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

Rebeka Fekete, Csaba Cserép, Nikolett Lénárt, Krisztina Tóth, Barbara Orsolits, Bernadett Martinecz, Előd Méhes, B. Szabó, Valéria Németh, Balázs Gönci, B. Sperlágh, Z. Boldogkői, A. Kittel, M. Baranyi, Szilamér Ferenczi, K. Kovács, Gergely Szalay, B. Rózsa, Connor Webb, Gabor G. Kovacs & 4 others T. Hortobágyi, Brian L. West, Zsuzsanna Környei, Ádám Dénes

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
JournalActa Neuropathologica
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Microglia
Virus Diseases
Monocytes
Brain
Infection
Neurons
Viral Encephalitis
Herpesviridae
Encephalitis
Leukocyte Count
Photons
Virion
Microscopy
Immune System
Nucleotides
Viruses

Keywords

  • Microglia
  • Neuroinflammation
  • Neurotropic virus
  • P2Y12
  • Transsynaptic spread

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. / Fekete, Rebeka; Cserép, Csaba; Lénárt, Nikolett; Tóth, Krisztina; Orsolits, Barbara; Martinecz, Bernadett; Méhes, Előd; Szabó, B.; Németh, Valéria; Gönci, Balázs; Sperlágh, B.; Boldogkői, Z.; Kittel, A.; Baranyi, M.; Ferenczi, Szilamér; Kovács, K.; Szalay, Gergely; Rózsa, B.; Webb, Connor; Kovacs, Gabor G.; Hortobágyi, T.; West, Brian L.; Környei, Zsuzsanna; Dénes, Ádám.

In: Acta Neuropathologica, 01.01.2018.

Research output: Contribution to journalArticle

Fekete, Rebeka ; Cserép, Csaba ; Lénárt, Nikolett ; Tóth, Krisztina ; Orsolits, Barbara ; Martinecz, Bernadett ; Méhes, Előd ; Szabó, B. ; Németh, Valéria ; Gönci, Balázs ; Sperlágh, B. ; Boldogkői, Z. ; Kittel, A. ; Baranyi, M. ; Ferenczi, Szilamér ; Kovács, K. ; Szalay, Gergely ; Rózsa, B. ; Webb, Connor ; Kovacs, Gabor G. ; Hortobágyi, T. ; West, Brian L. ; Környei, Zsuzsanna ; Dénes, Ádám. / Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. In: Acta Neuropathologica. 2018.
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AU - Fekete, Rebeka

AU - Cserép, Csaba

AU - Lénárt, Nikolett

AU - Tóth, Krisztina

AU - Orsolits, Barbara

AU - Martinecz, Bernadett

AU - Méhes, Előd

AU - Szabó, B.

AU - Németh, Valéria

AU - Gönci, Balázs

AU - Sperlágh, B.

AU - Boldogkői, Z.

AU - Kittel, A.

AU - Baranyi, M.

AU - Ferenczi, Szilamér

AU - Kovács, K.

AU - Szalay, Gergely

AU - Rózsa, B.

AU - Webb, Connor

AU - Kovacs, Gabor G.

AU - Hortobágyi, T.

AU - West, Brian L.

AU - Környei, Zsuzsanna

AU - Dénes, Ádám

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N2 - 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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