Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention - PubMed (original) (raw)

Review

Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention

Maxim C-J Cheeran et al. Clin Microbiol Rev. 2009 Jan.

Abstract

Congenital cytomegalovirus (CMV) infection is the leading infectious cause of mental retardation and hearing loss in the developed world. In recent years, there has been an improved understanding of the epidemiology, pathogenesis, and long-term disabilities associated with CMV infection. In this review, current concepts regarding the pathogenesis of neurological injury caused by CMV infections acquired by the developing fetus are summarized. The pathogenesis of CMV-induced disabilities is considered in the context of the epidemiology of CMV infection in pregnant women and newborn infants, and the clinical manifestations of brain injury are reviewed. The prospects for intervention, including antiviral therapies and vaccines, are summarized. Priorities for future research are suggested to improve the understanding of this common and disabling illness of infancy.

PubMed Disclaimer

Figures

FIG. 1.

FIG. 1.

Neurological outcomes of congenital CMV infection. Examples of computed tomography (A) and magnetic resonance imaging (B and C) of three infants with severe symptomatic congenital CMV infection with CNS involvement are shown. The classical pattern of injury described with congenital CMV infection involving the CNS is characterized by periventricular calcifications (panel A, arrow). Other consequences of fetal brain infection include abnormalities of neuronal migration, leading to polymicrogyria (panel B, arrows) and, in extreme cases, profound structural defects such as porencephalic cysts with associated schizencephaly (panel C, arrow).

FIG. 2.

FIG. 2.

Cellular tropism of CMV brain infection in vivo. Coronal murine brain sections immunostained with anti-β-galactosidase antibody display staining (green), indicative of viral infection with the _lacZ_-containing recombinant MCMV RM461. (A) Double immunohistochemical staining for β-galactosidase and glial fibrilary acidic protein (GFAP) (red) reveals that MCMV has a cellular tropism for astrocytes in the brain (yellow cells). (B) Double immunostaining with nestin (red) indicates that MCMV readily infects neural stem cells, seen just below the ependymal layer of the ventricules of an adult mouse. (C) Coronal section of guinea pig brain following intracerebral inoculation with an enhanced green fluorescent protein (eGFP)-expressing recombinant GPCMV (fluorescein isothiocyanate filter) demonstrating infection of cells in periventricular region. (D) Same section as in panel C following immunohistochemical staining for GFAP (red). (E) Merged image demonstrating eGFP and GFAP colocalization in astrocytes. Blue cells, DAPI (4′,6′-diamidino-2-phenylindole) stain.

FIG. 3.

FIG. 3.

TNF-α inhibits CMV MIEP activity in human astrocytes. (A) Schematic description of various truncated MIEP LacZ reporter constructs used to test the effect of cytokines on promoter activity in human astrocytes. M, modulator sequence; U, unique region; E, enhancer sequence; P, basal promoter sequence; L, leader sequence). Numerical positions were assigned relative to the most distal region of the full-length MIEP used. (B to D) Primary human astrocytes, either treated with TNF-α for 48 h or untreated, were transfected with each of the indicated plasmids using Fugene 6 reagent (Roche, Indianapolis, IN). Culture lysates were harvested at 72 h posttransfection and analyzed for β-galactosidase activity, which was normalized to total protein and compared to expression from untreated cells. (B) β-Galactosidase expression from truncated MIEP constructs are expressed as units of optical density at 595 nm (OD595) per mg protein. (C and D) The effect of gross deletions of the MIEP on TNF-α-mediated suppression of promoter activity in astrocytes is expressed as percent suppression, where expression levels from TNF-α-treated astrocytes were compared to the expression of the same plasmid construct in untreated cells. Based on the pattern of reduction of reporter gene expression among various constructs, the effect of TNF-α is mediated largely at the level of the enhancer. Data are representative of at least three experiments performed with astrocytes from different donors.

FIG. 4.

FIG. 4.

Schematic representation of neuropathogenic mechanisms during congenital CMV infection. CMV brain infection may have multifaceted influences on the developing brain. Neural stem cells (in blue), found along the lateral ventricular wall of the brain, are involved in the development of new neural circuits in both the developing and adult brain. These cells divide symmetrically, to renew the stem cell pool, or asymmetrically, to differentiate into new brain cells (astrocytes, oligodendrocytes, and neurons), either directly or via an intermediate transitional progenitor cell (red cells). The development path for new neural circuitry involves the migration of the early neuronal precursor, neuroblasts (green cells), through a directed path that is supported in part by astroglial cells. CMV brain infection may potentially affect any or all of these stages of development and influence the neurological outcomes of congenital infection. This schematic depicts potential mechanisms by which formation of new neural circuits in the developing brain may be affected by CMV infection. 1, Infection of neural stem cells may disrupt their ability to maintain a self-renewing cycle that would influence subsequent processes involved in brain development. 2, Differentiation of neural stem cells via the transitional cells and eventually neuroblasts may also be disrupted by CMV infection, potentially skewing their end-differentiated fate. 3, It has also been shown that brain infection affects the migratory patterns of neuroblasts, particularly during cortical and cerebellar development, which may involve inhibition of migration to distal brain structures. 4, This might alter the migratory patterning of specific brain structures, such as by causing improper layering of the neocortex. 5, Since glial cells are also susceptible to CMV infection, demonstrated both in vivo and in vitro, one could postulate that important functions of glia in directing neuronal layering patterns may be affected. 6, Finally, CMV infection can induce a myriad of inflammatory mediators, including cytokines, oxidative radicals, and other neurotoxic chemicals. These mediators may potentially affect the immature neuron by directly inducing cytotoxicity or may affect neuronal function by altering the microenvironment that alters normal brain cell physiology. In addition, immune-mediated clearance of infected cells may have an impact on the cellular milieu. Many of these concepts are still speculative, and more research is required to elucidate the neuropathogenesis of CMV infection.

References

    1. Abbott, N. J., L. Ronnback, and E. Hansson. 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7:41-53. - PubMed
    1. Adler, B., L. Scrivano, Z. Ruzcics, B. Rupp, C. Sinzger, and U. Koszinowski. 2006. Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J. Gen. Virol. 87:2451-2460. - PubMed
    1. Adler, S. P., J. W. Finney, A. M. Manganello, and A. M. Best. 2004. Prevention of child-to-mother transmission of cytomegalovirus among pregnant women. J. Pediatr. 145:485-491. - PubMed
    1. Adler, S. P., S. H. Hempfling, S. E. Starr, S. A. Plotkin, and S. Riddell. 1998. Safety and immunogenicity of the Towne strain cytomegalovirus vaccine. Pediatr. Infect. Dis. J. 17:200-206. - PubMed
    1. Adler, S. P., and G. Nigro. 2006. Interrupting intrauterine transmission of cytomegalovirus. Rev. Med. Virol. 16:69-71. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources