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Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A.

ABSTRACT: Although human polyomavirus JC (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals, the mechanism by which JCV crosses the blood-brain barrier (BBB) remains unclear. To test our hypothesis that cell-free JCV gains entry into the brain by infecting endothelial cells, we inoculated human brain microvascular endothelial (HBMVE) cells with 50 HAU (1.33+/-0.27 x 10(7) genome copies) of JCV(Mad1) and analyzed the expression of early and late viral genes and proteins by immunocytochemistry, quantitative real-time PCR (qPCR), quantitative real-time reverse transcriptase PCR (qRT-PCR) and immunoprecipitation followed by Western blotting. JCV infected and replicated efficiently in HBMVE cells and produced infectious virions several hundred fold higher than the infecting inoculum. HBMVE cells in vitro did not express serotonin receptor 2A (5HT(2A)R), and 5HT(2A)R blockers did not prevent JCV infection of HBMVE cells. Collectively, our data indicate that the productive in vitro infection of HBMVE cells by JCV is independent of 5HT(2A)R.

SUBMITTER: Chapagain ML

PROVIDER: S-EPMC2034208 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A.

Chapagain Moti L ML Verma Saguna S Mercier Frederic F Yanagihara Richard R Nerurkar Vivek R VR

Virology 20070330 1

Although human polyomavirus JC (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals, the mechanism by which JCV crosses the blood-brain barrier (BBB) remains unclear. To test our hypothesis that cell-free JCV gains entry into the brain by infecting endothelial cells, we inoculated human brain microvascular endothelial (HBMVE) cells with 50 HAU (1.33+/-0.27 x 10(7) genome copies) of JCV(Mad1) and analyzed the expression of early and late viral ...[more]

PMID: 17399760

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Project description:Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59) persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs), without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-?) and transiently induced, but failed to secrete, IFN-? and IFN-?. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7), IRF9, and IFN-stimulated genes (ISGs) 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV) persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread.IMPORTANCE ZIKV persists in patients, crossing placental and neuronal barriers, damaging neurons, and causing fetal microencephaly. We found that ZIKV persistently infects brain endothelial cells that normally protect neurons from viral exposure. hBMECs are not damaged by ZIKV infection and, analogous to persistent HCV infection, ZIKV constitutively induces and evades antiviral ISG and IFN responses to continuously replicate in hBMECs. As a result, hBMECs provide a protective niche for systemic ZIKV spread and a viral reservoir localized in the normally protective blood-brain barrier. Consistent with the spread of ZIKV into neuronal compartments, ZIKV was released basolaterally from hBMECs. Our findings define hBMEC responses that contribute to persistent ZIKV infection and potential targets for clearing ZIKV infections from hBMECs. These results further suggest roles for additional ZIKV-infected ECs to facilitate viral spread and persistence in the protected placental, retinal, and testicular compartments.

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Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A.

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Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A.

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