title: Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells.
abstract: After oral exposure, the early replication of certain prion strains upon stromal cell-derived follicular dendritic cells (FDC) in the Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. However, little is known of how prions are initially conveyed from the gut lumen to establish infection on FDC. Our previous data suggest that mononuclear phagocytes such as CD11c+conventional dendritic cells play an important role in the initial propagation of prions from the gut lumen into Peyer's patches. However, whether these cells conveyed orally acquired prions toward FDC within Peyer's patches was not known. The chemokine CXCL13 is expressed by FDC and follicular stromal cells and modulates the homing of CXCR5-expressing cells toward the FDC-containing B cell follicles. Here, novel compound transgenic mice were created in which a CXCR5 deficiency was specifically restricted to CD11c+cells. These mice were used to determine whether CXCR5-expressing conventional dendritic cells propagate prions toward FDC after oral exposure. Our data show that in the specific absence of CXCR5-expressing conventional dendritic cells the early accumulation of prions upon FDC in Peyer's patches and the spleen was impaired, and disease susceptibility significantly reduced. These data suggest that CXCR5-expressing conventional dendritic cells play an important role in the efficient propagation of orally administered prions toward FDC within Peyer's patches in order to establish host infection.IMPORTANCEMany natural prion diseases are acquired by oral consumption of contaminated food or pasture. Once the prions reach the brain they cause extensive neurodegeneration, which ultimately leads to death. In order for the prions to efficiently spread from the gut to the brain, they first replicate upon follicular dendritic cells within intestinal Peyer's patches. How the prions are first delivered to follicular dendritic cells to establish infection was unknown. Understanding this process is important since treatments which prevent prions from infecting follicular dendritic cells can block their spread to the brain. We created mice in which mobile conventional dendritic cells were unable to migrate toward follicular dendritic cells. In these mice the early accumulation of prions on follicular dendritic cells was impaired and oral prion disease susceptibility was reduced. This suggests that prions exploit conventional dendritic cells to facilitate their initial delivery toward follicular dendritic cells to establish host infection.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, United Kingdom.
authors.forename: Barry M
authors.initials: BM
authors.lastname: Bradford
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, United Kingdom neil.mabbott@roslin.ed.ac.uk.
authors.forename: Neil A
authors.identifier: http://orcid.org/0000-0001-7395-1796
authors.initials: NA
authors.lastname: Mabbott
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002417:Cattle; D054382:Chemokine CXCL13 / Q000235:genetics; D003713:Dendritic Cells / Q000473:pathology / Q000502:physiology; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000473:pathology; D004198:Disease Susceptibility; D016643:Encephalopathy, Bovine Spongiform / Q000276:immunology* / Q000503:physiopathology*; D015870:Gene Expression; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010581:Peyer's Patches / Q000276:immunology / Q000473:pathology; D011328:Prions / Q000472:pathogenicity* / Q000502:physiology; D054380:Receptors, CXCR5 / Q000235:genetics*; D012608:Scrapie / Q000503:physiopathology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D011328:Prions; D054380:Receptors, CXCR5
keywords: Peyer's patches; chemokines; dendritic cells; gastrointestinal infection; intestine; prions; transmissible spongiform encephalopathy