Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms

Fekete, Rebeka and Cserép, Csaba and Lénárt, Nikolett and Tóth, Krisztina and Orsolits, Barbara and Martinecz, Bernadett and Méhes, Előd and Szabó, Bálint and Németh, Valéria and Gönci, Balázs and Sperlágh, Beáta and Boldogkői, Zsolt and Kittel, Ágnes and Baranyi, Mária and Ferenczi, Szilamér and Kovács, Krisztina and Szalay, Gergely and Rózsa, Balázs and Webb, Connor and Kovács, Gábor G. and Hortobágyi, Tibor and Környei, Zsuzsanna and Dénes, Ádám (2018) Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. ACTA NEUROPATHOLOGICA, 136. pp. 461-482. ISSN 0001-6322 (print); 1432-0533 (online)

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Abstract

Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain's immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have remained unclear. Using a well-established model of alphaherpesvirus infection that reaches the brain exclusively via retrograde transsynaptic spread from the periphery, and in vivo two-photon imaging combined with high resolution microscopy, we show that microglia are recruited to and isolate infected neurons within hours. Selective elimination of microglia results in a marked increase in the spread of infection and egress of viral particles into the brain parenchyma, which are associated with diverse neurological symptoms. Microglia recruitment and clearance of infected cells require cell-autonomous P2Y12 signalling in microglia, triggered by nucleotides released from affected neurons. In turn, we identify microglia as key contributors to monocyte recruitment into the inflamed brain, which process is largely independent of P2Y12. P2Y12-positive microglia are also recruited to infected neurons in the human brain during viral encephalitis and both microglial responses and leukocyte numbers correlate with the severity of infection. Thus, our data identify a key role for microglial P2Y12 in defence against neurotropic viruses, whilst P2Y12-independent actions of microglia may contribute to neuroinflammation by facilitating monocyte recruitment to the sites of infection.

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