Viruses enter the brain by many routes. Rabies virus enters via a bite from a rabid bat or animal, replicates locally, crosses the neuromuscular synapse, and travels retrograde to the central nervous system (CNS). Mosquitoes infected with West Nile virus (WNV) sting a bird or mammal; WNV replicates locally and then travels hematogenously, infecting the brain endothelium. Human immunodeficiency virus (HIV), whether the virus entered by injection or semen, enters lymph nodes, replicates, and then is carried to the brain by infected monocytes that traverse the microvascular endothelium and enter the perivascular space, ultimately transmitting HIV to microglia. Other viruses, such as reovirus, replicate in peripheral tissues, circulate as free infectious virions, and can infect the vascular endothelium of the CNS. Viruses can be inhaled and replicate in the olfactory neuroepithelium and spread caudally across the cribriforme plate along the olfactory nerve. Herpes simplex virus (HSV) can infect the eye (keratitis) or the oral or vaginal mucosa, enter the local nerve, and then be transmitted by retrograde passage to a ganglion and sometimes to the CNS, causing encephalitis. Once within the brain, viruses replicate in a variety of cell types and induce local innate immune responses.
Every cell type (endothelial cells, ependymal cells, perivascular macrophages and pericytes, astrocytes, microglia, oligodendrocyes, Schwann cells, and neurons) in the CNS can be infected by different viruses. Viral infections of the CNS challenge the host with a different set of problems than do peripheral viral infections.