Incunabular Immunological Events in Prion Trafficking

Michel, Brady; Meyerett-Reid, Crystal; Johnson, Theodore; Ferguson, Adam R.; Wyckoff, Christy; Pulford, Bruce; Bender, Heather; Avery, Anne C.; Telling, Glenn C.; Dow, Steven; Zabel, Mark D.

doi:10.1038/srep00440

Cited by 33 publications

(54 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ST activity has also been found on the surface of dendritic cells and lymphocytes (48,49). Considering that a number of cells of immune system-including B lymphocytes, monocytes, plasmacytoid dendritic cells, natural killer cells, and others-sequester and disseminate PrP Sc (43,72,78), it is likely that sialylation of PrP Sc is not limited to macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…Of these four mechanisms, the first three could contribute to protection of prions due to enhanced PrP Sc sialylation in SLOs. Several types of cells-including macrophages, monocytes, B lymphocytes, and dendritic cells-capture prions at initial entry sites and transport them to SLOs (43,(71)(72)(73). In addition to trafficking of prions to SLOs, macrophages play a role in degrading prions (74)(75)(76)(77).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Post-conversion sialylation of prions in lymphoid tissues

Srivastava

Makarava

Katorcha

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Sialylated glycans on the surface of mammalian cells act as part of a "self-associated molecular pattern," helping the immune system to recognize "self" from "altered self" or "nonself." To escape the host immune system, some bacterial pathogens have evolved biosynthetic pathways for host-like sialic acids, whereas others recruited host sialic acids for decorating their surfaces. Prions lack nucleic acids and are not conventional pathogens. Nevertheless, prions might use a similar strategy for invading and colonizing the lymphoreticular system. Here we show that the sialylation status of the infectious, disease-associated state of the prion protein (PrP Sc ) changes with colonization of secondary lymphoid organs (SLOs). As a result, spleen-derived PrP Sc is more sialylated than brain-derived PrP Sc . Enhanced sialylation of PrPSc is recapitulated in vitro by incubating brain-derived PrP Sc with primary splenocytes or cultured macrophage RAW 264.7 cells. General inhibitors of sialyltranserases (STs), the enzymes that transfer sialic acid residues onto terminal positions of glycans, suppressed extrasialylation of PrP Sc . A fluorescently labeled precursor of sialic acid revealed ST activity associated with RAW macrophages. This study illustrates that, upon colonization of SLOs, the sialylation status of prions changes by host STs. We propose that this mechanism is responsible for camouflaging prions in SLOs and has broad implications.prions | prion diseases | sialic acid | sialylated glycans | macrophages

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Post-conversion sialylation of prions in lymphoid tissues

Srivastava

Makarava

Katorcha

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Arrival of prions to SLOs could be detected as early as 2 h after intraperitoneal administration (39). To test whether PrP Sc sialylation status controls prion trafficking to SLOs and other peripheral organs, wild type C57Bl mice were inoculated i.p.…”

mentioning

confidence: 99%

Sialylation Controls Prion Fate in Vivo

Srivastava

Katorcha

Daus

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Paul E. Fraser Prions or PrPSc are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrP C . The current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrP Sc from PrP C using protein misfolding cyclic amplification with beads (PMCAb), and also generated PrP Sc with reduced sialylation levels using the same method but with partially desialylated PrP C as a substrate (dsPMCAb (22,23). Sialylated glycans play an essential role in a broad range of cellular functions, but are especially important in immunity (24). Terminal sialic acid residues on the surface of mammalian cells act as a part of a "self-associated molecular pattern," providing molecular cues to the immune system for discriminating between "self," "altered self," or "non-self" (25, 26). Glycoproteins or glycolipids that lack sialic acids at terminal positions serve as a "pathogen-associated molecular pattern" used by mammalian immune systems to recognize pathogens or asialoglycoproteins that need to be removed (25). Bearing in mind that sialylation serves as a molecular marker of self versus nonself, we proposed a hypothesis that sialylation determines the fate of prions in an organism (27)

show abstract

“…These data reveal no differences in initial trafficking of inocula to spleens, but impaired prion replication during the nonclinical phase of disease, suggesting fH may stabilize prions or promote propagation once captured in the lymphoreticular system (LRS). We previously showed that prions could traffic to lymphoid tissues cell-autonomously (25), independent of an intact Complement system. Perhaps soluble fH acts as a transport chaperone for such autonomous prions.…”

Section: Discussionmentioning

confidence: 99%

“…Prion rods were enriched from infected brain as previously described (23–25). Briefly, brains from hamsters (5) infected with hyper- or drowsy- transmissible spongiform encephalopathies (HY- or DY-TME) were homogenized in 1X PBS to 10% (w/v) concentration.…”

Section: Methodsmentioning

confidence: 99%

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

Kane

Farley

Gordon

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Several Complement proteins exacerbate prion disease, including C3, C1q, and CD21/35. These proteins of the Complement cascade likely increase uptake, trafficking, and retention of prions in the lymphoreticular system, hallmark sites of early prion propagation. Complement regulatory protein Factor H (fH) binds modified host proteins and lipids to prevent C3b deposition and thus autoimmune cell lysis. Previous reports show fH binds various conformations of the cellular prion protein, leading us to question the role of fH in prion disease. Here we report transgenic mice lacking Cfh alleles exhibit delayed peripheral prion accumulation, replication and pathogenesis and onset of terminal disease in a gene-dose manner. We also report a biophysical interaction between purified fH and prion rods enriched from prion-diseased brain. Factor H also influences prion deposition in brains of infected mice. We conclude from these data and previous findings that the interplay between Complement and prions likely involves a complex balance of prion sequestration and destruction via local tissue macrophages, prion trafficking by B and dendritic cells within the lymphoreticular system, intranodal prion replication by B and Follicular Dendritic cells, and potential prion strain selection by CD21/35 and fH. These findings reveal a novel role for Complement regulatory proteins in prion disease.

show abstract

Incunabular Immunological Events in Prion Trafficking

Cited by 33 publications

References 40 publications

Post-conversion sialylation of prions in lymphoid tissues

Post-conversion sialylation of prions in lymphoid tissues

Sialylation Controls Prion Fate in Vivo

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

Contact Info

Product

Resources

About