Abstract
BackgroundCongenital cytomegalovirus (CMV) infection is the most common congenital viral infection in humans and the major nonhereditary cause of central nervous system (CNS) developmental disorders. Previous attempts to develop a murine CMV (MCMV) model of natural congenital human CMV (HCMV) infection have failed because MCMV does not cross the placenta in immunocompetent mice.ResultsIn marked contrast with immunocompetent mice, C.B-17 SCID (severe combined immunodeficient) mice were found to be highly susceptible to natural MCMV transplacental transmission and congenital infection. Timed-pregnant SCID mice were intraperitoneally (IP) injected with MCMV at embryonic (E) stages E0-E7, and vertical MCMV transmission was evaluated using nested polymerase chain reaction (nPCR), in situ hybridization (ISH) and immunohistochemical (IHC) assays. SCID mouse dams IP injected at E0 with 102 PFU of MCMV died or resorbed their fetuses by E18. Viable fetuses collected at E18 from SCID mice IP injected with 102–104 PFU of MCMV at E7 did not demonstrate vertical MCMV transmission. Notably, transplacental MCMV transmission was confirmed in E18 fetuses from SCID mice IP injected with 103 PFU of MCMV at stages E3-E5. The maximum rate of transplacental MCMV transmission (53%) at E18 occurred when SCID mouse dams were IP injected with 103 PFU of MCMV at E4. Congenital infection was confirmed by IHC immunostaining of MCMV antigens in 26% of the MCMV nPCR positive E18 fetuses. Transplacental MCMV transmission was associated with intrauterine growth retardation and microcephaly. Additionally, E18 fetuses with MCMV nPCR positive brains had cerebral interleukin-1α (IL-1α) expression significantly upregulated and cerebral IL-1 receptor II (IL-1RII) transcription significantly downregulated. However, MCMV-induced changes in cerebral cytokine expression were not associated with any histological signs of MCMV infection or inflammation in the brain.ConclusionSevere T- and B-cell immunodeficiencies in SCID mice significantly enhance the rate of natural MCMV transplacental transmission and congenital infection. During gestation MCMV exhibits a tissue tropism for the developing brain, and vertical MCMV transmission is correlated with fetal growth retardation and abnormal cerebral proinflammatory cytokine expression. These data confirm that natural vertical MCMV infection in SCID mice constitutes a useful new experimental rodent model of congenital HCMV infection.
Highlights
Congenital cytomegalovirus (CMV) infection is the most common congenital viral infection in humans and the major nonhereditary cause of central nervous system (CNS) developmental disorders
Vertical transmission of murine CMV (MCMV) was confirmed by nested polymerase chain reaction (nPCR) amplification of MCMV immediate-early-gene-1 in live fetuses collected from severe combined immunodeficient (SCID) mouse dams inoculated with 103 plaque forming units (PFU) of MCMV at E3 (33%), E4 (100%) and E5 (25%), but not from dams injected at E7 (0%) (Table 1)
Given that all of the SCID mouse dams IP injected with MCMV at E3-E7 exhibited significant clinical signs of MCMV viremia at E18, nPCR negative littermates constituted an experimental control group which confirmed that fetal brains and abdominal viscera samples were not contaminated during tissue collection by maternal blood
Summary
Congenital cytomegalovirus (CMV) infection is the most common congenital viral infection in humans and the major nonhereditary cause of central nervous system (CNS) developmental disorders. While the majority of congenital human CMV (HCMV) infections are asymptomatic, it has been estimated that 5–10% of HCMV congenitally infected neonates exhibit symptomatic, generalized cytomegalic inclusion disease (CID) [3]. 90% of congenital HCMV infected neonates are asymptomatic at birth, but later in life develop significant sensory system disorders. The most prevalent delayed-onset sensory system sequelae of congenital HCMV infection is sensorineural hearing loss (SNHL), and at least 25% of children with congenital CMV-induced auditory deficits develop their hearing losses only after the first year of life [10,11,12,13]. It has been estimated that the direct and indirect costs for treating the sequelae of congenital HCMV infections exceeds $1.9 billion per year [14]
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