and the infected animals suffer higher morbidity and mortality.
When spread occurs by neural pathways, innervation at the primary site of inoculation determines which neuronal circuits will be infected. The only areas in the brain or spinal cord that are targets for herpes simplex virus infection are those that contain neurons with axon terminals or dendrites connected to common sites of inoculation in the body. Reactivated herpes simplex virus uses the same neural circuits to return to those sites, where it causes lesions (for example, cold sores in the mouth).
Figure 2.12 Polarized release of viruses from cultured epithelial cells visualized by electron microscopy. (A) Influenza virus released by budding from the apical surface of canine kidney cells. (B) Budding of measles virus on the apical surface of human colon carcinoma cells. (C) Release of vesicular stomatitis virus at the basal surface of canine kidney cells. Arrows indicate virus particles. Magnification, ×324,000. Reprinted from Blau DM, Compans RW. 1996. Semin Virol 7:245–253, with permission. Courtesy of D. M. Blau and R. W. Compans, Emory University School of Medicine, Atlanta, GA.
The blood and neurons are the primary conduits for viruses to gain access to tissues distal to the site of the inoculation, and are discussed in greater detail below.
Hematogenous Spread
Disseminated infections typically occur by transport through the bloodstream (hematogenous spread). Entry may occur through broken blood vessels (human immunodeficiency virus type 1), through direct inoculation (for example, from the proboscis of an infected arthropod vector, a dirty needle, or the bite of a dog, as in West Nile virus, hepatitis C virus, and rabies virus, respectively), or by basolateral release of virus particles from infected capillary endothelial cells. Because every mammalian tissue is nourished by a web of blood vessels, virus particles in the blood have access to all host organs (Fig. 2.13).
Hematogenous spread begins when newly synthesized particles produced at the entry site are released into extracellular fluids and are taken up by the local lymphatic vascular system (Fig. 2.14). Lymphatic capillaries are considerably more permeable than those of the circulatory system, facilitating virus entry. Moreover, as lymphatic vessels ultimately drain into the circulatory system, virus particles in lymph have eventual, free access to the bloodstream. Because the lymphatic system and circulatory system “meet” in lymph nodes, and because nodes are home to lymphocytes and monocytes, some viruses, such as human immunodeficiency virus type 1, replicate extensively in these cells.
Figure 2.13 Entry, dissemination, and shedding of blood-borne viruses. Shown are the target organs for some viruses that enter at epithelial surfaces and spread via the blood. The sites of virus shedding (red arrows), which may lead to transmission to other hosts, are also shown.
Figure 2.14 The lymphatic system. Lymphocytes flow from the blood into the lymph node through postcapillary venules. Green indicates lymphatics; red indicates the bloodstream. Adapted from Mims CA et al. 1995. Mims' Pathogenesis of Infectious Disease (Academic Press, Orlando, FL), with permission.
The migratory nature of many immune cells allows viruses that infect these cells to move quickly and clandestinely throughout the host. Because viral components are inside a cell during transport, they are effectively shielded from antibody recognition. Traversing the blood-brain barrier poses a particular challenge for a free virion, as the capillaries that make up this unique barrier limit the access of serum molecules to the brain. However, activated macrophages can pass through, freely de livering viruses such as measles, some enteroviruses, and chikungunya virus into the brain tissue. This process is often referred to as the Trojan Horse approach, because of its similarity to the legend of how the Greeks invaded and captured the protected fortress of Troy. In this legend, the Greeks built a large wooden horse that was disguised as a victory trophy, but instead, many Greek soldiers hid within the hollow horse. Once the “gif horse” was safely inside the city walls, the soldiers emerged and quickly achieved victory.
The term viremia describes the presence of infectious virus particles in the blood. Active viremia is a consequence of reproduction in the host, whereas passive viremia results when particles are introduced into the blood without viral reproduction at the site of entry (as when an infected mosquito inoculates a susceptible host with West Nile virus). The release of progeny virus particles into the blood after initial reproduction at the site of entry constitutes the primary viremia phase. The concentration of particles during this early stage of infection is usually low. However, subsequent dissemination of the virus to other sites results in the release of considerably more virus particles. The delayed accumulation of a high concentration of infectious virus in the blood is termed secondary viremia (Fig. 2.15). The two phases of viremia were first described in classic studies of mousepox (Fig. 2.1).
Figure 2.15 Generic characteristics of viremia. Passive viremia occurs when the host is the recipient of infectious virus from an exogenous source (e.g., an infected mosquito). Soon thereafter, a modest primary viremia can occur as a result of virus reproduction at the site of entry. Virus then can be detected in blood, perfusing tissues such as muscle, spleen, and blood vessels. Following reproduction in these sites, a much more robust infection can be detected in the blood, which then can lead to infection of susceptible cells in other organs. Adapted from Nathanson N (ed). 2007. Viral Pathogenesis and Immunity (Academic Press, London, United Kingdom), with permission.
The concentration of virus particles in blood is determined by the rate of their synthesis in permissive tissues and by how quickly they are released into, and removed from, the blood. Circulating particles are engulfed and destroyed by phagocytic cells of the reticuloendothelial system in the liver, lungs, spleen, and lymph nodes. When serum antibodies appear, virus particles in the blood may be bound by them and neutralized (Chapter 4). Formation of a complex of antibodies and virus particles facilitates uptake by Fc receptors carried by macrophages lining the circulatory vessels. These virus-antibody complexes can be sequestered in significant quantities in the kidneys, spleen, and liver, prior to elimination from the host via urine or feces. On average, individual virus particles may remain in the blood from 1 to 60 min, depending on parameters such as the physiology of the host (e.g., age and health) and the size and structural integrity of the virus particles. Some viral infections are noteworthy for the long-lasting presence of infectious particles in the blood. Humans infected with hepatitis B and C viruses or mice infected with lymphocytic choriomeningitis virus may have active viremia that persists for months to years. In some cases, movement to the kidney and liver is aided by engagement of virus particles by scavenger receptors found on circulating and resident macrophages. Such receptors bind to common ligands on pathogens, such as lipoproteins, apoptosing cells, cholesterol, and carbohydrates, removing them from the blood. For example, the resident macrophages of the liver, kupffer cells, express
