DEVELOPMENTAL SUSCEPTIBILITY OF FETAL BRAIN TO CMV

Project: Research project

Project Details

Description

DESCRIPTION: Studies of congenital human cytomegalovirus (HCMV) infection have shown that maternal preconceptional seroimmunity reduces both the risk of congenital virus transmission and fetal organ damage associated with HCMV infection. This observation suggests that a threshold level of maternal anti-HCMV immunity can reduce the risk for developmental aberrations associated with HCMV infection. Other studies have suggested that primary congenital HCMV infection early in gestation increases the likelihood of fetal CNS disease, compared to infections in the second half of pregnancy. This observation implies that there may be a differential sensitivity of the developing brain to the pathogenic effects of HCMV. They hypothesize that neuropathogenic outcomes of fetal infection with HCMV are determined by two temporally regulated processes: (1) a developmentally-dependent susceptibility of the fetal CNS to damaging HCMV infection, and (ii) the developmentally-regulated transfer of protective antiviral antibodies to the fetus from the maternal circulation. According to this hypothesis, infection of the fetal CNS early in gestation in the absence of a threshold level of protective maternal antibodies increases the risk of CNS damage, whereas susceptibility of the fetal CNS to HCMV-induced disease decreases later in gestation concomitant with increased efficiency of transplacental transfer of maternal antiviral antibodies. This hypothesis will be tested in a novel non-human primate model for CMV-induced fetal neuropathogenesis. Direct inoculation of rhesus macaque fetuses by rhesus CMV (RhCMV) early in pregnancy results in severe neuropathogenic outcomes, including damage to the cochlea. In contrast, inoculations performed later in pregnancy result in normal CNS development and in diminished viral dissemination. The hypothesis will be tested by the following Specific Aims: (1) To characterize developmental and neurologic sequelae in fetuses infected with RhCMV at different stages of gestation and to relate protective maternal antiviral antibody responses to prevention of damaging CNS infection; (2) To define the kinetics of IgG placental transport by quantifying titers of maternal and fetal anti-RhCMV antibodies in relation to gestation age; (3) To determine early viral replication parameters in relation to timing of fetal infection and mechanisms of fetal pathogenesis and potential therapies that can limit or prevent disease associated with intrauterine HCMV infection.
StatusFinished
Effective start/end date4/1/983/31/03

Funding

  • National Institutes of Health: $290,475.00
  • National Institutes of Health
  • National Institutes of Health: $249,985.00
  • National Institutes of Health: $7,419.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $293,446.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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