Principles of Virology, Volume 2. S. Jane Flint

likely contaminants from laboratory reagents or the environment. These include sequences from nonhuman retroviruses, four different giant DNA viruses, and a virus of bees, all found in fewer than 10 samples. These findings illustrate the challenge in distinguishing bona fide human viruses from contaminants.

      Identifying viruses in blood is an important objective for ensuring the safety of the blood supply. Donor blood is currently screened for human immunodeficiency virus types 1 and 2, human T-cell lymphotropic virus-1 and -2, hepatitis C virus, hepatitis B virus, West Nile virus, and Zika virus. These viruses are pathogenic for humans and can be transmitted via the blood. Some viruses, such as anelloviruses and pegiviruses, are in most donated blood, yet their pathogenic potential is unknown. It is not feasible to reject donor blood that contains any type of viral nucleic acid—if we did, we would not have a blood supply.

      Continuing studies of the blood virome are needed to define which viruses should be tested for in donated blood. The human papillomavirus (17 people), Merkel cell polyomavirus (49 people), human herpesvirus type 8 (3 people), and adenovirus (9 people) detected in this study could be transmitted in the blood, and their presence should be monitored in future studies.

      It is important to emphasize that this work describes only viral DNA sequences, and not infectious virus particles. The blood supply is screened by nucleic acid tests, but it is crucial to determine if infectious virus particles are also present . If viral DNA is present in blood but particles are never found, then it might not be necessary to reject blood based on the presence of certain sequences.

       Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y, Bloom K, Delwart E, Nelson KE, Venter JC, Telenti A. 2017. The blood DNA virome in 8,000 humans. PLoS Pathog 13:e1006292.

Neural Spread

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.

BOX 2.10

      TERMINOLOGY

       Infection of the nervous system: definitions and distinctions

       A neuroinvasive virus can enter the central nervous system (spinal cord and brain) after infection of a peripheral site.

       A neurotropic virus can infect neurons; infection may occur by neural or hematogenous spread from a peripheral site.

       A neurovirulent virus can cause disease of nervous tissue, manifested by neurological symptoms and often death.

      Examples:

       Herpes simplex virus type 1 exhibits low neuroinvasiveness but high neuroviru lence. It always enters the peripheral nervous system but rarely gains access to the central nervous system. When it does, the consequences are severe, and can be fatal. Mumps virus exhibits high neuroinvasiveness but low neurovirulence. Most infections lead to invasion of the central nervous system, but neurological disease is mild. Rabies virus is highly neuroinvasive, with high neurovirulence. It readily infects the peripheral nervous system and spreads to the central nervous system with 100% lethality, unless postinfection vaccination is given.

      Primary mouse hippocampal neurons expressing a measles virus receptor, CD46, and infected with measles virus for 48 h. Virus-infected cells are stained brown. Black arrow: neuronal axon; white arrow: neuronal dendrites. Original magnification = ×200. Photo courtesy of the Rall laboratory.

Figure 2.16 Possible pathways for the spread of infection in nerves. Virus particles may enter sensory or motor neuron endings. They may be transported within axons, in which case viruses taken up at sensory endings reach dorsal root ganglion cells. Those taken up at motor endings reach motor neurons. Viruses may also travel in the