Trina Das

Publications (6)27.77 Total impact

• Article: Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg).

  Jean-Jacques Hoarau, Pascale Krejbich-Trotot, Marie-Christine Jaffar-Bandjee, Trina Das, Gerard-Vincent Thon-Hon, Shiril Kumar, Jim W Neal, Philippe Gasque
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  ABSTRACT: Innate immunity is an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons and involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the central nervous system (CNS) are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer's diseases (AD) being primary examples. Critically, neuroimmune regulatory proteins (NIReg) may control the adverse immune responses in health and diseases. NIRegs are found mainly on neurons, glia, endothelia and ependymal cells and include GPI-anchored molecules (CD24, CD90, complement regulators CD55 and CD59), molecules of the immunoglobulin superfamily (siglec CD22, Siglec 10, CD200, ICAM-5) and others (CD47, fractalkine, TAM receptor tyrosine kinase and complement C3a and factor H). These regulators modulate the innate immune response in the CNS and for instance critically control the level of phagocytosis and inflammation engaged by resident microglia and infiltrating immune cells. Others will sequester and neutralize proinflammatory molecules such as HMGB1 and DNA. Moreover, some NIRegs can instigate the recruitment of stem cells to mediate tissue repair. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury and an adverse inflammatory response in acute and chronic settings. The therapeutic applications of NIRegs should be exploited given their natural and selective healing properties.
  CNS & neurological disorders drug targets 02/2011; 10(1):25-43. · 3.57 Impact Factor
• Article: Activation and Control of CNS Innate Immune Responses in Health and Diseases: A Balancing Act Finely Tuned by Neuroimmune Regulators (NIReg)

  Jean-Jacques Hoarau, Pascale Krejbich-Trotot, Marie-Christine Jaffar-Bandjee, Trina Das, Gerard-Vincent Thon-Hon, Shiril Kumar, Jim W. Neal, Philippe Gasque
  [show abstract] [hide abstract]
  ABSTRACT: Innate immunity is an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons and involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the central nervous system (CNS) are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer's diseases (AD) being primary examples. Critically, neuroimmune regulatory proteins (NIReg) may control the adverse immune responses in health and diseases. NIRegs are found mainly on neurons, glia, endothelia and ependymal cells and include GPI-anchored molecules (CD24, CD90, complement regulators CD55 and CD59), molecules of the immunoglobulin superfamily (siglec CD22, Siglec 10, CD200, ICAM-5) and others (CD47, fractalkine, TAM receptor tyrosine kinase and complement C3a and factor H). These regulators modulate the innate immune response in the CNS and for instance critically control the level of phagocytosis and inflammation engaged by resident microglia and infiltrating immune cells. Others will sequester and neutralize proinflammatory molecules such as HMGB1 and DNA. Moreover, some NIRegs can instigate the recruitment of stem cells to mediate tissue repair. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury and an adverse inflammatory response in acute and chronic settings. The therapeutic applications of NIRegs should be exploited given their natural and selective healing properties.
  CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 01/2011; 10(1):25-43. · 3.81 Impact Factor
• Article: Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses.

  Pascale Krejbich-Trotot, Melanie Denizot, Jean-Jacques Hoarau, Marie-Christine Jaffar-Bandjee, Trina Das, Philippe Gasque
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  ABSTRACT: Chikungunya virus (CHIKV) surprised medical workers by a massive outbreak in the Indian Ocean region, reaching Europe in 2007, with exceptional pathologies in infants and elderly patients. Although CHIKV was recently shown to persist in myoblasts, monocytes, and macrophages, we argued that robust antiviral mechanisms, including apoptosis, are essential to ward off the virus. Herein, we tested the capacity of CHIKV to mobilize the apoptotic machinery in HeLa cells as well as primary fibroblasts, making use of several inhibitors of caspases, cell blebbing, and engulfment of the apoptotic blebs by neighboring cells. CHIKV triggered apoptosis through intrinsic and extrinsic pathways. Bystander apoptosis was also evidenced in neighboring cells in a caspase-8-dependent manner. Remarkably, by hiding in apoptotic blebs, CHIKV was able to infect neighboring cells. In HeLa cells, these events were inhibited specifically by zVAD-fmk and DEVD-cho (caspase inhibitors), blebbistatin, Y-27632 (ROCK inhibitor), and genistein, annexin V, and cytochalasin B (inhibitors of blebbing and engulfment). These CHIKV-apoptotic blebs were also capable of infecting macrophages (primary cultures, MM6- and THP1-PMA differentiated cells) otherwise refractory to infection by CHIKV alone. Remarkably, viral replication in macrophages did not yield a proinflammatory response. We describe a novel infectious mechanism by which CHIKV invades host cells and escapes the host response.
  The FASEB Journal 09/2010; 25(1):314-25. · 5.71 Impact Factor
• Article: Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.

  Jean-Jacques Hoarau, Marie-Christine Jaffar Bandjee, Pascale Krejbich Trotot, Trina Das, Ghislaine Li-Pat-Yuen, Bérengère Dassa, Mélanie Denizot, Elsa Guichard, Anne Ribera, Tawfiq Henni, [......], Philippe Morbidelli, Gérard Martigny, Michel Jolivet, Frederick Gay, Marc Grandadam, Hugues Tolou, Vincent Vieillard, Patrice Debré, Brigitte Autran, Philippe Gasque
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  ABSTRACT: Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the "recovered" or the "chronic" groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 10(10) viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-alpha mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4(++) but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence.
  The Journal of Immunology 05/2010; 184(10):5914-27. · 5.79 Impact Factor
• Source

  Available from: Melanie Denizot

  Article: Chikungunya virus takes centre stage in virally induced arthritis: possible cellular and molecular mechanisms to pathogenesis.

  Marie Christine Jaffar-Bandjee, Trina Das, Jean Jacques Hoarau, Pascale Krejbich Trotot, Mélanie Denizot, Anne Ribera, Pierre Roques, Philippe Gasque
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  ABSTRACT: Chikungunya virus (CHIKV) causes an acute symptomatic illness with fever, skin rash (hypersensitivity vasculitis), incapacitating arthralgia which can evolve to chronic arthritis in elderly patients. Clinical observations from cohort studies have been corroborated with data from experimental infection in several mouse and non-human primate models as discussed herein.
  Microbes and Infection 10/2009; 11(14-15):1206-18. · 3.10 Impact Factor
• Article: Complement factor H, a marker of self protects against experimental autoimmune encephalomyelitis.

  Mark R Griffiths, Jim W Neal, Marc Fontaine, Trina Das, Philippe Gasque
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  ABSTRACT: The CNS innate immune response is a "double-edged sword" representing a fine balance between protective antipathogen responses and detrimental neurocytotoxic effects. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. In analogy to the newly described neuroimmune regulatory proteins also known as "don't eat me" signals (CD200, CD47, CD22, fractalkine, semaphorins), we herein identify the key role of complement regulator factor H (fH) in controlling neuroinflammation initiated in an acute mouse model of Ab-dependent experimental autoimmune encephalomyelitis. Mouse fH was found to be abundantly expressed by primary cultured neurons and neuronal cell lines (N1E115 and Neuro2a) at a level comparable to BV2 microglia and CLTT astrocytes. Mouse neurons expressed other complement regulators crry and low levels of CD55. In the brain, the expression of fH was localized to neuronal bodies and axons, endothelial cells, microglia but not oligodendrocytes and myelin sheaths and was dramatically reduced in inflammatory experimental autoimmune encephalomyelitis settings. When exogenous human fH was administered to disease Ab-dependent experimental autoimmune encephalomyelitis animals, there was a significant decrease in clinical score, inflammation, and demyelination, as compared with PBS-injected animals. We found that the accumulation of human fH in the brain parenchyma protected neurons from complement opsonization, axonal injury, and leukocyte infiltration. Our data argue for a key regulatory activity of fH in neuroprotection and provide novel therapeutic avenues for CNS chronic inflammatory diseases.
  The Journal of Immunology 05/2009; 182(7):4368-77. · 5.79 Impact Factor