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Ann Clin Transl Neurol. 2014 Aug;1(8):570-88. doi: 10.1002/acn3.88. Epub 2014 Jul 28.

Aberrant fetal macrophage/microglial reactions to cytomegalovirus infection.

Author information

1
Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine Hamamatsu, Japan ; Department of Neurology, Hamamatsu University School of Medicine Hamamatsu, Japan.
2
Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine Hamamatsu, Japan.
3
Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine Hamamatsu, Japan ; Department of Respiratory Medicine, Hamamatsu University School of Medicine Hamamatsu, Japan.
4
Department of Neurology, Hamamatsu University School of Medicine Hamamatsu, Japan.
5
Faculty of Health Science, Tokoha University Hamamatsu, Japan.
6
Department of Microbiology and Immunology, Gifu Pharmaceutical University Gifu, Japan.

Abstract

OBJECTIVE:

Congenital cytomegalovirus (CMV) infection is the leading viral cause of neurodevelopmental disorders in humans, with the most severe and permanent sequelae being those affecting the cerebrum. As the fetal immune reactions to congenital CMV infection in the brain and their effects on cerebral development remain elusive, our aim was to investigate primitive innate immunity to CMV infection and its effects on cerebral corticogenesis in a mouse model for congenital CMV infection using a precise intraplacental inoculation method.

METHODS:

At 13.5 embryonic days (E13.5), pregnant C57BL/6 mice were intraplacentally infected with murine CMV (MCMV). Placentas and fetal organs were collected at 1, 3, and 5 days postinfection and analyzed.

RESULTS:

MCMV antigens were found frequently in perivascular macrophages, and subsequently in neural stem/progenitor cells (NSPCs). With increased expression of inducible nitric oxide synthase and proinflammatory cytokines, activated macrophages infiltrated into the infectious foci. In addition to the infected area, the numbers of both meningeal macrophages and parenchymal microglia increased even in the uninfected areas of MCMV-infected brain due to recruitment of their precursors from other sites. A bromodeoxyuridine (BrdU) incorporation experiment demonstrated that MCMV infection globally disrupted the self-renewal of NSPCs. Furthermore, BrdU-labeled neurons, particularly Brn2(+) neurons of upper layers II/III in the cortical plate, decreased in number significantly in the MCMV-infected E18.5 cerebrum.

INTERPRETATION:

Brain macrophages are crucial for innate immunity during MCMV infection in the fetal brain, while their aberrant recruitment and activation may adversely impact on the stemness of NSPCs, resulting in neurodevelopmental disorders.

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