- Email: [email protected]
ID: 15
Abstract / Cytokine 76 (2015) 58–60 receptor (TLRs) family, including TLR9, 7, or 3. Viral genomes can additionally be recognised in the cytosol by DExD/H-box helicases such as RIG-I, which are activated by RNAs bearing 5’ tri- and di-phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, we have recently found that some Syk-coupled C-type lectins are involved in functions other than microbial recognition by DC. One, CLEC-2, allows DCs to relax lymph node stromal cells, permitting expansion of lymph nodes upon inflammation. Another, DNGR-1, allows DCs to detect dead cells by binding exposed F-actin and facilitates cross-presentation of dead cell-associated antigens. Interestingly, DNGR-1 marks CD8a + DCs, a specialised subtype of DCs in mice and their human equivalents. DNGR-1 additionally can be used to fate map DCcommitted precursors in mouse to define DCs by ontogeny. These studies help build a global picture of the receptors and signalling pathways that regulate DC activation and have applications in immunotherapy of cancer and infectious diseases. http://dx.doi.org/10.1016/j.cyto.2015.08.013
ID: 252 Molecular mechanism for viral RNA detection: RIG-I-like receptors Sun Hur, Harvard Medical School, Boston, MA, USA Efficient host defense against viral infection depends on proper functions of pattern recognition receptors. One such family of receptors consists of RIG-I and MDA5, well-conserved cytoplasmic helicases that detect viral RNAs during infection and activate the type I interferon (IFN) signaling pathway. My laboratory has been investigating the molecular mechanisms by which these receptors recognize viral dsRNAs and elicit the IFN response against a broad range of viruses. In this talk, I will present our discoveries on the oligomerization of these receptors during viral RNA recognition and activation of the downstream adaptor molecule, MAVS. I will also describe our recent findings on the previously unappreciated effector-like functions of these receptors that are mediated by their abilities to remodel viral RNA: protein complexes. http://dx.doi.org/10.1016/j.cyto.2015.08.014
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ID: 11 IFN-induced factors with anti-HIV activity Michael Malim, Department of Infectious Diseases, King’s College London, UK Mike’s laboratory utilises molecular genetic, cultured cell, biochemical and structural, bioinformatic and cohort-based methodologies to study the biological principles that underpin HIV replication and pathogenesis (AIDS). Current areas of interest include host-virus interactions, cell-encoded mechanisms of anti-viral resistance and virus particle assembly. Over the last ten years, much of his group’s work has been devoted to the viral protein Vif; and it was through these efforts that the human anti-HIV gene APOBEC3G was recognised and characterised. More recently, his group identified the interferon-induced gene MX2 as a novel mediator of resistance to HIV infection that suppresses virus entry into the nucleus. http://dx.doi.org/10.1016/j.cyto.2015.08.016
ID: 253 Evolution of antiviral factors in primates Harmit Malik, Fred Hutchinson Cancer Research Center, Seattle, WA, USA We have dissected the evolutionary history of host-virus interactions between primate genomes and various viruses including retroviruses, poxviruses and polyomaviuses. Our evolution-guided functional virology approach has revealed not just an ancient history of genetic conflicts facing primate antiviral genes, but also the means to identify the specificity domains by virtue of signatures of rapid evolution. We highlight the use of such approaches to identify multiple, independently acting antiviral specificiaty domains in the primate antivial Mx GTPase proteins. These case studies of antiviral genes have revealed many common ‘evolutionary rules’ of genetic adaptation, using which it may be possible to even infer the action of past viral infections, even those that may not have left imprints in host genomes – a form of indirect ‘paleovirology’ (study of ancient viruses). More recently, we have discovered that one previously unappreciated form of viral adaptation is via ‘gene-accordions’ that facilitate acquisition of adaptive alleles. http://dx.doi.org/10.1016/j.cyto.2015.08.017
ID: 13 The biology of Interleukin-6 and strategies of blockade Stefan Rose-John, Department of Biochemistry, University of Kiel, Kiel, Germany Cytokines receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process ’trans-signaling’. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model. Defense against bacterial infections rely on the membrane bound IL-6R. Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease. The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer, pancreatic cancer, nephrotoxic nephritis and high fat diet induced obesity that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it underwent phase I clinical trials as an anti-inflammatory in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow in 2015/16. http://dx.doi.org/10.1016/j.cyto.2015.08.015
ID: 14 Immune regulation at barrier surfaces David Artis, Weill Cornell Medical College, New York, USA Employing models of microbial colonization, pathogen infection, chronic inflammation and tissue repair, research in the Artis lab is examining how mammalian host genetics and signals derived from the environment and commensal microbial communities influence innate and adaptive immune cell responses. We are employing gnotobiotic mice to examine the influence of defined commensal microbial communities on intestinal and peripheral immune cell development, function and influence on tissue homeostasis. Our recent findings indicate that commensal microbes have a significant regulatory influence on lymphocyte, innate lymphoid cell and granulocyte function associated with susceptibility to multiple infectious, inflammatory and metabolic disease processes. It is hoped that the results of these studies will advance understanding of the pathophysiology of multiple chronic inflammatory diseases, including asthma, allergy, inflammatory bowel disease and obesity, and provide a framework to test new therapeutic pathways to prevent and treat these diseases. http://dx.doi.org/10.1016/j.cyto.2015.08.018
ID: 15 The probacterial activity of Type I interferons: a target for disease intervention? Alan Sher 1,*, L. Antonelli 2, C. Feng 3, D. Costa 1, B. Andrade 4, A O’Garra 5, K. MayerMarber 1, 1 NIAID, NIH, Bethesda, MD, USA, 2 Fiocruz, Belo Horizonte, Brazil, 3 University of Sydney, Australia, 4 Fiocruz, Salvador, Brazil, 5 Francis Crick Institute, UK * Corresponding author. In addition to their well known anti-viral functions, Type I IFN’s and their associated genes have been shown to enhance certain bacterial infections. These
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Abstract / Cytokine 76 (2015) 58–60
observations have led to the concept that the positive vs negative effects of Type I IFN in infection may be context dependent and in the case of bacterial diseases such as tuberculosis and listeriosis raise the possibility of targeting Type IFN as an approach to therapy. Focusing on M. tuberculosis infection, I will summarize recent data on the association of Type I IFN with active disease, the mechanism(s) of bacterial induced Type I IFN production as well as the pathways by which the cytokine suppresses bacterial control. Finally, I will discuss strategies for targeting this regulatory loop,
focusing on our recent work in which eicosanoid manipulation was used to suppress Type-I IFN dependent progression of acute tuberculosis. This project received support from the intramural research program of the NIAID, NIH, USA. http://dx.doi.org/10.1016/j.cyto.2015.08.019
ID: 252 Molecular mechanism for viral RNA detection: RIG-I-like receptors Sun Hur, Harvard Medical School, Boston, MA, USA Efficient host defense against viral infection depends on proper functions of pattern recognition receptors. One such family of receptors consists of RIG-I and MDA5, well-conserved cytoplasmic helicases that detect viral RNAs during infection and activate the type I interferon (IFN) signaling pathway. My laboratory has been investigating the molecular mechanisms by which these receptors recognize viral dsRNAs and elicit the IFN response against a broad range of viruses. In this talk, I will present our discoveries on the oligomerization of these receptors during viral RNA recognition and activation of the downstream adaptor molecule, MAVS. I will also describe our recent findings on the previously unappreciated effector-like functions of these receptors that are mediated by their abilities to remodel viral RNA: protein complexes. http://dx.doi.org/10.1016/j.cyto.2015.08.014
59
ID: 11 IFN-induced factors with anti-HIV activity Michael Malim, Department of Infectious Diseases, King’s College London, UK Mike’s laboratory utilises molecular genetic, cultured cell, biochemical and structural, bioinformatic and cohort-based methodologies to study the biological principles that underpin HIV replication and pathogenesis (AIDS). Current areas of interest include host-virus interactions, cell-encoded mechanisms of anti-viral resistance and virus particle assembly. Over the last ten years, much of his group’s work has been devoted to the viral protein Vif; and it was through these efforts that the human anti-HIV gene APOBEC3G was recognised and characterised. More recently, his group identified the interferon-induced gene MX2 as a novel mediator of resistance to HIV infection that suppresses virus entry into the nucleus. http://dx.doi.org/10.1016/j.cyto.2015.08.016
ID: 253 Evolution of antiviral factors in primates Harmit Malik, Fred Hutchinson Cancer Research Center, Seattle, WA, USA We have dissected the evolutionary history of host-virus interactions between primate genomes and various viruses including retroviruses, poxviruses and polyomaviuses. Our evolution-guided functional virology approach has revealed not just an ancient history of genetic conflicts facing primate antiviral genes, but also the means to identify the specificity domains by virtue of signatures of rapid evolution. We highlight the use of such approaches to identify multiple, independently acting antiviral specificiaty domains in the primate antivial Mx GTPase proteins. These case studies of antiviral genes have revealed many common ‘evolutionary rules’ of genetic adaptation, using which it may be possible to even infer the action of past viral infections, even those that may not have left imprints in host genomes – a form of indirect ‘paleovirology’ (study of ancient viruses). More recently, we have discovered that one previously unappreciated form of viral adaptation is via ‘gene-accordions’ that facilitate acquisition of adaptive alleles. http://dx.doi.org/10.1016/j.cyto.2015.08.017
ID: 13 The biology of Interleukin-6 and strategies of blockade Stefan Rose-John, Department of Biochemistry, University of Kiel, Kiel, Germany Cytokines receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process ’trans-signaling’. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model. Defense against bacterial infections rely on the membrane bound IL-6R. Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease. The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer, pancreatic cancer, nephrotoxic nephritis and high fat diet induced obesity that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it underwent phase I clinical trials as an anti-inflammatory in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow in 2015/16. http://dx.doi.org/10.1016/j.cyto.2015.08.015
ID: 14 Immune regulation at barrier surfaces David Artis, Weill Cornell Medical College, New York, USA Employing models of microbial colonization, pathogen infection, chronic inflammation and tissue repair, research in the Artis lab is examining how mammalian host genetics and signals derived from the environment and commensal microbial communities influence innate and adaptive immune cell responses. We are employing gnotobiotic mice to examine the influence of defined commensal microbial communities on intestinal and peripheral immune cell development, function and influence on tissue homeostasis. Our recent findings indicate that commensal microbes have a significant regulatory influence on lymphocyte, innate lymphoid cell and granulocyte function associated with susceptibility to multiple infectious, inflammatory and metabolic disease processes. It is hoped that the results of these studies will advance understanding of the pathophysiology of multiple chronic inflammatory diseases, including asthma, allergy, inflammatory bowel disease and obesity, and provide a framework to test new therapeutic pathways to prevent and treat these diseases. http://dx.doi.org/10.1016/j.cyto.2015.08.018
ID: 15 The probacterial activity of Type I interferons: a target for disease intervention? Alan Sher 1,*, L. Antonelli 2, C. Feng 3, D. Costa 1, B. Andrade 4, A O’Garra 5, K. MayerMarber 1, 1 NIAID, NIH, Bethesda, MD, USA, 2 Fiocruz, Belo Horizonte, Brazil, 3 University of Sydney, Australia, 4 Fiocruz, Salvador, Brazil, 5 Francis Crick Institute, UK * Corresponding author. In addition to their well known anti-viral functions, Type I IFN’s and their associated genes have been shown to enhance certain bacterial infections. These
60
Abstract / Cytokine 76 (2015) 58–60
observations have led to the concept that the positive vs negative effects of Type I IFN in infection may be context dependent and in the case of bacterial diseases such as tuberculosis and listeriosis raise the possibility of targeting Type IFN as an approach to therapy. Focusing on M. tuberculosis infection, I will summarize recent data on the association of Type I IFN with active disease, the mechanism(s) of bacterial induced Type I IFN production as well as the pathways by which the cytokine suppresses bacterial control. Finally, I will discuss strategies for targeting this regulatory loop,
focusing on our recent work in which eicosanoid manipulation was used to suppress Type-I IFN dependent progression of acute tuberculosis. This project received support from the intramural research program of the NIAID, NIH, USA. http://dx.doi.org/10.1016/j.cyto.2015.08.019