Principles of Virology, Volume 2. S. Jane Flint

space, perineural lymphatics, or infected Schwann cells. Directional transport of virus particles inside the sensory neuron is defined as anterograde [movement from the (–) to the (+) ends of microtubules] or retrograde (vice versa).

Organ Invasion

      Once virus particles enter the blood or neurons and are dispersed from the primary site of infection, any subsequent reproduction requires invasion of other cells. We have already discussed viral movement into and among neurons to access the brain and spinal cord and will return to this issue in Chapter 5 when we discuss neuropathogenesis resulting from viral infections.

There are three main types of blood vessel-tissue junctions that serve as portals for tissue invasion (Fig. 2.18). In some tissues, the endothelial cells are continuous with a dense basement membrane. At other sites, the endothelium contains gaps, and at still others, there may be sinusoids, in which macrophages form part of the blood-tissue junction. Viruses can traverse all three types of junctions.

Entry into Organs with Sinusoids

Organs such as the liver, spleen, bone marrow, and adrenal glands are characterized by the presence of sinusoids, a type of capillary that has a large pore size to allow free exchange between the blood and the tissue. These capillaries are lined with macrophages, known somewhat misleadingly as the reticuloendothelial system (these macrophages are neither endothelial nor a “system”). These cells function to filter the blood and remove foreign particles, similar to a HEPA filter purifying incoming air. However, the macrophages in organs that possess sinusoids often provide the portal for entry of viral particles into tissues. For example, hepatitis viruses that infect the liver, the major filtering and detoxifying organ of the body, usually enter from the blood. The presence of virus particles in the blood can lead to the infection of Kupffer cells, the macrophages that line liver sinusoids (Fig. 2.19). Virus particles may be transcytosed across kupffer and endothelial cells without reproduction to reach the underlying hepatocytes. Alternatively, viruses may multiply in the kupffer cells, and then be released to infect hepatocytes. Either mechanism may induce inflammation and necrosis of liver tissue, a condition termed hepatitis.

Entry into Organs That Lack Sinusoids

      To enter tissues that lack sinusoids (Fig. 2.18), and that have tighter or more continuous capillary endothelial cells, virus particles must first adhere to the endothelial cells before crossing into the tissue. This often occurs in venules, where the flow is slowest and the capillary walls are thinnest. High viral loads and persistence of viral particles in the blood stream enhance the likelihood of tissue penetration. Once blood-borne virus particles have adhered to the vessel wall, they can more easily invade the renal glomerulus, pancreas, ileum, or colon. Invasion occurs because the endothelial cells that make up the capillaries of these tissues have pores or holes in the cell layer, called fenestrations, that permit virus particles or virus-infected cells to cross. Some viruses traverse the endothelium hidden in infected monocytes or lymphocytes, a process called diapedesis.

BOX 2.11

      TERMINOLOGY

       Which direction: anterograde or retrograde?

      Retrograde and anterograde spread of virus in nerves. (A) Anterograde spread of infection. The virus invades at dendrites or cell bodies and reproduces. Virus particles then spread to axon terminals, where they cross synaptic contacts to invade dendrites or cell bodies of the second neuron. (B) Retrograde spread of infection. The virus invades at axon terminals and spreads to the cell body, where reproduction occurs. Progeny virus particles spread to a neuron at sites of synaptic contact. Particles enter the axon terminal of the second neuron to initiate a second cycle of replication and spread. (C) Identification of a possible micro circuit in the rodent visual cortex (V2) after injection of a green fluorescent protein-expressing strain of pseudorabies virus into the synaptically connected, but distant, V1 region. Infection spread via V1 axons (V1 cell bodies are located far out of the field of view) in a retrograde manner to a subset of V2 cell bodies is seen here. Confocal microscopy and image reconstruction by Botond Roska, Friedrich Miescher Institute, Basel, Switzerland.

      Those who study virus spread in the nervous system often use the words retrograde and anterograde to describe direction. Confusion can arise because the terms can be used to describe directional movement of virus particles inside a cell, as well as spread between synaptically connected neurons. Spread from the primary neuron to a second-order neuron in the direction of the nerve impulse is called anterograde spread (see figure). Spread in the opposite direction is termed retrograde. Spread inside a neuron is defined by microtubule polarity. Anterograde transport occurs on micro tubules from the cell body toward the axon terminus; retrograde spread occurs from the axon terminus toward the cell body.

       Ekstrand MI, Enquist LW, Pomeranz LE. 2008. The alpha-herpesviruses: molecular pathfinders in nervous system circuits. Trends Mol Med 14:134–140.

Figure 2.17 Outline of the spread of alphaherpesviruses and relationship to disease. Although herpes simplex virus can infect many cell types, in most infected individuals, it remains restricted to the local site of infection and establishes latency in the ganglia that innervate that site. Under conditions when the host has a weakened immune system, viremia can result in which distal organs become infected and/or the virus may transition from the peripheral nervous system (PNS) to the central nervous system (CNS); again, this is a rare event.

Figure 2.18 Blood-tissue junction in a capillary, venule, and sinusoid. (Left) Sinusoids, lined with macrophages of the reticuloendothelial system, as found in the adrenal glands, liver, spleen, and bone marrow. (Center) Fenestrated endothelium found in the choroid plexus, villi of the intestine, renal glomerulus, pancreas, and endocrine glands. (Right) Continuous endothelium and basement membrane found in the central nervous system, connective tissue, skeletal and cardiac muscle, skin, and lungs. Adapted from Mims CA et al. 1995. Mims’ Pathogenesis of Infectious Disease (Academic Press, Orlando, FL).

Figure 2.19 How viruses gain access to the liver. Two layers of hepatocytes are shown, with the sinusoid at the center, lined with kupffer cells. On the left, transcytosis through the kupffer cells is shown; on the right, direct kupffer cell infection is illustrated, followed by infection of underlying hepatocytes. Viruses not taken up by either route will flow through. Adapted from Mims CA et al. 1995. Mims’ Pathogenesis of Infectious Disease (Academic Press, Orlando, FL).

Organs with Dense Basement Membranes

In the central nervous system, connective tissue, and skeletal and cardiac