sialylated O-glycans. Monocytes also express genes involved in the biosynthesis and modification of glycosaminoglycans, but display a limited expression of GTs implicated in glycolipid synthesis. Among genes expressed in monocytes (90 out of 175), one third is significantly modulated in DCs and Mphi respectively, most of them being increased in both cell types relative to monocytes. These changes might potentially enforce the capacity of differentiated cells to synthesize branched N-glycans and mucin-type O-glycans and to remodel cell surface proteoglycans. Stimulation of DCs and Mphis with lipopolysaccharide caused a general decrease in gene expression, mainly affecting genes found to be positively modulated during the differentiation steps. Interestingly, although a similar set of enzymes are modulated in the same direction in mature DCs and Mphis, cell specific genes are also differentially regulated during maturation, a phenomenon that may sustain functional specificities. Validation of this analysis was provided by quantitative real-time PCR and flow cytometry of cell surface glycan antigens. Collectively, this study implies an important modification of the pattern of glycosylation in DCs and Mphis undergoing differentiation and maturation with potential biological consequences.
  Glycoconjugate Journal 07/2009; 26(9):1259-74. · 2.12 Impact Factor