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Review
. 2015 Mar;12(2):180-91.
doi: 10.1038/cmi.2014.51. Epub 2014 Jul 21.

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Irena Slavuljica  1 , Daria Kveštak  2 , Peter Csaba Huszthy  3 , Kate Kosmac  4 , William J Britt  4 , Stipan Jonjić  2
Affiliations
Review

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Irena Slavuljica et al. Cell Mol Immunol. 2015 Mar.

Abstract

Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8(+) T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

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Figures

Figure 1
Figure 1
Kinetics of MCMV infection and immune cell influx in the CNS of newborn mice. (a) Following i.p. inoculation of newborn mice with MCMV, the virus reaches the CNS by postnatal day 7, and the virus titers peak between days 10–14 and become undetectable by day 21., After the resolution of productive infection, clearance of the viral genome is not achieved. MCMV infection induces an influx of systemic immune cells into the brain. NK cells and macrophages constitute the majority of the infiltrating cells early during infection, whereas T cells are most abundant during peak inflammation and thereafter.,, The accumulation of CD8+ T cells correlates with a rapid decline in viral titers, indicating their critical role in resolution of the MCMV infection. As virus replication is controlled, the number of inflammatory cells decreases; however, CD8+ T cells persist in the brain after productive infection is resolved., The magnitude of the CD4+ T-cell response remains relatively constant throughout the infection and is outnumbered by CD8+ T cells by approximately three to one., (b) Brain paraffin sections were stained with anti-MCMV IE1/pp89 mAb (upper row), anti-CD8 mAb (bottom row, first three images) or anti-F40/80 mAb (bottom row, last image) and counterstained with hematoxylin. From left to right, virus-infected cells located in the cerebellar cortex, hippocampus, cerebellum and periventricular region are shown (PN day 11; original magnification, ×40). From left to right, CD8+ cell infiltrates in the cerebellar cortex (PN day 42), hippocampus (PN day 42), cerebellum (PN day 42), and vascular infiltration macrophages (PN day 21) are shown (original magnification, ×40). Note the focal nature of infection and mononuclear infiltrates without any evidence of tissue damage. (c) Liver paraffin sections from naive control (left) and MCMV-infected (right) newborn mice were stained with hematoxylin and eosin (PN day 14; original magnification, ×40). Note the degeneration and coagulation necrosis of hepatocytes in infected animals. (d) Newborn mice (6–18 h postpartum) were inoculated i.p. with 200 PFU of tissue culture-derived MCMV. Single-cell suspensions of brain tissue obtained from naive control or MCMV-infected animals was separated on a two-layer Percoll gradient to isolate mononuclear cells that were subsequently labeled with the indicated Abs and analyzed using flow cytometry. The dot plots are representative of at least three replicates, with 2–3 mice pooled per replicate. MCMV infection induces the accumulation of CD45hi cells, which represent brain-infiltrating mononuclear cells. In naive animals, the predominant population is CD45intCD11bhi cells, which are microglia with minimal CD45hi peripheral cell infiltration. The percentage of NK and T cells or CD8+ and CD4+ T cells within the CD45hi cell population are compared at the indicated times points. At day 8 p.i., NK cells represent ∼20% of the CD45hi brain-infiltrating mononuclear cells, while, at day 18 p.i., the percentage decreases to ∼1%. The predominant population becomes CD3+ cells, representing ∼60% of the CD45hi cells at day 18 p.i. with a ratio between CD8+ and CD4+ T cells of ∼3∶1. CNS, central nervous system; i.p., intraperitoneal; mAb, monoclonal antibody; MCMV, murine cytomegalovirus; NK, natural killer; PN, postnatal.
Figure 2
Figure 2
Altered brain development in MCMV-infected newborn mice. Cerebellum paraffin sections from naïve control and MCMV-infected newborn mice were stained with anti-calbindin and counterstained with hematoxylin (a) or cresyl violet (b and c). Note the impaired alignment and arborization of Purkinje neurons in the stratum gangliosum (a), increased thickness of the external granular layer (b) and smaller size and delayed fissure formation in the cerebellum of infected animals. Original magnification ×4 (c), ×10 (a) and ×20 (b). MCMV, murine cytomegalovirus.
Figure 3
Figure 3
Immunobiology of perinatal MCMV infection in the CNS. (a) The possible mechanisms by which MCMV enters the CNS include infection of brain microvascular endothelial cells with basolateral spread of the virus (1), loss of integrity of the BBB with disruption of tight junctions (2) and the ‘Trojan Horse' model of intracellular transport within infected monocytes (3). Once the virus is in the CNS, it infects different target cells, with astrocytes being the major, productively infected cell population., Infection initiates the production of chemokines and pro-inflammatory cytokines, resulting in glial cell activation and recruitment of inflammatory cells to the CNS., NK cells, neutrophils and monocytes are the first cells to be recruited into the brain and initiate clearance of the virus before the adaptive immune response takes place.,, Recruited monocytes are precursors of macrophages and possibly microglia. (b) Within a few days of CNS infection, infiltration of CD8+ and CD4+ T cells, which are activated in secondary lymphoid organs, begins., The chemoattractant CXCL10 promotes trafficking of CD8+ T cells via binding to its receptor, CXCR3., CD8+ T cells are crucial for eliminating replicating virus from the CNS,, which may be cell type-specific. Cytolytic mechanisms (perforin, FAS–FASL) may be important for viral clearance from non-neuronal cells, whereas non-cytolytic clearance without concomitant cell loss may predominate in neurons. IFN-γ secreted by activated CD8+ T cells effectively inhibits virus replication but does not necessarily eliminate virus DNAs from the cell. The direct antiviral role of CD4+ T cells is unclear; however, they may enhance CD8+ T-cell survival and function., (c) Virus-specific CD8+ T cells persist in the brain after resolution of productive infection and play a dominant role in the maintenance of virus latency., A proportion of these cells may be TRM cells, which are characterized by high expression of the integrin CD103 and a long-lasting resident nature. These cells most likely survive without replenishment from the circulation. In addition to IL-7 and IL-15, local environmental cues and CD4+ T-cell help may be required for TRM cell maintenance in the brain. Antiviral antibodies limit dissemination of recurrent virus., CNS, central nervous system; IFN, interferon; MCMV, murine cytomegalovirus.
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