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

Abstract

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.).

Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

“…Wild-type JCV strains are also able to make facultative use of the GAG-dependent entry pathway, allowing them to remain partially infectious when either GAG or sialic acid engagement is blocked. The existence of this previously unknown sialylated glycan-independent infectious entry pathway could help explain why JCV can robustly infect human astrocytes and oligodendrocytes in vivo (Kondo et al, 2014), despite the fact that these cell types appear to lack previously identified sialylated glycan receptors for the virus (Haley et al, 2015). …”

JC Polyomavirus Attachment and Entry: Potential Sites for PML Therapeutics

“…It is possible that JCPyV binding to and infection of cells in the brain including, astrocytes, oligodendrocytes, and neurons, is sialic-acid-independent in an in vivo infection. Haley et al demonstrated that astrocytes and oligodendrocytes from human brain tissues were negative for LSTc [81]. Therefore, viruses isolated from PML patients with mutations in VP1 within the sialic acid binding sites could possibly lead to neuroinvasion via a sialic acid-independent manner through interactions with an alternate receptor or through a receptor-independent invasion mechanism that has been demonstrated for other viruses [82, 83].…”

“…Interestingly, 5-HT 2 Rs are expressed on a variety of cells in the CNS, including astrocytes and oligodendrocytes, and in the kidney, including the distal tubules and collecting ducts, all of which are sites of JCPyV infection [81, 88, 89]. Furthermore, 5-HT 2 Rs are expressed on neurons, and subtype 2A is found abundantly in the cerebral cortex [90] where JCPyV has been identified in sites of significant demyelination in individuals with PML [41, 43].…”

“…Furthermore, 5-HT 2 Rs are expressed on neurons, and subtype 2A is found abundantly in the cerebral cortex [90] where JCPyV has been identified in sites of significant demyelination in individuals with PML [41, 43]. Interestingly, JCPyV is not able to infect microglia, cells that express 5-HT 2 Rs but lack expression of the JCPyV attachment factor LSTc, further indicating that 5-HT 2 Rs are not the sole requirement for viral infection [81]. …”

Converting Pasteurella multocida α2–3-sialyltransferase 1 (PmST1) to a regioselective α2–6-sialyltransferase by saturation mutagenesis and regioselective screening

“…5 The resulting Neu5Acα2–6LNnT (LSTc) represents a common structure found in human milk 11 and on mammalian cell surface. 53 …”