Development of a new mouse model for coxsackievirus-inducedmyocarditis by attenuating coxsackievirus B3 virulence in the pancreas

Autor: J Lin, Dirk Lassner, Kathleen Pappritz, Klaus Peter Knoch, Fengquan Dong, Jens Kurreck, Luisa Hinze, Michele Solimena, Carsten Tschöpe, Sophie Van Linthout, Ziya Kaya, Muhammad El-Shafeey, Karin Klingel, Markian Pryshliak, Robert Klopfleisch, Babette Dieringer, Katrin Schaar, Ahmet Hazini, Henry Fechner, Sandra Pinkert, Antje Beling
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Pathology
medicine.medical_specialty
Myocarditis
Genotype
Physiology
Coxsackievirus Infections
Inflammation
030204 cardiovascular system & hematology
Coxsackievirus
Virus Replication
Virus
Proinflammatory cytokine
03 medical and health sciences
0302 clinical medicine
In vivo
Physiology (medical)
medicine
Animals
Humans
Myocytes
Cardiac
3' Untranslated Regions
Pancreas
Mice
Inbred BALB C
biology
Virulence
business.industry
Editorials
biology.organism_classification
medicine.disease
Coxsackievirusb3
Pancreatitis
Mouse Model
Intravenous
Intraperitoneal
Heart
Icrorna Target Sites
Fibrosis
Enterovirus B
Human
Mice
Inbred C57BL
Disease Models
Animal
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
HEK293 Cells
Phenotype
Female
medicine.symptom
Cardiology and Cardiovascular Medicine
business
HeLa Cells
Zdroj: Cardiovasc. Res. 116, 1756-1766 (2020)
Cardiovasc Res
Popis: Aims The coxsackievirus B3 (CVB3) mouse myocarditis model is the standard model for investigation of virus-induced myocarditis but the pancreas, rather than the heart, is the most susceptible organ in mouse. The aim of this study was to develop a CVB3 mouse myocarditis model in which animals develop myocarditis while attenuating viral infection of the pancreas and the development of severe pancreatitis. Methods and results We developed the recombinant CVB3 variant H3N-375TS by inserting target sites (TS) of miR-375, which is specifically expressed in the pancreas, into the 3ʹUTR of the genome of the pancreo- and cardiotropic CVB3 variant H3. In vitro evaluation showed that H3N-375TS was suppressed in pancreatic miR-375-expressing EndoC-βH1 cells >5 log10, whereas its replication was not suppressed in isolated primary embryonic mouse cardiomyocytes. In vivo, intraperitoneal (i.p.) administration of H3N-375TS to NMRI mice did not result in pancreatic or cardiac infection. In contrast, intravenous (i.v.) administration of H3N-375TS to NMRI and Balb/C mice resulted in myocardial infection and acute and chronic myocarditis, whereas the virus was not detected in the pancreas and the pancreatic tissue was not damaged. Acute myocarditis was characterized by myocardial injury, inflammation with mononuclear cells, induction of proinflammatory cytokines, and detection of replicating H3N-375TS in the heart. Mice with chronic myocarditis showed myocardial fibrosis and persistence of H3N-375TS genomic RNA but no replicating virus in the heart. Moreover, H3N-375TS infected mice showed distinctly less suffering compared with mice that developed pancreatitis and myocarditis after i.p. or i.v application of control virus. Conclusion In this study, we demonstrate that by use of the miR-375-sensitive CVB3 variant H3N-375TS, CVB3 myocarditis can be established without the animals developing severe systemic infection and pancreatitis. As the H3N-375TS myocarditis model depends on pancreas-attenuated H3N-375TS, it can easily be used in different mouse strains and for various applications.
Databáze: OpenAIRE
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