Tumor necrosis factor alpha-deficient, but not mterleukin-6-deficient, mice resist peripheral infection with scrapie

In most peripheral infections of rodents and sheep with scrapie, infectivit y is found first in lymphoid tissues and later in the central nervous syste m (CNS), Cells within the germinal centers (GCs) of the spleen and lymph no des are important sites of extraneural replication from which infection is likely to spread to the CNS along peripheral nerves. Here, using immunodefi cient mice, we investigate the identity of the cells in the spleen that are important for disease propagation. Despite possessing functional T and B l ymphocytes, tumor necrosis factor alpha-deficient (TNF-alpha(-/-)) mice lac k GCs and follicular dendritic cell (FDC) networks in lymphoid tissues. In contrast, lymphoid tissues of interleukin-6-deficient (IL-6(-/-)) mice poss ess FDC networks but have impaired GCs. When the CNSs of TNF-alpha(-/-), IL -6(-/-), and wild-type mice were directly challenged with the ME7 scrapie s train, 100% of the mice were susceptible, developing disease after closely similar incubation periods, However, when challenged peripherally (intraper itoneally), most TNF-alpha(-/-) mice failed to develop scrapie up to 503 da ys postinjection. All wild-type and IL-6(-/-) mice succumbed to disease app roximately 300 days after the peripheral challenge, High levels of scrapie infection and the disease-specific isomer of the prion protein, PrPSc, were detectable in spleens from challenged wild-type and IL-6(-/-) mice but not from TNF-alpha(-/-) mice. Histopathological analysis of spleen tissue demo nstrated heavy PrP accumulations in direct association with FDCs in challen ged wild-type and IL-6(-/-) mice, No PrPSc accumulation was detected in spl eens from TNF-alpha(-/-) mice. We conclude that, for the ME7 scrapie strain , mature FDCs are critical for replication in lymphoid tissues and that in their absence, neuroinvasion following peripheral challenge is impaired.