Читать книгу Principles of Virology, Volume 2 - Jane Flint, S. Jane Flint - Страница 86

Some viruses spread from the primary site of infection by entering local nerve endings. In some cases, neuronal spread is the definitive characteristic of pathogenesis, notably by rabies virus and alphaherpesviruses, which cause infections that primarily impact neuronal function or survival. In other cases, invasion of the nervous system is a rare, typically dead-end, diversion from the normal site of reproduction (e.g., poliovirus, reovirus). Mumps virus, rubella virus, human immunodeficiency virus type 1, and measles virus can reproduce in the brain but access the central nervous system by the hematogenous route, often ferried into the brain by infected lymphocytes or monocytes. The molecular mechanisms that dictate spread into the brain by neural or hematogenous pathways are not well understood, and the way these viruses are defined can lead to further confusion (Box 2.10). For those neurotropic viruses that enter the brain via neuronal circuitry, viral reproduction usually occurs first in nonneuronal cells such as muscle cells near the site of infection. Following reproduction in these cells, virus particles subsequently spread into afferent (e.g., sensory) or efferent (e.g., motor) nerve fibers that innervate the infected tissue, usually crossing neuromuscular junctions to do so (Fig. 2.16).

Neurons are polarized cells with structurally and functionally distinct processes (axons and dendrites) that can be separated by enormous distances. For example, in adult humans, the axon terminals of motor neurons that control stomach muscles can be 50 centimeters away from the cell bodies and dendrites in the brain stem. Certainly, neurotropic viruses do not traverse these great distances by Brownian (random) motion. Rather, the neuronal cytoskeleton, including microtubules and actin, provides the “train tracks” that enable movement of mitochondria, synaptic vesicles, and virus particles to and from the synapse. Molecular motor proteins, such as dyneins and kinesins, are the “engines” that move along these cellular highways (Box 2.11). Drugs, such as colchicine, that disrupt microtubules efficiently block the spread of many neurotropic viruses from the site of peripheral inoculation to the central nervous system.

With few exceptions, cells of the peripheral nervous system are the first to be infected by neurotropic viruses. These neurons represent the first cells in circuits connecting the innervated peripheral tissue with the spinal cord and brain. Once in the nervous system, alphaherpesviruses and some rhabdoviruses (e.g., rabies virus), flaviviruses (e.g., West Nile virus), and paramyxoviruses (e.g., measles and canine distemper virus) can spread among neurons connected by synapses (Box 2.11). Virus spread by this mode can continue through chains of connected neurons of the peripheral nervous system and may eventually reach the spinal cord and brain, often with devastating results (Fig. 2.17). Nonneuronal support cells and satellite cells in ganglia may also become infected.

Movement of virus particles and their release from infected cells are important features of neuronal infections. As is true for polarized epithelial cells discussed earlier, directional release of virus particles from neurons affects the outcome of infection. Alphaherpesviruses become latent in peripheral neurons that innervate the site of infection. Reactivation from the latent state results in viral reproduction in the primary neuron and subsequent transport of progeny virus particles from the neuron cell body back to the innervated peripheral tissue where the infection originated. Alternatively, virus particles can spread from the peripheral to the central nervous system. The direction taken matters tremendously: going one way results in a minor local infection (a cold sore); going the other way can cause a life-threatening viral encephalitis. Luckily, spread back to the peripheral site (away from the brain) is far more common.