A fatal case of <scp>JC</scp> virus meningitis presenting with hydrocephalus in a human immunodeficiency virus–seronegative patient

Agnihotri, Shruti; Wüthrich, Christian; Dang, Xin; Nauen, David W.; Karimi, Reza; Viscidi, Raphael P.; Bord, Evelyn; Batson, Stephanie; Troncoso, Juan C.; Koralnik, Igor J.

doi:10.1002/ana.24192

Cited by 47 publications

(54 citation statements)

References 20 publications

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“…82 Here, we show that the CPE expresses both the JCPyV attachment and entry receptors and that the virus interaction with the CPE is LSTc dependent. Recently, JCPyV VP1 was detected in the CPE in a case of JCPyV-associated meningitis, 83 demonstrating that JCPyV can productively infect these cells. Direct infection of the CPE could allow JCPyV access to brain parenchyma.…”

Section: Direct Binding Of Jcpyv To Barriers Of the Cnsmentioning

confidence: 98%

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Haley

O’Hara

Nelson

et al. 2015

The American Journal of Pathology

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The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy, a rare demyelinating disease that occurs in the setting of prolonged immunosuppression. After initial asymptomatic infection, the virus establishes lifelong persistence in the kidney and possibly other extraneural sites. In rare instances, the virus traffics to the central nervous system, where oligodendrocytes, astrocytes, and glial precursors are susceptible to lytic infection, resulting in progressive multifocal leukoencephalopathy. The mechanisms by which the virus traffics to the central nervous system from peripheral sites remain unknown. Lactoseries tetrasaccharide c (LSTc), a pentasaccharide containing a terminal a2,6elinked sialic acid, is the major attachment receptor for polyomavirus. In addition to LSTc, type 2 serotonin receptors are required for facilitating virus entry into susceptible cells. We studied the distribution of virus receptors in kidney and brain using lectins, antibodies, and labeled virus. The distribution of LSTc, serotonin receptors, and virus binding sites overlapped in kidney and in the choroid plexus. In brain parenchyma, serotonin receptors were expressed on oligodendrocytes and astrocytes, but these cells were negative for LSTc and did not bind virus. LSTc was instead found on microglia and vascular endothelium, to which virus bound abundantly. Receptor distribution was not changed in the brains of patients with progressive multifocal leukoencephalopathy. Virus infection of oligodendrocytes and astrocytes during disease progression is LSTc independent. (Am J Pathol 2015, 185: 2246e2258; http://dx.doi.org/10.1016/j.ajpath.2015.04.003)The human polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a rapidly progressing, often fatal neurodegenerative disease. Although PML is rare, JCPyV infection is widespread, infecting approximately 50% to 80% of the healthy adult population. 1,2 As the initial infection is asymptomatic, the mode of JCPyV transmission is unknown. The virus establishes a persistent infection in the kidney and urinary tract of immunocompetent hosts, 3 and about 20% of these infected individuals shed virus in their urine. 4 JCPyV DNA has also been detected in other tissues, including B lymphocytes in the bone marrow, tonsillar stromal cells, lungs, spleen, and brain, 5e13 suggesting additional sites of viral persistence. The route of viral transmission from the initial site(s) of infection and latency to the central nervous system (CNS), the main site of pathogenesis, is not clearly understood.Under conditions of immunosuppression, JCPyV infects and destroys the myelin-producing oligodendrocytes, resulting in demyelination, which is the hallmark of this fatal disease; to a Supported by NIH grants R01NS043097 (W.J.A.) and P01NS065719 (W.J.A.).

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Section: Direct Binding Of Jcpyv To Barriers Of the Cnsmentioning

confidence: 98%

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Haley

O’Hara

Nelson

et al. 2015

The American Journal of Pathology

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“…Post mortem exam showed productive JCV Infection of leptomeningeal and choroid plexus cells. Molecular analyses from the CSF JCV strain demonstrated an archetype-like RR, but no VP1 gene or agnogene mutations such as those found in cases of JCV GCN of JCVE [10]. Further studies on the role of JCV in aseptic meningitis and idiopathic hydrocephalus are warranted.…”

Section: Jc Virus Meningitis (Jcvm)mentioning

confidence: 99%

“…JCVE was found to be caused by a productive infection of cortical pyramidal neurons. Finally, in 2014, we observed a fatal case of JCV meningitis (JCVM) in an HIV-negative patient who had an extremely high CSF JC viral load and productive JCV infection of leptomeningeal cells [10]. In this review, we will discuss these syndromes in detail and how their discoveries have expanded our understanding of the pathogenesis of JCV in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Novel syndromes associated with JC virus infection of neurons and meningeal cells

Miskin

Koralnik

2015

Current Opinion in Neurology

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Purpose of review The availability of a growing number of immunomodulatory medications over the past few years has been associated with various JC Virus (JCV) associated brain syndromes in patients with autoimmune diseases, including multiple sclerosis, Crohn’s disease and psoriasis which had not been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy (PML). This review covers the three novel syndromes discovered in the last decade which are caused by JCV infection of neurons and meningeal cells. Recent findings For more than 30 years, JCV was thought to exclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressed individuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matter junction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV can trigger a change in tropism leading to involvement of other cell types, such as neurons and meningeal cells, causing clinically distinct entities. These new features of JCV infection provide challenges for clinicians taking care of affected patients and investigators studying the biology of this polyomavirus, its pathogenesis, and tropism. Summary We hope that increasing awareness of these syndromes will lead to early diagnosis, and pave the way for new avenues of research to better understand all aspects of JCV pathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant and open to the possibility that additional JC variants or yet unknown polyomaviruses may be associated with neurological diseases as well.

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“…It is possible that neurons may be the first cells of the CNS parenchyma to be infected by JCV. The recent demonstration that JCV can cause meningeal infection (41) supports the view that the virus could spread to cortical cells first, prior to infecting glia at the GWJ and in the WM. If that is the case, chronic infection of cortical pyramidal or granule cell neurons might cause neurologic dysfunction, although absence of cytolysis may preclude detection of the lesions on MRI.…”

Section: Discussionmentioning

confidence: 72%

Lack of Major Histocompatibility Complex Class I Upregulation and Restrictive Infection by JC Virus Hamper Detection of Neurons by T Lymphocytes in the Central Nervous System

Wüthrich

Batson

Koralnik

2015

J Neuropathol Exp Neurol

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The human polyomavirus JC (JCV) infects glial cells in immunosuppressed individuals leading to progressive multifocal leukoencephalopathy (PML). JCV can also infect neurons in patients with JCV granule cell neuronopathy and JCV encephalopathy. CD8-positive T-cells play a crucial role in viral containment and outcome in PML but whether CD8-positive T-cells can also recognize JCV-infected neurons is unclear. We used immunohistochemistry to determine the prevalence of T-cells in neuron-rich areas of archival brain samples from 77 patients with JCV CNS infections and 94 control subjects. Neurons predominantly sustained a restrictive infection with expression of JCV regulatory protein T antigen (T Ag), while glial cells were productively infected and expressed both T Ag and the capsid protein VP1. T-cells were more prevalent near JCV-infected cells with intact nuclei expressing both T Ag and VP1 compared to those expressing either protein alone. CD8-positive T-cells also colocalized more with JCV-infected glial cells than with JCV-infected neurons. Major histocompatibility complex I (MHC I) expression was upregulated in JCV-infected areas but could only be detected in rare neurons interspersed with infected glial cells. These results suggest that isolated neurons harboring restrictive JCV-infection do not upregulate MHC I and thus may escape recognition by CD8-positive T-cells.

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A fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus–seronegative patient

Cited by 47 publications

References 20 publications

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

Novel syndromes associated with JC virus infection of neurons and meningeal cells

Lack of Major Histocompatibility Complex Class I Upregulation and Restrictive Infection by JC Virus Hamper Detection of Neurons by T Lymphocytes in the Central Nervous System

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