Differences in kinetics of human cytomegalovirus cell-free viral release after in vitro infection of human microglial cells, astrocytes and monocyte-derived macrophages

mentioning

confidence: 99%

Long-Term Infection and Shedding of Human Cytomegalovirus in T98G Glioblastoma Cells

Luo

Fortunato

2007

“…Published studies have described somewhat conflicting results, but some clear messages can be gleaned: (i) NPCs, from which all of the main CNS cell types are derived, were permissive for infection and likely released virions (6,22,25,26) and (ii) astrocytes were fully permissive and released significant quantities of virus (6,16,17,22). The data on both microglia (16,17,31) and neurons (6,17,22) were conflicting, with some studies claiming these cell types to be somewhat permissive (shedding small amounts of virus) (16,22,31) and others claiming both cell types to be nonpermissive (6,17).…”

mentioning

confidence: 99%

Neonatal Neural Progenitor Cells and Their Neuronal and Glial Cell Derivatives Are Fully Permissive for Human Cytomegalovirus Infection

Luo

Schwartz

Fortunato

2008

123

Congenital human cytomegalovirus (HCMV) infection causes central nervous system structural abnormalities and functional disorders, affecting both astroglia and neurons with a pathogenesis that is only marginally understood. To better understand HCMV's interactions with such clinically important cell types, we utilized neural progenitor cells (NPCs) derived from neonatal autopsy tissue, which can be differentiated down either glial or neuronal pathways. Studies were performed using two viral isolates, Towne (laboratory adapted) and TR (a clinical strain), at a multiplicity of infection of 3. NPCs were fully permissive for both strains, expressing the full range of viral antigens (Ags) and producing relatively large numbers of infectious virions. NPCs infected with TR showed delayed development of cytopathic effects (CPE) and replication centers and shed less virus. This pattern of delay for TR infections held true for all cell types tested. Differentiation of NPCs was carried out for 21 days to obtain either astroglia (>95% GFAP ؉ ) or a 1:5 mixed neuron/astroglia population (␤-tubulin III ؉ /GFAP ؉ ). We found that both of these differentiated populations were fully permissive for HCMV infection and produced substantial numbers of infectious virions. Utilizing a difference in plating efficiencies, we were able to enrich the neuron population to ϳ80% ␤-tubulin III ؉ cells. These ␤-tubulin III ؉ -enriched populations remained fully permissive for infection but were very slow to develop CPE. These infected enriched neurons survived longer than either NPCs or astroglia, and a small proportion were alive until at least 14 days postinfection. These surviving cells were all ␤-tubulin III ؉ and showed viral Ag expression. Surprisingly, some cells still exhibited extended processes, similar to mock-infected neurons. Our findings strongly suggest neurons as reservoirs for HCMV within the developing brain.Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that is the most common cause of virus-induced birth defects. Primary infection during pregnancy poses a 30 to 40% risk of intrauterine transmission, with adverse outcomes more likely if the infection is within the first half of the gestation period (37). Each year, about 1% of all newborns are congenitally infected, and 5 to 10% of these infants manifest signs of serious neurological defects, including deafness, mental retardation, blindness, microencephaly, hydrocephalus, and cerebral calcification (1, 3, 37). An additional 10% of congenitally infected infants are asymptomatic at birth and subsequently develop brain disorders, the most common of which is sensorineural hearing loss (7, 27). Thus, in the United States, some 8,000 children annually suffer the obvious consequences of congenital HCMV infection. Additionally, recent investigations have suggested that more subtle abnormal changes in human brain development, such as autism (with an incidence of 1:200), may in some cases be related to congenital HCMV infection (38,43).Although HCMV has a wide range of ...

“…Human neural precursor cells can be expanded as neurospheres, giving rise to both phenotypic neuronal and glial cells following differentiation in vitro. Although astrocytes (31,33), neurons (35), the neuronal cell line HCN-A1 (45), and an oligodendrocytic cell line (54) can all be infected with HCMV, only astrocytes and neurons appear to be fully permissive for such infection. In mixed cultures of the latter two types of cells, HCMV seems to preferentially infect astrocytes (33,57).…”

mentioning

confidence: 99%

Human Cytomegalovirus Inhibits Neuronal Differentiation and Induces Apoptosis in Human Neural Precursor Cells

Odeberg

Wolmer

Falci

et al. 2006

145

165

Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5 and 2.2% and consequences varying from asymptomatic infection to lethal conditions for the fetus. Infants that are asymptomatic at birth may still develop neurological sequelae, such as hearing loss and mental retardation, at a later age. Infection of neural stem and precursor cells by HCMV and consequent disruption of the proliferation, differentiation, and/or migration of these cells may be the primary mechanism underlying the development of brain abnormalities. In the present investigation, we demonstrate that human neural precursor cells (NPCs) are permissive for HCMV infection, by both the laboratory strain Towne and the clinical isolate TB40, resulting in 55% and 72% inhibition of induced differentiation of human NPCs into neurons, respectively, when infection occurred at the onset of differentiation. This repression of neuronal differentiation required active viral replication and involved the expression of late HCMV gene products. This capacity of HCMV to prevent neuronal differentiation declined within 24 h after initiation of differentiation. Furthermore, the rate of cell proliferation in infected cultures was attenuated. Surprisingly, HCMV-infected cells exhibited an elevated frequency of apoptosis at 7 days following the onset of differentiation, at which time approximately 50% of the cells were apoptotic at a multiplicity of infection of 10. These findings indicate that HCMV has the capacity to reduce the ability of human NPCs to differentiate into neurons, which may offer one explanation for the abnormalities in brain development associated with congenital HCMV infection.