Cytomegalovirus Cell Tropism, Replication, and Gene Transfer in Brain

Pol, Anthony N. van den; Mocarski, Edward S.; Saederup, Noah; Vieira, Jeffrey; Meier, Timothy J.

doi:10.1523/jneurosci.19-24-10948.1999

Cited by 125 publications

(128 citation statements)

References 61 publications

(46 reference statements)

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“…The adult brain is protected from CMV by a number of mechanisms, including a CD4 (39) and peripheral CD8 (36) T-cell response. We have previously shown that developing brain cells in vivo and in vitro are more likely to show mCMV infections than mature brain cells, and that this preference is independent of the host B-and T-cell responses (57,61). In the present study, we compared the innate IFN-mediated antiviral responses to mCMV in mature and developing brains.…”

Section: Discussionmentioning

confidence: 84%

“…We next tested the hypothesis that human brain cells are similarly protected from hCMV by IFN and that hCMV infection induces an antiviral response from human brain cells. Primary human brain cells were cultured and then infected with an hCMV that contains a gene coding for GFP (25,57). Two types of human brain cells were used.…”

Section: Induction Of Intrinsic Antiviral Response By Neurons and Glimentioning

confidence: 99%

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Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Pol¹,

Robek

Ghosh³

et al. 2007

J Virol

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Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B-and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human ( Cytomegalovirus (CMV), a double-stranded DNA virus of the betaherpesvirus family, is considered the most common infectious agent that causes permanent neurological dysfunction of the developing brain (2, 62). Human CMV (hCMV) infections in the developing brain can lead to mental retardation, epilepsy, microcephaly, microgyria, hydrocephalus, and deafness (4, 21, 37). The developing brain is particularly sensitive to CMV infection (6,29,54,55,58) due to both the immature state of the systemic immune system and a preference of CMV for developing glia and neurons (61). CMV in the mature brain is less of a concern, except in immunocompromised individuals (22,23,32).Outside the brain, interferon (IFN) has been reported to limit some CMV infections (27,30,66). A number of reports have suggested that brain cells differ from cells of other organs relative to innate and systemic antiviral immune responses. The brain has some characteristics of an immunologically privileged region. For instance, although most cells outside the brain express major histocompatibility complex (MHC) class I molecules, neurons in the brain either do not express MHC class I or do so at a substantially reduced level (45). This may be beneficial due to the fact that neurons do not replicate, and so a vigorous attack by the immune system on virally infected postmitotic neurons may cause more problems than the virus itself. In the brain, functional receptors for IFN-␥ are expressed in all cells, but they are expressed at different levels, and actions of IFN-␣/␤ on microglia, astrocytes, and neurons have also been described (12,13,31,43). Most cells, including astrocytes and microglia, are able to produce IFN-␣/␤ as an initial nonspecific immune response against virus infection (52, 64); IFN-␥ is released by activated T lymphocytes as part of the specific immune response. The intrinsic IFN system provides the first line of defense against viral infections, including systemic CMV infections, and can delay viral replication allowing the activation of the systemic adaptive immune responses.One explanation for the increased pathogenesis in the developing brain compared to that in the mature brain is that the systemic immune system is too immature during development to fight CMV infection. T and B lymphocytes of the adaptive immune system, as well as other cells of the systemic immune system, including natural killer cells and macrophages/monocytes, are involved in combating CMV infections (2,5,8,9,10,20,46,49), and the efficacies of these systems increase with development. Another mechanism that might underlie the susceptibility of developing...

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Section: Discussionmentioning

confidence: 84%

Section: Induction Of Intrinsic Antiviral Response By Neurons and Glimentioning

confidence: 99%

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Pol¹,

Robek

Ghosh³

et al. 2007

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the temporal course of these changes was different, which could be attributed to HCMV doses. Syncytia formation has also been reported in other cellular types, and it seems to be related to cell fusion induced by viral glycoproteins present in the plasma membrane (Belec et al 1990;van Den Pol et al 1999;Kinzler and Compton 2005). On the other hand, when we infected SK-N-MC with the MOI of 0.01, cellular prolongations were observed suggesting cellular differentiation to a neuron-like morphology, an unexpected finding since we did not add any other stimulus that may account for these changes, and this normally does not occur in an spontaneous way (Higgins et al 2009).…”

Section: Discussionmentioning

confidence: 91%

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

et al. 2015

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Cytomegalovirus (CMV) is the most common cause of congenital infection in developed countries and a major cause of neurological disability in children. Although CMV can affect multiple organs, the most important sequelae of intrauterine infection are related to lesions of the central nervous system. However, little is known about the pathogenesis and the cellular events responsible for neuronal damage in infants with congenital infection. Some studies have demonstrated that neural precursor cells (NPCs) show the greatest susceptibility to CMV infection in the developing brain. We sought to establish an in vitro model of CMV infection of the developing brain in order to analyze the cellular events associated with invasion by this virus. To this end, we employed two cell lines as a permanent source of NPC, avoiding the continuous use of human fetal tissue, the human SK-N-MC neuroblastoma cell line, and an immortalized cell line of human fetal neural origin, hNS-1. We also investigated the effect of the differentiation stage in relation to the susceptibility of these cell lines by comparing the neuroblastoma cell line with the multipotent cell line hNS-1. We found that the effects of the virus were more severe in the neuroblastoma cell line. Additionally, we induced hNS-1 to differentiate and evaluated the effect of CMV in these differentiated cells. Like SK-N-MC cells, hNS-1-differentiated cells were also susceptible to infection. Viability of differentiated hNS-1 cells decreased after CMV infection in contrast to undifferentiated cells. In addition, differentiated hNS-1 cells showed an extensive cytopathic effect whereas the effect was scarce in undifferentiated cells. We describe some of the effects of CMV in neural stem cells, and our observations suggest that the degree of differentiation is important in the acquisition of susceptibility.

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“…28,56 These findings argue against direct virus cytopathology and suggest an indirect, virus-induced mechanism as more probable. CNS structural abnormalities and functional disorders caused by congenital CMV infection may be due to MCMV infection of radial glial cells, which play an important role in guiding neuron migration in the neonatal mouse cerebrum, [58][59][60] but could also be the result of an insufficient cerebral blood supply caused by endothelial cell infection and inflammation of the vessel wall 61 (Figure 1b) or by infection of NSPCs. 47,54,62 NSPCs, which are located predominantly in the ventricular/periventricular zone, have the ability to migrate, proliferate, and differentiate into neurons, astrocytes, and oligodendrocytes and are fully permissive to CMV infection.…”

Section: Cmv-induced Developmental Brain Abnormalitiesmentioning

confidence: 99%

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

et al. 2014

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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 1 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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Cytomegalovirus Cell Tropism, Replication, and Gene Transfer in Brain

Cited by 125 publications

References 61 publications

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

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

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