TY - JOUR
T1 - Coxsackievirus b3 infection early in pregnancy induces congenital heart defects through suppression of fetal cardiomyocyte proliferation
AU - Sharma, Vipul
AU - Goessling, Lisa S.
AU - Brar, Anoop K.
AU - Joshi, Chetanchandra S.
AU - Mysorekar, Indira U.
AU - Eghtesady, Pirooz
N1 - Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2021/1/19
Y1 - 2021/1/19
N2 - BACKGROUND: Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through cox-sackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. METHODS AND RESULTS: We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-p1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. CONCLUSIONS: We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.
AB - BACKGROUND: Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through cox-sackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. METHODS AND RESULTS: We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-p1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. CONCLUSIONS: We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.
KW - Congenital heart defect
KW - Coxsackie type B
KW - Infection
KW - Pregnancy
KW - Virus
UR - http://www.scopus.com/inward/record.url?scp=85100125088&partnerID=8YFLogxK
U2 - 10.1161/JAHA.120.017995
DO - 10.1161/JAHA.120.017995
M3 - Article
C2 - 33440998
AN - SCOPUS:85100125088
SN - 2047-9980
VL - 10
SP - 1
EP - 16
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 2
M1 - e017995
ER -