Astrocytes provide metabolic support for neurons and modulate their functions by releasing a plethora of neuroactive molecules diffusing to neighboring cells. Here we report that astrocytes also play a role in cortical neurons' vulnerability to Herpes simplex virus type-1 (HSV-1) infection through the release of extracellular ATP. We found that the interaction of HSV-1 with heparan sulfate proteoglycans expressed on the plasma membrane of astrocytes triggered phospholipase C-mediated IP3 -dependent intracellular Ca2+ transients causing extracellular release of ATP. ATP binds membrane purinergic P2 receptors (P2Rs) of both neurons and astrocytes causing an increase in intracellular Ca2+ concentration that activates the Glycogen Synthase Kinase (GSK)-3β, whose action is necessary for HSV-1 entry/replication in these cells. Indeed, in co-cultures of neurons and astrocytes HSV-1-infected neurons were only found in proximity of infected astrocytes releasing ATP, whereas in the presence of fluorocitrate, an inhibitor of astrocyte metabolism, switching-off the HSV-1-induced ATP release, very few neurons were infected. The addition of exogenous ATP, mimicking that released by astrocytes after HSV-1 challenge, restored the ability of HSV-1 to infect neurons co-cultured with metabolically-inhibited astrocytes. The ATP-activated, P2R-mediated, and GSK-3-dependent molecular pathway underlying HSV-1 infection is likely shared by neurons and astrocytes, given that the blockade of either P2Rs or GSK-3 activation inhibited infection of both cell types. These results add a new layer of information to our understanding of the critical role played by astrocytes in regulating neuronal functions and their response to noxious stimuli including microbial agents via Ca2+ -dependent release of neuroactive molecules.

Ca2+-dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons / Donatella Li Puma, Domenica; Marcocci, Maria Elena; Lazzarino, Giacomo; De Chiara, Giovanna; Tavazzi, Barbara; Palamara, ANNA TERESA; Piacentini, Roberto; Grassi, Claudio. - In: GLIA. - ISSN 0894-1491. - (2021). [10.1002/glia.23895]

Ca2+-dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons

Maria Elena Marcocci;Anna Teresa Palamara;
2021

Abstract

Astrocytes provide metabolic support for neurons and modulate their functions by releasing a plethora of neuroactive molecules diffusing to neighboring cells. Here we report that astrocytes also play a role in cortical neurons' vulnerability to Herpes simplex virus type-1 (HSV-1) infection through the release of extracellular ATP. We found that the interaction of HSV-1 with heparan sulfate proteoglycans expressed on the plasma membrane of astrocytes triggered phospholipase C-mediated IP3 -dependent intracellular Ca2+ transients causing extracellular release of ATP. ATP binds membrane purinergic P2 receptors (P2Rs) of both neurons and astrocytes causing an increase in intracellular Ca2+ concentration that activates the Glycogen Synthase Kinase (GSK)-3β, whose action is necessary for HSV-1 entry/replication in these cells. Indeed, in co-cultures of neurons and astrocytes HSV-1-infected neurons were only found in proximity of infected astrocytes releasing ATP, whereas in the presence of fluorocitrate, an inhibitor of astrocyte metabolism, switching-off the HSV-1-induced ATP release, very few neurons were infected. The addition of exogenous ATP, mimicking that released by astrocytes after HSV-1 challenge, restored the ability of HSV-1 to infect neurons co-cultured with metabolically-inhibited astrocytes. The ATP-activated, P2R-mediated, and GSK-3-dependent molecular pathway underlying HSV-1 infection is likely shared by neurons and astrocytes, given that the blockade of either P2Rs or GSK-3 activation inhibited infection of both cell types. These results add a new layer of information to our understanding of the critical role played by astrocytes in regulating neuronal functions and their response to noxious stimuli including microbial agents via Ca2+ -dependent release of neuroactive molecules.
2021
ATP; GSK-3β; P2Rs; astrocytes; herpes simplex virus
01 Pubblicazione su rivista::01a Articolo in rivista
Ca2+-dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons / Donatella Li Puma, Domenica; Marcocci, Maria Elena; Lazzarino, Giacomo; De Chiara, Giovanna; Tavazzi, Barbara; Palamara, ANNA TERESA; Piacentini, Roberto; Grassi, Claudio. - In: GLIA. - ISSN 0894-1491. - (2021). [10.1002/glia.23895]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1713573
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