Antibody treatment promotes compensation for human cytomegalovirus-induced pathogenesis and a hypoxia-like condition in placentas with congenital infection.
Human cytomegalovirus (HCMV) is the major viral cause of birth defects worldwide. Affected infants can have temporary symptoms that resolve soon after birth, such as growth restriction, and permanent disabilities, including neurological impairment. Passive immunization of pregnant women with primary HCMV infection is a promising treatment to prevent congenital disease. To understand the effects of sustained viral replication on the placenta and passive transfer of protective antibodies, we performed immunohistological analysis of placental specimens from women with untreated congenital infection, HCMV-specific hyperimmune globulin treatment, and uninfected controls. In untreated infection, viral replication proteins were found in trophoblasts and endothelial cells of chorionic villi and uterine arteries. Associated damage included extensive fibrinoid deposits, fibrosis, avascular villi, and edema, which could impair placental functions. Vascular endothelial growth factor and its receptor fms-like tyrosine kinase 1 (Flt1) were up-regulated, and amniotic fluid contained elevated levels of soluble Flt1 (sFlt1), an antiangiogenic protein, relative to placental growth factor. With hyperimmune globulin treatment, placentas appeared uninfected, vascular endothelial growth factor and Flt1 expression was reduced, and sFlt1 levels in amniotic fluid were lower. An increase in the number of chorionic villi and blood vessels over that in controls suggested compensatory development for a hypoxia-like condition. Taken together the results indicate that antibody treatment can suppress HCMV replication and prevent placental dysfunction, thus improving fetal outcome.
Maidji
Ekaterina
E
Department of Cell and Tissue Biology, School of Dentistry, University of California-San Francisco, San Francisco, CA 94143, USA.
Nigro
Giovanni
G
Tabata
Takako
T
McDonagh
Susan
S
Nozawa
Naoki
N
Shiboski
Stephen
S
Muci
Stefania
S
Anceschi
Maurizio M
MM
Aziz
Natali
N
Adler
Stuart P
SP
Pereira
Lenore
L
D000704:Analysis of Variance; D002824:Chorionic Villi / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D010920:Placenta / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1