Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice

ABSTRACT Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of...

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Autores principales:	Sarah J. Kane, Eric Swanson, Elizabeth O. Gordon, Savannah Rocha, Heather R. Bender, Luke R. Donius, Adriano Aguzzi, Jonathan P. Hannan, Mark D. Zabel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	complement receptors prions spleen Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6f2c9ec8c79d4d4f811b088391cc4531
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spelling	oai:doaj.org-article:6f2c9ec8c79d4d4f811b088391cc45312021-11-15T15:21:51ZRelative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice10.1128/mSphereDirect.00493-172379-5042https://doaj.org/article/6f2c9ec8c79d4d4f811b088391cc45312017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphereDirect.00493-17https://doaj.org/toc/2379-5042ABSTRACT Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of the B cell coreceptor with CD19 and CD81. Differential splicing of transcripts from the mouse Cr2 gene generates isoforms with both shared and unique complement binding capacities and cell-type expression. In mouse models, genetic depletion of Cr2 causes either a delay or complete prevention of prion disease, but the relative importance of CD35 versus CD21 in promoting prion disease remains unknown. Here we show that both isoforms act as high-affinity cell surface prion receptors. However, mice lacking CD21 succumbed to terminal prion disease significantly later than mice lacking CD35 or wild-type and hemizygous mice. CD21-deficient mice contained fewer splenic prions than CD35 knockout mice early after infection that contributed to delayed prion neuroinvasion and terminal disease, despite forming follicular networks closer to proximal nerves. While we observed no difference in B cell networks, PrPC expression, or number of follicles, CD21-deficient mice formed more fragmented, less organized follicular networks with fewer Mfge8-positive FDCs and/or tingible body macrophages (TBMφs) than wild-type or CD35-deficient mice. In toto, these data demonstrate a more prominent role for CD21 for proper follicular development and organization leading to more efficient lymphoid prion replication and expedited prion disease than in mice expressing the CD35 isoform. IMPORTANCE Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer’s disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis.Sarah J. KaneEric SwansonElizabeth O. GordonSavannah RochaHeather R. BenderLuke R. DoniusAdriano AguzziJonathan P. HannanMark D. ZabelAmerican Society for Microbiologyarticlecomplement receptorsprionsspleenMicrobiologyQR1-502ENmSphere, Vol 2, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	complement receptors prions spleen Microbiology QR1-502
spellingShingle	complement receptors prions spleen Microbiology QR1-502 Sarah J. Kane Eric Swanson Elizabeth O. Gordon Savannah Rocha Heather R. Bender Luke R. Donius Adriano Aguzzi Jonathan P. Hannan Mark D. Zabel Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
description	ABSTRACT Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of the B cell coreceptor with CD19 and CD81. Differential splicing of transcripts from the mouse Cr2 gene generates isoforms with both shared and unique complement binding capacities and cell-type expression. In mouse models, genetic depletion of Cr2 causes either a delay or complete prevention of prion disease, but the relative importance of CD35 versus CD21 in promoting prion disease remains unknown. Here we show that both isoforms act as high-affinity cell surface prion receptors. However, mice lacking CD21 succumbed to terminal prion disease significantly later than mice lacking CD35 or wild-type and hemizygous mice. CD21-deficient mice contained fewer splenic prions than CD35 knockout mice early after infection that contributed to delayed prion neuroinvasion and terminal disease, despite forming follicular networks closer to proximal nerves. While we observed no difference in B cell networks, PrPC expression, or number of follicles, CD21-deficient mice formed more fragmented, less organized follicular networks with fewer Mfge8-positive FDCs and/or tingible body macrophages (TBMφs) than wild-type or CD35-deficient mice. In toto, these data demonstrate a more prominent role for CD21 for proper follicular development and organization leading to more efficient lymphoid prion replication and expedited prion disease than in mice expressing the CD35 isoform. IMPORTANCE Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer’s disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis.
format	article
author	Sarah J. Kane Eric Swanson Elizabeth O. Gordon Savannah Rocha Heather R. Bender Luke R. Donius Adriano Aguzzi Jonathan P. Hannan Mark D. Zabel
author_facet	Sarah J. Kane Eric Swanson Elizabeth O. Gordon Savannah Rocha Heather R. Bender Luke R. Donius Adriano Aguzzi Jonathan P. Hannan Mark D. Zabel
author_sort	Sarah J. Kane
title	Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
title_short	Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
title_full	Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
title_fullStr	Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
title_full_unstemmed	Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice
title_sort	relative impact of complement receptors cd21/35 (cr2/1) on scrapie pathogenesis in mice
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/6f2c9ec8c79d4d4f811b088391cc4531
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Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice

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