Environmental and host factors that contribute to prion strain evolution.

Prions are novel pathogens that are composed entirely of PrPSc, the self-templating conformation of the host prion protein, PrPC. Prion strains are operationally defined as a heritable phenotype of disease that are encoded by strain-specific conformations of PrPSc. The factors that influence the relative distribution of strains in a population are only beginning to be understood. For prions with an infectious etiology, environmental factors, such as strain-specific binding to surfaces and resistance to weathering, can influence which strains are available for transmission to a naïve host. Strain-specific differences in efficiency of infection by natural routes of infection can also select for prion strains. The host amino acid sequence of PrPC has the greatest effect on dictating the repertoire of prion strains. The relative abundance of PrPC, post-translational modifications of PrPC and cellular co-factors involved in prion conversion can also provide conditions that favor the prevalence of a subset of prion strains. Additionally, prion strains can interfere with each other, influencing the emergence of a dominant strain. Overall, both environmental and host factors may influence the repertoire and distribution of strains within a population.

Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase.

Prion infections in the central nervous system (CNS) can cause extensive neurodegeneration. Systemic inflammation can affect the progression of some neurodegenerative disorders. Therefore, we used the gastrointestinal helminth pathogen Trichuris muris to test the hypothesis that a chronic systemic inflammatory response to a gastrointestinal infection would similarly affect CNS prion disease pathogenesis. Mice were injected with prions directly into the CNS and subsequently orally co-infected with T. muris before the onset of clinical signs. We show that co-infection with a low dose of T. muris that leads to the development of a chronic T helper cell type 1-polarized systemic immune response accelerated the onset of clinical prion disease. In contrast, co-infection with a high dose of T. muris that induces a T helper cell type 2-polarized immune response did not affect prion disease pathogenesis. The reduced survival times in mice co-infected with a low dose of T. muris on d 105 after CNS prion infection coincided with enhanced astrocyte activation in the brain during the preclinical phase. These data aid our understanding of how systemic inflammation may augment the progression of neurodegeneration in the CNS.

The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.

UNLABELLED: Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease. IMPORTANCE: Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence.

¿Podrían los ectoparásitos actuar como vectores de las enfermedades priónicas? / Could ectoparasites act as vectors for prion diseases?

Las enfermedades priónicas son enfermedades neurodegenerativas raras de los seres humanos y de los animales con una evolución mortal. Algunos tipos de células encontrados en la piel humana, como las queratinocitos, fibroblastos y linfocitos, son sensibles a la isoforma infectiva anormal de la proteína priónica, que transforma la piel produciendo un blanco potencial para la infección priónica. También se descubrió la transmisión yatrogénica de la enfermedad de Creutzfeldt-Jakob después de realizar trasplantes de córnea en seres humanos y el scrapie se transmitió a ratones tras la instilación ocular de tejido cerebral infectado, lo que confirma que estas nuevas vías, así como la inoculación cerebral y la ingestión oral, podrían ser importantes en las infecciones por priones. Las infecciones priónicas en animales, como el scrapie (en ovejas) y la "enfermedad de las vacas locas" (ganado bovino) han demostrado un modelo de transmisión horizontal en granjas y se ha demostrado que algunos ectoparásitos son portadores de partículas priónicas en experimentos de laboratorio. Las larvas de moscas y ácaros se expusieron a material cerebral infectado y fueron capaces de transmitir el scrapie a hámsters. Nuevas líneas de evidencia han confirmado que las moscas adultas son capaces también de expresar proteínas priónicas. Las miasis oculares y cerebrales y la infestación por ácaros no son raras en el mundo, y la mayoría de los casos se deben a larvas de moscas o ácaros del heno que generalmente afectan a ovejas y vacas, por lo que es importante valorar la posibilidad de que estos ectoparásitos puedan actuar como reservorios y/o vectores de las enfermedades priónicas (AU)