Human glial chimeric mice reveal astrocytic dependence of JC virus infection

Kondo, Yoichi; Windrem, Martha S.; Zou, Liling; Chandler-Militello, Devin; Schanz, Steven J.; Auvergne, Romane; Betstadt, Sarah J.; Harrington, Amy; Johnson, Mahlon D.; Kazarov, Alexander R.; Gorelik, Leonid; Goldman, Steven A.

doi:10.1172/jci76629

Cited by 69 publications

(89 citation statements)

References 59 publications

(64 reference statements)

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“…In addition, the production of human glial chimeric mice, in which all resident OPCs as well as oligodendrocytes are human , suggested the value of animals engrafted with these cells as models for human myelin disease as well Kondo et al, 2014). Thus, as techniques for the production, isolation and transplantation of OPCs have evolved, it has become increasingly realistic to consider these cells both as vectors for modeling the treatment of myelin diseases and, looking ahead, as scalable agents that might offer effective cell therapy to the multitude of patients with structural diseases of the brain and spinal cord.…”

Section: Resultsmentioning

confidence: 99%

“…These results were analogous to the rescue of shiverer mice afforded by fetal human tissue-derived OPCs (Windrem et al, 2008); remarkably, the survival rate of hiPSC OPC-transplanted shiverer mice actually surpassed that of mice transplanted with fetal tissue-derived counterparts. These data indicated not only that congenitally hypomyelinated mice could be clinically rescued by hiPSC-derived OPC transplants, but also that the rescued mice can develop a completely humanized hiPSC OPC-derived white matter, in which human myelin maturation and ultrastructure, as well as pathophysiology (Kondo et al, 2014;Windrem et al, 2014), may be assessed in vivo.…”

Section: How To Use Hpsc-derived Opcs To Myelinate the Brainmentioning

confidence: 86%

“…Besides their value as cell therapeutics, pluripotent stem cell-derived OPCs may also be used to model the effects of agents designed to influence myelination as well as glial function. Moreover, patient-derived hiPSC-derived OPCs can be engrafted into neonatal mice to produce human glial chimeric mice , which can be used to assess the contributions of oligodendrocytes and astrocytes, as well as of residual OPCs, to diseases in which their respective roles had hitherto been unclear (Kondo et al, 2014). Such patient-and disease-specific human glial chimeric mice might allow the development of personalized glial-directed treatments.…”

Section: Introductionmentioning

confidence: 99%

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How to make an oligodendrocyte

2015

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Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation.

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Section: Resultsmentioning

confidence: 99%

Section: How To Use Hpsc-derived Opcs To Myelinate the Brainmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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How to make an oligodendrocyte

2015

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“…Oligodendrocytes are myelin-producing cells, and astrocytes have been demonstrated to be critical to the process of CNS myelination (9-11). Infection of astrocytes and glial progenitor cells (GPCs), together with virusinduced cytolytic destruction of oligodendrocytes, causes the demyelinating disease progressive multifocal leukoencephalopathy (PML) (12)(13)(14). The disease, once considered fatal, is now managed with immune reconstitution therapy, but surviving patients remain severely debilitated (15).…”

Section: Importancementioning

confidence: 99%

The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity

Stroh

Maginnis

Blaum

et al. 2015

J Virol

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The human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidneys of the majority of the population and is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require ␣2,6-linked sialic acid on the lactoseries tetrasaccharide c (LSTc) glycan for attachment to host cells. In contrast, a JCPyV kidney isolate type 3 strain, WT3, has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and correlated these data with the results of infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement, while the more weakly binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis. IMPORTANCEViral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidneys of the majority of the population and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection. J C polyomavirus (JCPyV) infects ϳ50% of healthy individuals and causes an asymptomatic, lifelong persistent infection in the kidney (1, 2). The form of the virus that resides in the kidney is nonpathogenic and is excreted in the urine (3, 4). In immunosuppressed individuals, JCPyV can spread from the site of persistence to the central nervous system (CNS) (5, 6) and infect the glial cells astrocytes and oligodendroctyes (7,8). Oligod...

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“…Steve Goldman and his group first established a line of mice whose brains were chimeric for human glial cells [50], and then showed that JC virus infected astrocytes rather than oligodendrocytes in a PML model using these chimeric mice [51]. This human/mouse model proved useful in tracing some of the parameters of the oligodendrocyte -astrocyte lineage fate switch [52]. When we probed acute MS lesions for HHV-6, the viral DNA was easily identified in plaque regions; however, HHV-6 antigens were very weakly expressed, and appeared in cells with astrocytic rather than oligodendrocytic morphology.…”

Section: The Staining Problem In Glial Cells In Ms and Pml -Gliogenesmentioning

confidence: 99%

The Secret Lives of Human Herpes Virus 6 (HHV-6)

Blumberg¹

2017

Journal of Neurological Disorders

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Human glial chimeric mice reveal astrocytic dependence of JC virus infection

Cited by 69 publications

References 59 publications

How to make an oligodendrocyte

How to make an oligodendrocyte

The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity

The Secret Lives of Human Herpes Virus 6 (HHV-6)

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