Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells

Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data.

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Porcine Choroid Plexus Epithelial Cells Induce Streptococcus suis Bacteriostasis In Vitro

Infection and Immunity ◽

10.1128/iai.72.5.3084-3087.2004 ◽

2004 ◽

Vol 72 (5) ◽

pp. 3084-3087 ◽

Cited By ~ 13

Author(s):

Rüdiger A. Adam ◽

Tobias Tenenbaum ◽

Peter Valentin-Weigand ◽

Maurice Laryea ◽

Bernd Schwahn ◽

...

Keyword(s):

Epithelial Cells ◽

Bacterial Meningitis ◽

Choroid Plexus ◽

Host Defense ◽

Streptococcus Suis ◽

Active Role ◽

Necrosis Factor Alpha ◽

Ifn Γ ◽

Choroid Plexus Epithelial

ABSTRACT The involvement of the choroid plexus in host defense during bacterial meningitis is unclear. Aiming to elucidate possible antibacterial mechanisms, we stimulated primary porcine choroid plexus epithelial cells (pCPEC) with proinflammatory cytokines and challenged them with various Streptococcus suis strains. In the supernatant of gamma interferon (IFN-γ)-stimulated pCPEC, streptococcal growth was markedly suppressed. Costimulation with tumor necrosis factor alpha enhanced this bacteriostatic effect, while supplementation of l-tryptophan completely eliminated it. We also demonstrate that an activation of indoleamine 2,3-dioxygenase in the pCPEC seems to be responsible for the IFN-γ-induced bacteriostasis. This supports the hypothesis of an active role of the choroid plexus in host defense against bacterial meningitis.

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Genetic and pharmacological inactivation of apical Na+-K+-2Cl− cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter

AJP Cell Physiology ◽

10.1152/ajpcell.00026.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. C525-C544 ◽

Cited By ~ 18

Author(s):

Jeannine M. C. Gregoriades ◽

Aaron Madaris ◽

Francisco J. Alvarez ◽

Francisco J. Alvarez-Leefmans

Keyword(s):

Epithelial Cells ◽

Choroid Plexus ◽

Basolateral Membrane ◽

Water Volume ◽

Water Fluxes ◽

Membrane Location ◽

Flux Mode ◽

Choroid Plexus Epithelial

Choroid plexus epithelial cells (CPECs) secrete cerebrospinal fluid (CSF). They express Na+-K+-ATPase and Na+-K+-2Cl− cotransporter 1 (NKCC1) on their apical membrane, deviating from typical basolateral membrane location in secretory epithelia. Given this peculiarity, the direction of basal net ion fluxes mediated by NKCC1 in CPECs is controversial, and cotransporter function is unclear. Determining the direction of basal NKCC1-mediated fluxes is critical to understanding the function of apical NKCC1. If NKCC1 works in the net efflux mode, it may be directly involved in CSF secretion. Conversely, if NKCC1 works in the net influx mode, it would have an absorptive function, contributing to intracellular Cl− concentration ([Cl−]i) and cell water volume (CWV) maintenance needed for CSF secretion. We resolve this long-standing debate by electron microscopy (EM), live-cell-imaging microscopy (LCIM), and intracellular Na+ and Cl− measurements in single CPECs of NKCC1+/+ and NKCC1−/− mouse. NKCC1-mediated ion and associated water fluxes are tightly linked, thus their direction is inferred by measuring CWV changes. Genetic or pharmacological NKCC1 inactivation produces CPEC shrinkage. EM of NKCC1−/− CPECs in situ shows they are shrunken, forming large dilations of their basolateral extracellular spaces, yet remaining attached by tight junctions. Normarski LCIM shows in vitro CPECs from NKCC1−/− are ~17% smaller than NKCC1+/+. CWV measurements in calcein-loaded CPECs show that bumetanide (10 μM) produces ~16% decrease in CWV in NKCC1+/+ but not in NKCC1−/− CPECs. Our findings suggest that under basal conditions apical NKCC1 is continuously active and works in the net inward flux mode maintaining [Cl−]i and CWV needed for CSF secretion.

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