Abstract

In FY08 we studied the pathogenic process involved in prion/TSE diseases by using mice genetically deficient in a chemokine receptor gene, CCR1. These mice succumbed more rapidly than wild-type (WT) mice following scrapie infection, but the levels of the disease-associated protease-resistant PrP were paradoxically lower in CCR1 knockout (KO) mice. Infected KO mice had upregulation of CCL3, a CCR1 ligand, and CCR5, a receptor with specificity for CCL3. Both infected KO and WT mice had upregulation of CCR5-mediated signaling involving activation of Erk1/2 in astrocytes; however, activation was earlier in KO mice suggesting a role in pathogenesis. In both mouse strains activation of the Erk1/2 pathway may lead to astrocyte dysfunction resulting in neurodegeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000937-05
Application #
7732592
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2008
Total Cost
$776,511
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Race, Brent; Meade-White, Kimberly; Race, Richard et al. (2009) Prion infectivity in fat of deer with chronic wasting disease. J Virol 83:9608-10
Tribouillard-Tanvier, Deborah; Striebel, James F; Peterson, Karin E et al. (2009) Analysis of protein levels of 24 cytokines in scrapie agent-infected brain and glial cell cultures from mice differing in prion protein expression levels. J Virol 83:11244-53
LaCasse, Rachel A; Striebel, James F; Favara, Cynthia et al. (2008) Role of Erk1/2 activation in prion disease pathogenesis: absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression. J Neuroimmunol 196:16-26
Kercher, Lisa; Favara, Cynthia; Striebel, James F et al. (2007) Prion protein expression differences in microglia and astroglia influence scrapie-induced neurodegeneration in the retina and brain of transgenic mice. J Virol 81:10340-51
Race, Brent L; Meade-White, Kimberly D; Ward, Anne et al. (2007) Levels of abnormal prion protein in deer and elk with chronic wasting disease. Emerg Infect Dis 13:824-30
Meade-White, Kimberly; Race, Brent; Trifilo, Matthew et al. (2007) Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein. J Virol 81:4533-9
Skinner, Pamela J; Abbassi, Hayet; Chesebro, Bruce et al. (2006) Gene expression alterations in brains of mice infected with three strains of scrapie. BMC Genomics 7:114
Trifilo, Matthew J; Yajima, Toshitaka; Gu, Yusu et al. (2006) Prion-induced amyloid heart disease with high blood infectivity in transgenic mice. Science 313:94-7
Criado, Jose R; Sanchez-Alavez, Manuel; Conti, Bruno et al. (2005) Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis 19:255-65
Chesebro, Bruce; Race, Richard; Kercher, Lisa (2005) Scrapie pathogenesis in brain and retina: effects of prion protein expression in neurons and astrocytes. J Neurovirol 11:476-80

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