Innate Immune Activation in Malaria

Summary

Principal Investigator: Douglas T Golenbock
Abstract: DESCRIPTION (provided by applicant): Malaria remains a major cause of illness and death worldwide. Two major unresolved issues concerning the pathogenesis of malaria are: 1) what molecules from the parasite activate the innate immune system and cause inflammation and, 2) what are the receptors that are ligated by these microbial products. The overall goal of this project is to identify the molecular mechanisms of systemic inflammation and fever in individuals infected with Plasmodium falciparum. Our preliminary data demonstrate that malaria DNA, especially when complexed to the malarial pigment hemozoin, activates inflammation. The underlying HYPOTHESIS of this proposal is that fever and inflammation in acute malaria are initiated by the interaction of malarial DNA with DNA receptors expressed by phagocytes. We further hypothesize that the innate immune response to malarial DNA is mediated by two receptors: TLR9 and an as yet unidentified receptor for AT-rich DNA motifs. This hypothesis challenges the concept that malarial glycosylphosphatidylinositol (GPI)-lipid anchors, which are primarily TLR2/CD14 agonists, are the primary cause of systemic inflammation in malaria. In order to test this hypothesis, we propose to combine an examination of immune activation in cells from patients with acute febrile malaria with in vitro work. We propose three Aims. The first Aim is to determine if innate immune activation induced by malaria, occurs primarily in TLR9+ cells, or in cells that primarily express TLR2 and/or CD14. We will profile gene induction in purified cells with defined TLR expression in culture and from patients in order to determine which receptors and signaling pathways are employed. DNA, and oligonucleotides derived from the malarial genome, will be compared to purified malarial GPI anchors. In our second Aim, we will assess the importance of hemozoin in inflammation. PBMC will be collected from malaria patients, sorted into hemozoin positive and negative monocytes and DCs, and assessed for markers of immune activation. We will perform confocal imaging studies of hemozoin and malarial DNA trafficking in immune cells. These studies will determine the temperospatial relationships between trafficking and innate immune responses, including the engagement of specific DNA receptors and the activation of the inflammasome. In the final Aim, we will focus on the immune activity of AT-rich oligonucleotides whose sequences are derived from the malarial genome. We will focus on;1) those signaling pathways that result in the production of Type I interferons, which we have found to be a critical determinant of outcome in mouse cerebral malaria;and 2) activation of the inflammasome, primarily through NRLP3 and AIM2, an inflammasome component that we recently discovered. Signaling pathways will be established using both a molecular genetics approach and the use of proteomics. We will test inflammasome knockout mice, including a new AIM2 KO, in mouse cerebral malaria, thus relating our in vitro findings with in vivo disease. Our ultimate goal is to define the relative role of malarial DNA in mediating innate immune responses during malarial infection and to definitively identify related DNA receptors. PUBLIC HEALTH RELEVANCE: Malaria is the world's most common infectious disease, and kills millions of individuals annually. US citizens risk obtaining malaria when they travel or are engaged in military operations in tropical areas. The purpose of this grant is to gain a better understanding of why malaria causes disease in the hopes that better therapies can be devised, including an effective vaccine that might prevent malaria.
Funding Period: 2009-09-24 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Recognition of herpesviruses by the innate immune system
    Søren R Paludan
    Department of Medical Microbiology and Immunology, The Bartholin Building, Aarhus University, DK 8000 Aarhus C, Denmark
    Nat Rev Immunol 11:143-54. 2011
  2. pmc Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria
    Parisa Kalantari
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Rep 6:196-210. 2014
  3. pmc Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection
    Peter Liehl
    Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal
    Nat Med 20:47-53. 2014
  4. pmc Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens
    Colette Cywes-Bentley
    Division of Infectious Diseases, Department of Medicine, Brigham and Women s Hospital Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:E2209-18. 2013
  5. pmc Dried whole plant Artemisia annua as an antimalarial therapy
    Mostafa A Elfawal
    Laboratory of Medical Zoology, Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, United States of America
    PLoS ONE 7:e52746. 2012
  6. pmc Neutrophil paralysis in Plasmodium vivax malaria
    Fabiana Maria de Souza Leoratti
    Laboratorio de Imunopatologia, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
    PLoS Negl Trop Dis 6:e1710. 2012
  7. pmc Regulation of inflammasome signaling
    Vijay A K Rathinam
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    Nat Immunol 13:333-42. 2012
  8. pmc Beyond empiricism: informing vaccine development through innate immunity research
    Stuart M Levitz
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell 148:1284-92. 2012
  9. pmc Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome
    Shruti Sharma
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
    Immunity 35:194-207. 2011
  10. pmc Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi
    Bráulia C Caetano
    Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    J Immunol 187:1903-11. 2011

Detail Information

Publications14

  1. pmc Recognition of herpesviruses by the innate immune system
    Søren R Paludan
    Department of Medical Microbiology and Immunology, The Bartholin Building, Aarhus University, DK 8000 Aarhus C, Denmark
    Nat Rev Immunol 11:143-54. 2011
    ....
  2. pmc Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria
    Parisa Kalantari
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Rep 6:196-210. 2014
    ..Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria. ..
  3. pmc Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection
    Peter Liehl
    Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal
    Nat Med 20:47-53. 2014
    ..Together, our results show that the liver has sensor mechanisms for Plasmodium that mediate a functional antiparasite response driven by type I IFN. ..
  4. pmc Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens
    Colette Cywes-Bentley
    Division of Infectious Diseases, Department of Medicine, Brigham and Women s Hospital Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:E2209-18. 2013
    ..Vaccination targeting PNAG could contribute to immunity against serious and diverse prokaryotic and eukaryotic pathogens, and the conserved production of PNAG suggests that it is a critical factor in microbial biology...
  5. pmc Dried whole plant Artemisia annua as an antimalarial therapy
    Mostafa A Elfawal
    Laboratory of Medical Zoology, Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, United States of America
    PLoS ONE 7:e52746. 2012
    ..annua might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality...
  6. pmc Neutrophil paralysis in Plasmodium vivax malaria
    Fabiana Maria de Souza Leoratti
    Laboratorio de Imunopatologia, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
    PLoS Negl Trop Dis 6:e1710. 2012
    ..Here, we examined the activation and function of neutrophils during acute episodes of malaria...
  7. pmc Regulation of inflammasome signaling
    Vijay A K Rathinam
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    Nat Immunol 13:333-42. 2012
    ..Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance...
  8. pmc Beyond empiricism: informing vaccine development through innate immunity research
    Stuart M Levitz
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell 148:1284-92. 2012
    ..Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection...
  9. pmc Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome
    Shruti Sharma
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
    Immunity 35:194-207. 2011
    ..Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria...
  10. pmc Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi
    Bráulia C Caetano
    Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    J Immunol 187:1903-11. 2011
    ..cruzi infection, triple TLR3/7/9(-/-) mice had similar phenotype than 3d mice. These data imply that the nucleic acid-sensing TLRs are critical determinants of host resistance to primary infection with T. cruzi...
  11. pmc Toll-like receptors participate in macrophage activation and intracellular control of Leishmania (Viannia) panamensis
    Carolina Gallego
    Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia
    Infect Immun 79:2871-9. 2011
    ..Together, these findings support the participation of TLR4 and endosomal TLRs in the activation of host macrophages by L. panamensis and in the early control of infection...
  12. pmc Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria
    Bernardo S Franklin
    Laboratory of Immunopathology, René Rachou Research Center, Oswaldo Cruz Foundation, Belo Horizonte, 30190 002, Minas Gerais, Brazil
    Proc Natl Acad Sci U S A 108:3689-94. 2011
    ....
  13. pmc Increased survival in B-cell-deficient mice during experimental cerebral malaria suggests a role for circulating immune complexes
    Rosane B de Oliveira
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    MBio 5:e00949-14. 2014
    ..We also provide evidence demonstrating the importance of immunoglobulins in the pathogenesis of cerebral malaria in mice. These findings may have important implications in human cerebral malaria...

Research Grants31

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  3. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  4. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  5. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  6. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
    ....
  7. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  8. Structure-function based development of JC virion specific antagonists for PML
    Walter Atwood; Fiscal Year: 2013
    ..The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application. ..
  9. Innate Immune Activation in Malaria
    Douglas T Golenbock; Fiscal Year: 2013
    ..Gallego spends in South America will increase, with the ultimate goal of exporting cutting edge technology and expertise to the scientific community in Colombia. ..
  10. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  11. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  12. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  13. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....