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Journal of Virology, December 2008, p. 12464-12471, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01371-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Accelerated Prion Replication in, but Prolonged Survival Times of, Prion-Infected CXCR3–/– Mice{triangledown}

Constanze Riemer,1 Julia Schultz,1 Michael Burwinkel,1 Anja Schwarz,1 Simon W. F. Mok,1 Sandra Gültner,1,2 Theresa Bamme,1 Stephen Norley,3 Frank van Landeghem,4 Bao Lu,5 Craig Gerard,5 and Michael Baier1*

Project Neurodegenerative Diseases, Robert-Koch-Institut, Nordufer 20, 13353 Berlin, Germany,1 Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany,2 Project AIDS—Immunopathogenesis and Vaccine Development, Robert-Koch-Institut, Nordufer 20, 13353 Berlin, Germany,3 Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany,4 Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 021155

Received 1 July 2008/ Accepted 28 September 2008

Prion diseases have a significant inflammatory component. Glia activation, which is associated with increased production of cytokines and chemokines, may play an important role in disease development. Among the chemokines upregulated highly and early upregulated during scrapie infections are ligands of CXCR3. To gain more insight into the role of CXCR3 in a prion model, CXCR3-deficient (CXCR3–/–) mice were infected intracerebrally with scrapie strain 139A and characterized in comparison to similarly infected wild-type controls. CXCR3–/– mice showed significantly prolonged survival times of up to 30 days on average. Surprisingly, however, they displayed accelerated accumulation of misfolded proteinase K-resistant prion protein PrPSc and 20 times higher infectious prion titers than wild-type mice at the asymptomatic stage of the disease, indicating that these PrP isoforms may not be critical determinants of survival times. As demonstrated by immunohistochemistry, Western blotting, and gene expression analysis, CXCR3-deficient animals develop an excessive astrocytosis. However, microglia activation is reduced. Quantitative analysis of gliosis-associated gene expression alterations demonstrated reduced mRNA levels for a number of proinflammatory factors in CXCR3–/– compared to wild-type mice, indicating a weaker inflammatory response in the knockout mice. Taken together, this murine prion model identifies CXCR3 as disease-modifying host factor and indicates that inflammatory glial responses may act in concert with PrPSc in disease development. Moreover, the results indicate that targeting CXCR3 for treatment of prion infections could prolong survival times, but the results also raise the concern that impairment of microglial migration by ablation or inhibition of CXCR3 could result in increased accumulation of misfolded PrPSc.

* Corresponding author. Mailing address: Project Neurodegenerative Diseases, Robert-Koch-Institut, Nordufer 20, 13353 Berlin, Germany. Phone: 49 3045472230. Fax: 49 3045472609. E-mail: adddress: baierm{at}rki.de

{triangledown} Published ahead of print on 8 October 2008.

Journal of Virology, December 2008, p. 12464-12471, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01371-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tribouillard-Tanvier, D., Striebel, J. F., Peterson, K. E., Chesebro, B. (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: 11244-11253 [Abstract] [Full Text]  


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