TLRs in Innate Immunity to Viral Infection

Summary

Principal Investigator: Robert Finberg
Abstract: Respiratory Syncytial Virus (RSV) is a major cause of pneumonia in young children. Our experiments indicate that this organism interacts with monocytes to produce inflammatory cytokines which are important in the host response to infection. Monocytes are key components of the innate immune system in humans. These cells express an array of pattern recognition receptors and co-factors on their surface, including CD14 and Toll-like receptors (TLRs). The role of monocyte cell surface CD14 in the innate immune response to bacteria has been well documented. Recent studies suggest that TLR2 and TLR4 are important co-receptors for monocyte responses to lipopolysaccharide, lipopeptides and other microbial antigens. Our data indicate that TLR2, TLR4 and CD14 are important in the response to RSV. Using chimeric proteins and knock-out mice we will define the pathophysiology of the innate immune response to RSV and other viral pathogens, including Newcastle disease virus and polyoma virus. These studies should enable us to better understand the pathophysiology of viral infections.
Funding Period: 2002-04-01 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. ncbi MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, USA
    Eur J Immunol 35:822-30. 2005
  2. pmc Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical Center, Worcester, 01605, USA
    J Virol 79:12658-66. 2005
  3. pmc Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605, USA
    J Neuroimmunol 194:70-82. 2008
  4. pmc Respiratory syncytial virus activates innate immunity through Toll-like receptor 2
    Matthew R Murawski
    Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, Massachusetts 01605, USA
    J Virol 83:1492-500. 2009
  5. pmc Discovery of a novel TLR2 signaling inhibitor with anti-viral activity
    Shenghua Zhou
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605 2216, USA
    Antiviral Res 87:295-306. 2010
  6. pmc Induction and inhibition of type I interferon responses by distinct components of lymphocytic choriomeningitis virus
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    J Virol 84:9452-62. 2010
  7. pmc MyD88 intrinsically regulates CD4 T-cell responses
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, 01605, USA
    J Virol 83:1625-34. 2009
  8. pmc Toll-like receptor-mediated activation of neutrophils by influenza A virus
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Blood 112:2028-34. 2008
  9. ncbi Innate immunity to respiratory viruses
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Cell Microbiol 9:1641-6. 2007
  10. ncbi Role of MyD88 in route-dependent susceptibility to vesicular stomatitis virus infection
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605, USA
    J Immunol 178:5173-81. 2007

Scientific Experts

  • Shenghua Zhou
  • Robert Finberg
  • Jennifer P Wang
  • Eva Szomolanyi-Tsuda
  • Evelyn A Kurt-Jones
  • Matthew R Murawski
  • Heath M Guay
  • Anna M Cerny
  • Damon R Asher
  • Annett Schoenemeyer
  • Ralph A Tripp
  • Glennice N Bowen
  • Larry J Anderson
  • Lia M Haynes
  • Tatyana A Andreyeva
  • Raymond M Welsh
  • Robert L Garcea
  • Katherine A Fitzgerald
  • Paula M Pitha
  • Betsy J Barnes
  • Peter E Newburger
  • Margo E Mancl
  • Catherine Yu
  • Eicke Latz
  • Melvin Chan
  • David M Knipe
  • John Belko
  • Douglas T Golenbock
  • Nadege Goutagny

Detail Information

Publications17

  1. ncbi MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, USA
    Eur J Immunol 35:822-30. 2005
    ..We demonstrate that TLR-mediated responses are important in the innate immune response to LCMV and that MyD88 is essential for the control of the LCMV infection and the maturation/activation of virus-specific CD8(+) T cells...
  2. pmc Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical Center, Worcester, 01605, USA
    J Virol 79:12658-66. 2005
    ..Together, these results suggest that TLR2 may play a role in the inflammatory response to VZV infection...
  3. pmc Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605, USA
    J Neuroimmunol 194:70-82. 2008
    ..These results define a functional role for TLR signaling in viral infection-induced activation of CNS glial cells as well as for the immunopathology in the CNS...
  4. pmc Respiratory syncytial virus activates innate immunity through Toll-like receptor 2
    Matthew R Murawski
    Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, Massachusetts 01605, USA
    J Virol 83:1492-500. 2009
    ..Additionally, TLR2 interactions with RSV promoted neutrophil migration and dendritic cell activation within the lung. Collectively, these studies indicate that TLR2 is involved in RSV recognition and subsequent innate immune activation...
  5. pmc Discovery of a novel TLR2 signaling inhibitor with anti-viral activity
    Shenghua Zhou
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605 2216, USA
    Antiviral Res 87:295-306. 2010
    ..We also demonstrated that E567 inhibits cytokine responses in the mouse. Remarkably, E567 is also capable of inhibiting LCMV replication in mice. This is a new model for developing drugs for use in treating viral illnesses...
  6. pmc Induction and inhibition of type I interferon responses by distinct components of lymphocytic choriomeningitis virus
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    J Virol 84:9452-62. 2010
    ..These virus-host interactions may play important roles in the pathogeneses of LCMV and other human arenavirus diseases...
  7. pmc MyD88 intrinsically regulates CD4 T-cell responses
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, 01605, USA
    J Virol 83:1625-34. 2009
    ....
  8. pmc Toll-like receptor-mediated activation of neutrophils by influenza A virus
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Blood 112:2028-34. 2008
    ..These studies demonstrate neutrophil activation by influenza virus and highlight the importance of TLR7 and TLR8 in that response...
  9. ncbi Innate immunity to respiratory viruses
    Jennifer P Wang
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Cell Microbiol 9:1641-6. 2007
    ..We also provide an overview of the current knowledge of regulation of type I interferons and inflammatory cytokines in viral infection...
  10. ncbi Role of MyD88 in route-dependent susceptibility to vesicular stomatitis virus infection
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605, USA
    J Immunol 178:5173-81. 2007
    ..We believe that these results explain how the route of infection, probably by virtue of activating different cell populations, can lead to entirely different outcomes of infection based on the underlying genetics of the host...
  11. ncbi MyD88 is required for the formation of long-term humoral immunity to virus infection
    Heath M Guay
    Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    J Immunol 178:5124-31. 2007
    ..Our findings show that MyD88-dependent signaling pathways in B cells are essential for effectively generating long-term Ab responses and implicate a role for TLR in the formation of long-term humoral immunity...
  12. ncbi Cutting Edge: Antibody-mediated TLR7-dependent recognition of viral RNA
    Jennifer P Wang
    Department of Medicine, University of Massachusetts, 364 Plantation, Worcester, MA 01605, USA
    J Immunol 178:3363-7. 2007
    ..These data define a pathway by which intracellular TLR7 senses viral RNA and indicate a role for TLRs in association with Abs in sustaining virus-specific responses...
  13. ncbi Toll like receptors and viruses
    Robert W Finberg
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Rev Med Virol 17:35-43. 2007
    ..A greater understanding of relationships between viruses or viral products and TLRs should improve understanding of pathogenesis and lead to the development of new anti-viral therapies...
  14. pmc Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo
    Eva Szomolanyi-Tsuda
    Department of Pathology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, Massachusetts 01655, USA
    J Virol 80:4286-91. 2006
    ..Our studies suggest that in addition to the reported involvement of TLR9 and TLR3, TLR2 is also involved in innate immune responses to MCMV infection...
  15. pmc The erythrocyte viral trap: transgenic expression of viral receptor on erythrocytes attenuates coxsackievirus B infection
    Damon R Asher
    Department of Medicine, University of Massachusetts Medical School, 227 Lazare Research Building, 364 Plantation Street, Worcester, MA 01605, USA
    Proc Natl Acad Sci U S A 102:12897-902. 2005
    ..Erythrocytes also may be coated with a variety of receptors by nontransgenic methods, making this a very flexible model for the treatment of infectious diseases in humans...
  16. ncbi The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling
    Annett Schoenemeyer
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Biol Chem 280:17005-12. 2005
    ..IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling...
  17. ncbi The role of toll-like receptors in herpes simplex infection in neonates
    Evelyn A Kurt-Jones
    Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Infect Dis 191:746-8. 2005
    ..This may explain the sepsis syndrome that is seen with HSV (and other virus infections) in neonates...