AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis

Paolo Carai; Giulia Ruozi; Alexandra Paye; Yannick Debing; Francesca Bortolotti; Julie Lecomte; Lorena Zentilin; Elizabeth A.V. Jones; Mauro Giacca; Stephane Heymans

doi:10.1038/s41598-022-11131-w

AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis

Paolo Carai, Giulia Ruozi, Alexandra Paye, Yannick Debing, Francesca Bortolotti, Julie Lecomte, Lorena Zentilin, Elizabeth A.V. Jones, Mauro Giacca, Stephane Heymans^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model. Two consecutive rounds of in vivo FunSel using an expression library of 60 cytokines were sufficient to identify five cardioprotective factors (IL9, IL3, IL4, IL13, IL15). The screening also revealed three cytokines (IL18, IL17b, and CCL11) that were counter-selected and likely to exert a detrimental effect. The pooled overexpression of the five most enriched cytokines using AAV9 vectors decreased inflammation and reduced cardiac dilatation, persisting at 1 month after treatment. Individual overexpression of IL9, the top ranking in our functional selection, markedly reduced cardiac inflammation and injury, concomitant with an increase of anti-inflammatory Th2-cells and a reduction of pro-inflammatory Th17- and Th22-cells at 14 days post-infection. AAV9-mediated FunSel cardiac screening identified IL9 and other four cytokines (IL3, IL4, IL13, and IL15) as cardioprotective factors in CVB3-induced VM in mice.

Original language	English
Article number	7304
Journal	Scientific Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-11131-w
Publication status	Published - Dec 2022

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@article{6c497ed38cc941bcbba105f83cd6961f,

title = "AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis",

abstract = "Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model. Two consecutive rounds of in vivo FunSel using an expression library of 60 cytokines were sufficient to identify five cardioprotective factors (IL9, IL3, IL4, IL13, IL15). The screening also revealed three cytokines (IL18, IL17b, and CCL11) that were counter-selected and likely to exert a detrimental effect. The pooled overexpression of the five most enriched cytokines using AAV9 vectors decreased inflammation and reduced cardiac dilatation, persisting at 1 month after treatment. Individual overexpression of IL9, the top ranking in our functional selection, markedly reduced cardiac inflammation and injury, concomitant with an increase of anti-inflammatory Th2-cells and a reduction of pro-inflammatory Th17- and Th22-cells at 14 days post-infection. AAV9-mediated FunSel cardiac screening identified IL9 and other four cytokines (IL3, IL4, IL13, and IL15) as cardioprotective factors in CVB3-induced VM in mice.",

author = "Paolo Carai and Giulia Ruozi and Alexandra Paye and Yannick Debing and Francesca Bortolotti and Julie Lecomte and Lorena Zentilin and Jones, {Elizabeth A.V.} and Mauro Giacca and Stephane Heymans",

note = "Funding Information: The research leading to these results has received funding from the ERA-Net-CVD project MacroERA, 01KL1706 to PC and SH, and the project LYMIT-Dis to EAVJ. We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with the Dutch Heart Foundation's support on human research within the CVON Arena-PRIME, 2017–2018 to SH. Furthermore, we acknowledge the support of FWO G091018N to SH and EAVJ. The funders had no role in study design, collection and analysis of data, decision to publish, or preparation of the manuscript. Funding Information: We are grateful to the laboratory members of Prof. Heymans{\textquoteright} group in the Department of Cardiology of Maastricht University, and Prof. Jones{\textquoteright} group in the Centre of Molecular and Vascular Biology, Department of Cardiovascular Science of the KU Leuven for the valuable scientific and technical assistance, especially to Dr. Steven Simmonds, Dr. Laia Gifre Renom, Laura Florit Gonz{\'a}lez, Bram Callewaert, and Daria De Giorgio. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41598-022-11131-w",

language = "English",

volume = "12",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis

AU - Carai, Paolo

AU - Ruozi, Giulia

AU - Paye, Alexandra

AU - Debing, Yannick

AU - Bortolotti, Francesca

AU - Lecomte, Julie

AU - Zentilin, Lorena

AU - Jones, Elizabeth A.V.

AU - Giacca, Mauro

AU - Heymans, Stephane

N1 - Funding Information: The research leading to these results has received funding from the ERA-Net-CVD project MacroERA, 01KL1706 to PC and SH, and the project LYMIT-Dis to EAVJ. We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with the Dutch Heart Foundation's support on human research within the CVON Arena-PRIME, 2017–2018 to SH. Furthermore, we acknowledge the support of FWO G091018N to SH and EAVJ. The funders had no role in study design, collection and analysis of data, decision to publish, or preparation of the manuscript. Funding Information: We are grateful to the laboratory members of Prof. Heymans’ group in the Department of Cardiology of Maastricht University, and Prof. Jones’ group in the Centre of Molecular and Vascular Biology, Department of Cardiovascular Science of the KU Leuven for the valuable scientific and technical assistance, especially to Dr. Steven Simmonds, Dr. Laia Gifre Renom, Laura Florit González, Bram Callewaert, and Daria De Giorgio. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model. Two consecutive rounds of in vivo FunSel using an expression library of 60 cytokines were sufficient to identify five cardioprotective factors (IL9, IL3, IL4, IL13, IL15). The screening also revealed three cytokines (IL18, IL17b, and CCL11) that were counter-selected and likely to exert a detrimental effect. The pooled overexpression of the five most enriched cytokines using AAV9 vectors decreased inflammation and reduced cardiac dilatation, persisting at 1 month after treatment. Individual overexpression of IL9, the top ranking in our functional selection, markedly reduced cardiac inflammation and injury, concomitant with an increase of anti-inflammatory Th2-cells and a reduction of pro-inflammatory Th17- and Th22-cells at 14 days post-infection. AAV9-mediated FunSel cardiac screening identified IL9 and other four cytokines (IL3, IL4, IL13, and IL15) as cardioprotective factors in CVB3-induced VM in mice.

AB - Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model. Two consecutive rounds of in vivo FunSel using an expression library of 60 cytokines were sufficient to identify five cardioprotective factors (IL9, IL3, IL4, IL13, IL15). The screening also revealed three cytokines (IL18, IL17b, and CCL11) that were counter-selected and likely to exert a detrimental effect. The pooled overexpression of the five most enriched cytokines using AAV9 vectors decreased inflammation and reduced cardiac dilatation, persisting at 1 month after treatment. Individual overexpression of IL9, the top ranking in our functional selection, markedly reduced cardiac inflammation and injury, concomitant with an increase of anti-inflammatory Th2-cells and a reduction of pro-inflammatory Th17- and Th22-cells at 14 days post-infection. AAV9-mediated FunSel cardiac screening identified IL9 and other four cytokines (IL3, IL4, IL13, and IL15) as cardioprotective factors in CVB3-induced VM in mice.

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U2 - 10.1038/s41598-022-11131-w

DO - 10.1038/s41598-022-11131-w

M3 - Article

C2 - 35508525

AN - SCOPUS:85129414406

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JF - Scientific Reports

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ER -

AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis

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