Knockout of sialoadhesin enhances microglial accumulation during prion pathogenesis

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

During the peripheral pathogenesis of prion infection the replication
of PrPSc upon follicular dendritic cells (FDC) in lymphoid
tissues is important for efficient neuroinvasion.1,2 The mechanism
of how the agent is transported to and into lymphoid follicles is
currently unknown but has been shown to be dependent upon
integrin α X (CD11c) expressing mononuclear phagocytes.3,4
One particular group of these cells reside within the splenic
marginal zone or lymph node subcapsular sinus and function to
trap blood borne antigen.5 These cells are classically identified
by expression of high levels of sialoadhesin (Siglec1 or CD169).6
Sialoadhesin binds to sialic acid moieties on N- and O-glycans
and functions as a cell-cell or cell-pathogen recognition molecule
and possible internalization receptor similar to other Siglec family
members.7 Sialoadhesin expression is restricted to members
of the mononuclear phagocyte lineage. Sialoadhesin is constitutively
expressed upon the above mentioned splenic and lymph
node resident cell populations but is also stimulated in response
to inflammatory stimuli8 upon tissue macrophages or microglia.9
The prion protein is variably glycosylated and heavily sialylated,10
with evidence showing that the sialylation status of PrP is altered
during infection.11 To determine if disease-associated PrP is collected
by sialoadhesin for transference into the lymphoid follicle
we have infected Sialoadhesin-deficient mice with the mouseadapted
scrapie strain ME7. Following intraperitoneal infection
no differences were observed upon the early accumulation of
PrPSc within lymphoid follicles. Similarly sialoadhesin-deficient
mice showed no deficiency in trapping and retention of preformed
immune-complexes upon FDC. Investigation of disease
incubation period and pathological outcome following intraperitoneal
infection are currently in progress. Data will be presented
at the meeting on the effects of sialoadhesin-deficiency on disease
susceptibility after peripheral exposure. Following intracerebral
infection however, sialoadhesin-deficient mice showed an
increase in the accumulation of activated-microglia in the brain
compared with wild type mice. This resulted in elevated levels of
vacuolation occurring specifically within the hippocampal CA1
and septum brain regions. No statistically significant differences
were observed in disease incubation period following intracerebral
infection of wild type and sialoadhesin-deficient mice. These
results reveal that knockout of sialoadhesin results in increased
activated microglial accumulation in brain areas targeted by prion
infection, with large multi-cellular foci in sialoadhesin-deficient
mice. These results suggest that knockout of sialoadhesin may
interfere with microglial cell-cell recognition, phagocytosis of
apoptotic neurones, suppression of anti-inflammatory signaling
and microglial neuroprotective functions.12
References
1. Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, et al. Scrapie
replication in lymphoid tissues depends on prion protein-expressing follicular dendritic
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2. McCulloch L, Brown KL, Bradford BM, Hopkins J, Bailey M, Rajewsky K, et al.
Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain
prion infection in the spleen. PLoS Pathog 2011; 7:e1002402; PMID:22144895;
http://dx.doi.org/10.1371/journal.ppat.1002402.
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scrapie agent neuroinvasion from the intestine. J Immunol 2007; 179:7758-66;
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a macrophage sialic acid-binding receptor on microglia. J Cell Sci 1992; 101:201-7;
PMID:1569124.
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12. Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11.
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JNEUROSCI.3940-09.2010.
Original languageEnglish
Pages (from-to)49
Number of pages1
JournalPrion
Volume6
Issue number4 (Suppt 1)
Publication statusPublished - 2012
EventPrion2012 - Amsterdam, United Kingdom
Duration: 9 May 201212 May 2012

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  • Prion 2012

    Barry Bradford (Participant)

    9 May 201212 May 2012

    Activity: Participating in or organising an event typesParticipation in conference

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