Transplacental murine cytomegalovirus infection in the brain of SCID mice

doi:10.1186/1743-422X-4-26

Virology Journal

Volume 4

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Koehrn FJ

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Transplacental murine cytomegalovirus infection in the brain of SCID mice

Nigel K Woolf¹^,2 , Dawn V Jaquish¹^,2 and Fred J Koehrn¹^,2

¹Departments of Surgery/Anatomy, University of California Medical School at San Diego Life, 9500 Gilman Drive, La Jolla, CA 92093-0604, USA

²Department of Surgery, Veterans Affairs Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, La Jolla, CA 92161, USA

author email corresponding author email

Virology Journal 2007, 4:26doi:10.1186/1743-422X-4-26


Published:	9 March 2007

Abstract

Background

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. 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.

Results

In 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 10²PFU of MCMV died or resorbed their fetuses by E18. Viable fetuses collected at E18 from SCID mice IP injected with 10²–10⁴PFU 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 10³PFU 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 10³PFU 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.

Conclusion

Severe 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.