Coronaviruses (CoVs) are widespread emerging RNA viruses in man and animals. Murine CoV, mouse hepatitis virus (MHV), is the prototype of group II CoV. Different MHV isolates induce acute fatal encephalitis and encephalomyelitis associated with acute and chronic demyelination. The chronic pathological changes in the absence of overt infectious virus are similar to human CNS diseases with suspected or potential viral etiologies, such as multiple sclerosis. During acute infection, both neurons and glial cells become productively infected. Mammalian Toll-Like Receptors (TLRs) constitute a family of pattern recognition receptors which detect conserved pathogen-associated molecular patterns. Viruses may trigger inflammatory cytokine production via multiple TLRs. Little is known about the interplay and subcellular localization of TLRs in the CNS in response to viral infections, and how virus sensing by TLRs may affect encephalitis outcome. Whether CoV infection activates inflammatory responses via TLRs and if so, which TLR is primarily utilized for the innate response remains unknown. Here, we will test the hypothesis that CoVs may counteract the innate immune response in the CNS by modulation of TLR responses. Using two MHV strains that markedly differ in their neurovirulence (MHV-JHM, a highly neurovirulent strain that produces severe and often fatal encephalitis;and MHV-A59, a mildly neurovirulent strain that induces acute meningoencephalitis and chronic demyelination), we have preliminary data demonstrating striking differences between them in the modulation of expression of TLR2 and 3, and in the functional consequences (NF-?B activation, cytokine production) of MHV-sensing by TLR2 and 3. Therefore, our Specific Aims are: 1) to define CoV determinants of TLR-mediated inflammatory response with a well-defined set of recombinant wild-type and chimeric viruses;and 2) to determine the role of TLR2 and TLR3 in coronavirus-induced encephalitis in vivo with pathogenesis studies in wild-type and knockout mice, and ex vivo investigating cytokine and chemokine production in primary microglia and astrocyte cultures. This experimental model will provide a distinctive opportunity to define the role of TLR2- and TLR3- mediated neuroinflammatory response and a better understanding of the function of TLR2 and TLR3 in viral encephalitis and chronic demyelination.

Public Health Relevance

The relative contribution of TLRs pathways in viral recognition versus viral pathogenesis is unclear. This experimental model will provide a distinctive opportunity to define coronavirus determinants of TLR2 and 3- mediated inflammatory response and a better understanding of the role of TLRs in viral encephalitis and chronic demyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
1R03NS061179-01A1
Application #
7897067
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$76,875
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Perales-Linares, Renzo; Navas-Martin, Sonia (2013) Toll-like receptor 3 in viral pathogenesis: friend or foe? Immunology 140:153-67
Swaminathan, Gokul; Martin-Garcia, Julio; Navas-Martin, Sonia (2013) RNA viruses and microRNAs: challenging discoveries for the 21st century. Physiol Genomics 45:1035-48
Mazaleuskaya, Liudmila; Veltrop, Rogier; Ikpeze, Nneka et al. (2012) Protective role of Toll-like Receptor 3-induced type I interferon in murine coronavirus infection of macrophages. Viruses 4:901-23
Gupta, Archana; Swaminathan, Gokul; Martin-Garcia, Julio et al. (2012) MicroRNAs, hepatitis C virus, and HCV/HIV-1 co-infection: new insights in pathogenesis and therapy. Viruses 4:2485-513
Swaminathan, Gokul; Rossi, Fiorella; Sierra, Luz-Jeannette et al. (2012) A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. PLoS Pathog 8:e1002937