7 research outputs found
Experimental Bovine Spongiform Encephalopathy in Squirrel Monkeys:The Same Complex Proteinopathy Appearing after Very Different Incubation Times
Incubation periods in humans infected with transmissible spongiform encephalopathy (TSE) agents can exceed 50 years. In humans infected with bovine spongiform encephalopathy (BSE) agents, the effects of a “species barrier,” often observed when TSE infections are transmitted from one species to another, would be expected to increase incubation periods compared with transmissions of same infectious agents within the same species. As part of a long-term study investigating the susceptibility to BSE of cell cultures used to produce vaccines, we inoculated squirrel monkeys (Saimiri sp., here designated SQ) with serial dilutions of a bovine brain suspension containing the BSE agent and monitored them for as long as ten years. Previously, we showed that SQ infected with the original “classical” BSE agent (SQ-BSE) developed a neurological disease resembling that seen in humans with variant CJD (vCJD). Here, we report the final characterization of the SQ-BSE model. We observed an unexpectedly marked difference in incubation times between two animals inoculated with the same dilution and volume of the same C-BSE bovine brain extract on the same day. SQ-BSE developed, in addition to spongiform changes and astrogliosis typical of TSEs, a complex proteinopathy with severe accumulations of protease-resistant prion protein (PrP(TSE)), hyperphosphorylated tau (p-tau), ubiquitin, and α-synuclein, but without any amyloid plaques or β-amyloid protein (Aβ) typical of Alzheimer’s disease. These results suggest that PrP(TSE) enhanced the accumulation of several key proteins characteristically seen in human neurodegenerative diseases. The marked variation in incubation periods in the same experimental TSE should be taken into account when modeling the epidemiology of human TSEs
Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys
Both murine host and inoculum modulate expression of experimental variant Creutzfeldt–Jakob disease
Candidate Cell Substrates, Vaccine Production, and Transmissible Spongiform Encephalopathies
Candidate cell substrates neither accumulated abnormal prion protein nor propagated infectivity
Disruption of a Plasmodium falciparum Multidrug Resistance-associated Protein (PfMRP) Alters Its Fitness and Transport of Antimalarial Drugs and Glutathione*S⃞
ATP-binding cassette transporters play an important role in drug resistance
and nutrient transport. In the human malaria parasite Plasmodium
falciparum, a homolog of the human p-glycoprotein (PfPgh-1) was
shown to be involved in resistance to several drugs. More recently, many
transporters were associated with higher IC50 levels in responses
to chloroquine (CQ) and quinine (QN) in field isolates. Subsequent studies,
however, could not confirm the associations, although inaccuracy in drug tests
in the later studies could contribute to the lack of associations. Here we
disrupted a gene encoding a putative multidrug resistance-associated protein
(PfMRP) that was previously shown to be associated with P. falciparum
responses to CQ and QN. Parasites with disrupted PfMRP (W2/MRPΔ) could
not grow to a parasitemia higher than 5% under normal culture conditions,
possibly because of lower efficiency in removing toxic metabolites. The
W2/MRPΔ parasite also accumulated more radioactive glutathione, CQ, and
QN and became more sensitive to multiple antimalarial drugs, including CQ, QN,
artemisinin, piperaquine, and primaquine. PfMRP was localized on the parasite
surface membrane, within membrane-bound vesicles, and along the straight side
of the D-shaped stage II gametocytes. The results suggest that PfMRP plays a
role in the efflux of glutathione, CQ, and QN and contributes to parasite
responses to multiple antimalarial drugs, possibly by pumping drugs outside
the parasite