Riemer C, Schultz J, Burwinkel M, Schwarz A, Mok SWF, Gültner S, Bamme T, Norley S, van Landeghem F, Lu B, Gerard C, Baier M (2008): Accelerated prion replication but prolonged survival times of prion-infected CXCR3-/--mice
J. Virol. 82 (24): 12464-12471. Epub Oct 8.

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 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 in average up to 30 days. 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 developed an excessive astrocytosis. However, microglia activation was reduced. Quantitative analysis of gliosis-associated gene expresssion 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 knock-out 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 raise the concern that impairment of microglial migration by ablation or inhibition of CXCR3 could result in increased accumulation of misfolded PrP^Sc.