Journal Article

Illuminating viral infections in the nervous system

McGavern, Dorian B., Kang, Silvia S.

2011

Overview

Key Points Specialized endothelial cells in the central nervous system (CNS) limit cellular and ionic movement into the brain parenchyma and act as a critical component of the blood–cerebral spinal fluid and blood–brain barriers. In certain anatomical locations, macrophages, microglia and astrocytes are juxtaposed to CNS blood vessels, and this positions these cells to present foreign antigens and/or provide additional barrier support. Innate immune cells such as macrophages and dendritic cells are also found in the meninges and choroid plexus, enabling surveillance of fluid spaces. Viruses use several different strategies to bypass protective barriers and access the CNS. These strategies include haematological entry mechanisms, such as direct infection of vascular endothelium or travelling in immune cells across CNS barriers through a 'Trojan horse' mechanism. Viruses can also access peripheral nerves that reside outside the protective CNS barriers. Immune responses to neurotropic viruses can promote viral clearance or latency, but sometimes give rise to pathology and disease. HIV persists in CNS myeloid cells (macrophages and microglia), giving rise to chronic innate and adaptive immune responses. This pro-inflammatory milieu can eventually cause neuronal damage and dementia. By contrast, herpes simplex virus latency in sensory ganglion neurons is maintained without injury, in part by innate cytokines and virus-specific T cells. Two-photon laser scanning microscopy (TPLSM) is a microscopic technique that can be used to monitor the dynamics of immune responses to neurotropic viruses in real time. When conducting TPLSM experiments, the tissue preparation must be carefully considered because certain preparations can give rise to injury responses that confound data interpretation. Craniotomies and acute brain slices induce considerable tissue damage, whereas skull thinning opens a window for TPLSM imaging without brain injury. Intravital TPLSM imaging of innate immune sentinels, such as dendritic cells, macrophages and microglia, can provide novel insights into their function within the normal and inflamed brain. Studies have revealed that microglia, for example, are highly dynamic under steady-state conditions and rapidly redirect their cellular processes to engulf debris following tissue injury. Intravital imaging of CNS-infiltrating leukocytes during fatal viral meningitis has revealed that recruitment of myelomonocytic cells by virus-specific cytotoxic lymphocytes causes severe vascular injury and the rapid onset of convulsive seizures. Future imaging studies of CNS inflammatory responses following viral infection are required to determine how the immune system operates during states of viral clearance, latency and persistence. This Review describes the anatomical features of the central nervous system (CNS) barriers and focuses on the way in which the immune system responds to neurotropic viruses that establish latent or persistent infections in the CNS. It also discusses imaging technologies that can be used to understand viral entry and antiviral immune responses in the CNS. Viral infections are a major cause of human disease. Although most viruses replicate in peripheral tissues, some have developed unique strategies to move into the nervous system, where they establish acute or persistent infections. Viral infections in the central nervous system (CNS) can alter homeostasis, induce neurological dysfunction and result in serious, potentially life-threatening inflammatory diseases. This Review focuses on the strategies used by neurotropic viruses to cross the barrier systems of the CNS and on how the immune system detects and responds to viral infections in the CNS. A special emphasis is placed on immune surveillance of persistent and latent viral infections and on recent insights gained from imaging both protective and pathogenic antiviral immune responses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2152/1566/1572 / 631/250/255/2514 / 631/250/371 / Animals / Biomedical and Life Sciences / Biomedicine / Blood-Brain Barrier - virology / Blood-Nerve Barrier - virology / Capillary Permeability / Central nervous system / Central Nervous System - anatomy & histology / Central Nervous System - immunology / Central Nervous System - virology / Central Nervous System Viral Diseases - immunology / Central Nervous System Viral Diseases - virology / Chikungunya virus / Cytomegalovirus / Encephalitis / Endothelium, Vascular - virology / Homeostasis / Humans / Immune response / Immune system / Immunology / Infections / Inflammation / Inflammatory diseases / Measles / Meningitis / Nervous system / Peripheral Nervous System - virology / Physiological aspects / Rabies / review-article / Spinal cord / Transgenic animals / Viral infections / Virus diseases / Virus Internalization / Virus Latency / Viruses / Viruses - immunology / Viruses - pathogenicity / West Nile virus