TY - JOUR
T1 - APOBEC3A is upregulated by human cytomegalovirus (HCMV) in the maternal-fetal interface, acting as an innate anti-HCMV effector
AU - Weisblum, Yiska
AU - Oiknine-Djian, Esther
AU - Zakay-Rones, Zichria
AU - Vorontsov, Olesya
AU - Haimov-Kochman, Ronit
AU - Nevo, Yuval
AU - Stockheim, David
AU - Yagel, Simcha
AU - Panet, Amos
AU - Wolf, Dana G.
N1 - Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues- constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.
AB - Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues- constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.
KW - Antiviral cellular restrictions
KW - APOBEC
KW - Congenital infection
KW - Decidua
KW - HCMV
KW - Intrinsic immunity
KW - Placental innate immunity
KW - Viral placental transmission
UR - http://www.scopus.com/inward/record.url?scp=85033787760&partnerID=8YFLogxK
U2 - 10.1128/JVI.01296-17
DO - 10.1128/JVI.01296-17
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C2 - 28956761
AN - SCOPUS:85033787760
SN - 0022-538X
VL - 91
JO - Journal of Virology
JF - Journal of Virology
IS - 23
M1 - e01296-17
ER -