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.
