Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Abstract

Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from midgestation placentas formed foci of infection, and interferon-b production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x L by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x L , indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment. (Am J Pathol 2016 http://dx

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

“…However, there was significant heterogeneity in viral burden and distribution among fetal tissue types; some fetuses had high copy number virus in nearly every tissue tested (174-97, IM67), while others only had virus detectable in the cochlea (GI73, HD79) ( Figure 6C). This heterogeneity is consistent with previous reports for HCMV suggesting that the virus can replicate in the amniotic membrane without observable fetal infection (34). It is unclear from the data whether cochlear infection might have occurred via direct inoculation of the ear canal or if fetal immune control could have led to isolated virus detectable in the cochlea.…”

Comparison of quantitative real‐time PCR and short‐term (18‐hour) microculture in diagnosis of fetal cytomegalovirus infection: Impact of hyperimmunoglobulin treatment

“…Most asymptomatically infected newborns in our cohort showed higher VLs between 1028 and 4.6 × 10 6 IU/mL in AC. Recent reports indicating that HCMV establishes persistent infection in amniotic epithelium could explain extremely high VLs in AF even after HIG treatment and without poor outcome for the fetus . The availability of the WHO DNA Standard from HCMV strain Merlin now offers the standardisation of qPCR from bodily fluids .…”

“…Recent reports indicating that HCMV establishes persistent infection in amniotic epithelium could explain extremely high VLs in AF even after HIG treatment and without poor outcome for the fetus. 35 The availability of the WHO DNA Standard from HCMV strain Merlin now offers the standardisation of qPCR from bodily fluids. 28 Recent results indicate that VLs reported in copies/mL and IU/mL are comparable because of assay calibration on this standard, but the observed range of results was smaller, when reported in IU/mL.…”

Zika virus infection of first-trimester human placentas: utility of an explant model of replication to evaluate correlates of immune protection ex vivo

“…We were tempted to believe that the causative agent might be other viruses [1*], such as human cytomegalovirus (HCMV), long known to transmit infection across the human placenta, causing microcephaly and neurological defects [2,3]. In fact, we had modeled HCMV infection in explants of early gestation placentas, focusing on the very question of how maternal virus breaches the placental barrier, identifying specialized cells involved in dissemination [4–11] and antiviral antibodies as a correlate of protection [12–16]. But HCMV did not cause a rash or epidemics [17].…”