Fachbereich Veterinärmedizin


Service-Navigation

    Publikationsdatenbank

    Accelerated prion replication in, but prolonged survival times of, prion-infected CXCR3-/- mice (2008)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Riemer, Constanze
    Schultz, Julia
    Burwinkel, Michael
    Schwarz, Anja
    Mok, Simon W F
    Gültner, Sandra
    Bamme, Theresa
    Norley, Stephen
    van Landeghem, Frank
    Lu, Bao
    Gerard, Craig
    Baier, Michael
    Quelle
    Journal of virology; 82(24) — S. 12464–12471
    ISSN: 0022-538x
    Sprache
    Englisch
    Verweise
    DOI: 10.1128/JVI.01371-08
    Pubmed: 18842729
    Kontakt
    Institut für Immunologie und Molekularbiologie

    Robert-von-Ostertag-Str. 7-13
    Gebäude 35
    14163 Berlin
    Tel.+49 30 838 - 518 34 Fax.+49 30 838 451 834

    Abstract / Zusammenfassung

    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 PrP(Sc) 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 PrP(Sc) 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 PrP(Sc).