Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time.

Prion diseases are fatal transmissible diseases, where conversion of the endogenous prion protein (PrPC ) into a misfolded isoform (PrPSc ) leads to neurodegeneration. Microglia, the immune cells of the brain, are activated in neurodegenerative disorders including prion diseases; however, their impact on prion disease pathophysiology is unclear with both beneficial PrPSc -clearing and detrimental potentially neurotoxic effects. Moreover, monocytes entering the brain from the periphery during disease course might add to disease pathophysiology. Here, the degree of microglia activation in the brain of prion infected mice with and without an additional intraperitoneal retrovirus infection was studied. Peripheral murine retrovirus infection leads to activation of parenchymal microglia without recruitment of monocytes. This activation correlated with transient clearance or delay in accumulation of infectious prions specifically from the brain at early time points in the diseases course. Microglia expression profiling showed upregulation of genes involved in protein degradation coinciding with prion clearance. This enforces a concept where microglia act beneficial in prion disease if adequately activated. Once microglia activation has ceased, prion disease reemerges leading to disease kinetics undistinguishable from the situation in prion-only infected mice. This might be caused by the loss of microglial homeostatic function at clinical prion disease.

Myositis facilitates preclinical accumulation of pathological prion protein in muscle.

BACKGROUND: In human and animal prion diseases, pathological prion protein, PrPSc, as well as prion infectivity is mainly found in the central nervous system, but also in lymphoid organs and muscle. Pathophysiology of prion colonization of lymphoid organs has been studied intensively, yet how myositis influences prion accumulation in muscle is unknown. RESULT: We have investigated the influence of myositis on PrPSc accumulation and prion infectivity in two distinct mouse models of experimental autoimmune myositis. Furthermore, we have addressed the relevance of PrPC expression in the lymphoreticular system in myositis by generating bone marrow chimeras.Here we show that myositis positively influences muscular PrPSc accumulation at preclinical time points and that PrPC-expression in the lymphoid system is critical for this. In muscle, PrPSc and prion infectivity are uncoupled with detectable PrPSc but no prion infectivity at preclinical time points. Muscle has an intrinsically high ability to clear PrPSc once myositis has ceased, possibly involving autophagy. CONCLUSION: Our findings provide new insights into the pathophysiology of prion colonization in muscle pointing out that myositis leads to enhanced prion colonization of muscle in subclinical prion disease.