TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection

Renée M. van der Sluis; Lamin B. Cham; Albert Gris-Oliver; Kristine R. Gammelgaard; Jesper G. Pedersen; Manja Idorn; Ulvi Ahmadov; Sabina Sanches Hernandez; Ena Cémalovic; Stine H. Godsk; Jacob Thyrsted; Jesper D. Gunst; Silke D. Nielsen; Janni J. Jørgensen; Tobias Wang Bjerg; Anders Laustsen; Line S. Reinert; David Olagnier; Rasmus O. Bak; Mads Kjolby; Christian K. Holm; Martin Tolstrup; Søren R. Paludan; Lasse S. Kristensen; Ole S. Søgaard; Martin R. Jakobsen

doi:10.15252/embj.2021109622

TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection

Renée M. van der Sluis, Lamin B. Cham, Albert Gris-Oliver, Kristine R. Gammelgaard, Jesper G. Pedersen, Manja Idorn, Ulvi Ahmadov, Sabina Sanches Hernandez, Ena Cémalovic, Stine H. Godsk, Jacob Thyrsted, Jesper D. Gunst, Silke D. Nielsen, Janni J. Jørgensen, Tobias Wang Bjerg, Anders Laustsen, Line S. Reinert, David Olagnier, Rasmus O. Bak, Mads KjolbyChristian K. Holm, Martin Tolstrup, Søren R. Paludan, Lasse S. Kristensen, Ole S. Søgaard, Martin R. Jakobsen^*

^*Corresponding author for this work

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Abstract

Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.

Original language	English
Article number	e109622
Journal	EMBO Journal
Volume	41
Issue	10
Number of pages	19
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.2021109622
Publication status	Published - May 2022

Keywords

innate immune sensing
neuropilin-1
pDC
SARS-CoV-2
TLR7
RECEPTOR
TMPRSS2
EXPRESSION
Neuropilin-1/immunology
Humans
COVID-19/immunology
Toll-Like Receptor 7/immunology
Interleukin-6/immunology
Interferon-alpha/immunology
Dendritic Cells/immunology
Interferon Type I/immunology
Cytokines/metabolism
Toll-Like Receptor 2/immunology

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10.15252/embj.2021109622Licence: CC BY-NC-ND

The EMBO Journal - 2022 - SluisFinal published version, 2.98 MBLicence: CC BY-NC-ND

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van der Sluis, R. M., Cham, L. B., Gris-Oliver, A., Gammelgaard, K. R., Pedersen, J. G., Idorn, M., Ahmadov, U., Hernandez, S. S., Cémalovic, E., Godsk, S. H., Thyrsted, J., Gunst, J. D., Nielsen, S. D., Jørgensen, J. J., Bjerg, T. W., Laustsen, A., Reinert, L. S., Olagnier, D., Bak, R. O., ... Jakobsen, M. R. (2022). TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. EMBO Journal, 41(10), Article e109622. https://doi.org/10.15252/embj.2021109622

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title = "TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection",

abstract = "Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.",

keywords = "innate immune sensing, neuropilin-1, pDC, SARS-CoV-2, TLR7, RECEPTOR, TMPRSS2, EXPRESSION, Neuropilin-1/immunology, Humans, COVID-19/immunology, Toll-Like Receptor 7/immunology, Interleukin-6/immunology, Interferon-alpha/immunology, Dendritic Cells/immunology, Interferon Type I/immunology, Cytokines/metabolism, Toll-Like Receptor 2/immunology",

author = "{van der Sluis}, {Ren{\'e}e M.} and Cham, {Lamin B.} and Albert Gris-Oliver and Gammelgaard, {Kristine R.} and Pedersen, {Jesper G.} and Manja Idorn and Ulvi Ahmadov and Hernandez, {Sabina Sanches} and Ena C{\'e}malovic and Godsk, {Stine H.} and Jacob Thyrsted and Gunst, {Jesper D.} and Nielsen, {Silke D.} and J{\o}rgensen, {Janni J.} and Bjerg, {Tobias Wang} and Anders Laustsen and Reinert, {Line S.} and David Olagnier and Bak, {Rasmus O.} and Mads Kjolby and Holm, {Christian K.} and Martin Tolstrup and Paludan, {S{\o}ren R.} and Kristensen, {Lasse S.} and S{\o}gaard, {Ole S.} and Jakobsen, {Martin R.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors Published under the terms of the CC BY NC ND 4.0 license",

year = "2022",

month = may,

doi = "10.15252/embj.2021109622",

language = "English",

volume = "41",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "10",

}

van der Sluis, RM , Cham, LB, Gris-Oliver, A, Gammelgaard, KR, Pedersen, JG, Idorn, M , Ahmadov, U , Hernandez, SS, Cémalovic, E, Godsk, SH , Thyrsted, J , Gunst, JD , Nielsen, SD , Jørgensen, JJ , Bjerg, TW, Laustsen, A, Reinert, LS , Olagnier, D , Bak, RO , Kjolby, M , Holm, CK , Tolstrup, M , Paludan, SR , Kristensen, LS , Søgaard, OS & Jakobsen, MR 2022, 'TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection', EMBO Journal, vol. 41, no. 10, e109622. https://doi.org/10.15252/embj.2021109622

TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. / van der Sluis, Renée M.; Cham, Lamin B.; Gris-Oliver, Albert et al.
In: EMBO Journal, Vol. 41, No. 10, e109622, 05.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection

AU - van der Sluis, Renée M.

AU - Cham, Lamin B.

AU - Gris-Oliver, Albert

AU - Gammelgaard, Kristine R.

AU - Pedersen, Jesper G.

AU - Idorn, Manja

AU - Ahmadov, Ulvi

AU - Hernandez, Sabina Sanches

AU - Cémalovic, Ena

AU - Godsk, Stine H.

AU - Thyrsted, Jacob

AU - Gunst, Jesper D.

AU - Nielsen, Silke D.

AU - Jørgensen, Janni J.

AU - Bjerg, Tobias Wang

AU - Laustsen, Anders

AU - Reinert, Line S.

AU - Olagnier, David

AU - Bak, Rasmus O.

AU - Kjolby, Mads

AU - Holm, Christian K.

AU - Tolstrup, Martin

AU - Paludan, Søren R.

AU - Kristensen, Lasse S.

AU - Søgaard, Ole S.

AU - Jakobsen, Martin R.

PY - 2022/5

Y1 - 2022/5

N2 - Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.

AB - Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.

KW - innate immune sensing

KW - neuropilin-1

KW - pDC

KW - SARS-CoV-2

KW - TLR7

KW - RECEPTOR

KW - TMPRSS2

KW - EXPRESSION

KW - Neuropilin-1/immunology

KW - Humans

KW - COVID-19/immunology

KW - Toll-Like Receptor 7/immunology

KW - Interleukin-6/immunology

KW - Interferon-alpha/immunology

KW - Dendritic Cells/immunology

KW - Interferon Type I/immunology

KW - Cytokines/metabolism

KW - Toll-Like Receptor 2/immunology

UR - http://www.scopus.com/inward/record.url?scp=85125415941&partnerID=8YFLogxK

U2 - 10.15252/embj.2021109622

DO - 10.15252/embj.2021109622

M3 - Journal article

C2 - 35178710

AN - SCOPUS:85125415941

SN - 0261-4189

VL - 41

JO - EMBO Journal

JF - EMBO Journal

IS - 10

M1 - e109622

ER -

TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection

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