nfections USUALLY begin in peripheral tissues and can invade the mammalian nervous system (NS), spreading into the peripheral (PNS) and more rarely the central nervous systems (CNS). The CNS is protected from most virus infections by effective immune responses and multi-layer barriers. However, some viruses ENTER the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal CELL biology. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathology. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.IntroductionMost acute and persistent viral infections begin in the periphery, often at epithelial or endothelial cell surfaces. Infection of cells at these sites usually induces a tissue-specific antiviral response that includes both a cell autonomous response (intrinsic immunity) and paracrine signaling from the infected cell to surrounding uninfected cells by secreted cytokines (innate immunity). This local inflammatory response usually contains the infection. After several days, the adaptive immune response may be activated and the infection cleared by the ACTION of infection-specific antibodies and T cells (acquired immunity). Viral infections that escape local control at the site of primary infection can spread to other tissues where they can cause more serious problems due to robust virus replication or, overreacting innate immune response. This latter reaction is sometimes called a `cytokine storm` because both pro-inflammatory and antiinflammatory cytokines are elevated in the serum leading to vigorous systemic immune activity (Figure 1). Such a response in the brain is usually devastating and can lead to meningitis, encephalitis, meningoencephalitis or deathEntering the nervous systemWhile the PNS is relatively more accessible to peripheral infections because nerves are in direct contact with tissues of all types, the CNS proper has several layers of protection. Spread of infection from the blood to the cerebral spinal fluid and CNS cells is limited by the blood brain barrier (BBB). The BBB is mainly composed of endothelial cells, pericytes, astrocytes and the basement membrane (Figure 2D). Pericytes project finger-like processes to ensheath the capillary wall and coordinate the neurovascular functions of the BBB. The star shaped astrocytes (i.e. astroglia) are the major glial cell type in the CNS. The astrocyte endfeet projections ensheath the capillary, regulating BBB homeostasis and blood-flow. Brain microvascular endothelial cells (BMVECs) that line the CNS vasculature are connected by tight junctions not found in capillaries in other tissues. These junctions restrict the egress of bacteria, virus particles, and large protein molecules from the lumen of the blood vessel, while allowing the transport of metabolites, small hydrophobic proteins, and dissolved gasses in and out of the CNS. The basement membrane, a thick extracellular matrix, also surrounds these capillaries further limiting MOVEMENT of pathogens. Perivascular macrophages (i.e. migroglia) residing between the endothelial and glial cells further provide immune surveillance in the CNS tissue. Virus infections that leave the periphery and find their way into the PNS or CNS do so either by direct infection of nerve endings in the tissues, or by infecting cells of the circulatory system that ultimately carry the infection through the BBB into the CNS