Spread by the Bloodstream Viremia

The blood is the most effective and rapid vehicle for the spread of Vitus through the body. Once a virus has reached the bloodstream, usually via the lymphatic system (Fig. 6-3), it can localize in any part of the body within minutes. The first entry of virus into the blood is called primary virnura. This early viremia may be clinically silent, known to have taken place only because of the invasion of distant organs. Further replication in these sites leads to the sustained liberation of much higher concentrations of virus, producing a s re-

ondary viremia (Fig. 6-4), which can in turn lead to the establishment of infection in yet other parts of the body

In the blood, virions may be free in the plasma or may be associated with leukocytes, platelets, or erythrocytes. Viruses carried in leukocytes, generally lymphocytes or monocytes, are not cleared as readily or in the same way as viruses circulating free in the plasma; being protected from antibodies and other plasma components they can be carried to distant tissues Monocyte-associaled viremia is a feature of measles and many herpesvirus infections, for example. Rarely, as in Rift Valley fever and Colorado tick fever, virions may be associated with erythrocytes. Certain mouse leukemia viruses infect megakaryocytes; the circulating platelets derived from them are infected but do not appear to be important in the pathogenesis of viral infections. Neutrophils have a very short life span and powerful antimicrobial mechanisms; they are rarely infected, although they may contain phagocytosed virions. Hepadnaviruses, togaviruses, flaviviruses, and the enteroviruses that cause viremia circulate free in the plasma.

Virions circulating in the plasma encounter many kinds of cells, but two kinds play a special role in determining their subsequent fate: macrophages and vascular endothelial cells.

Role of Macrophages

Macrophages are very efficient phagocytes and are present in all compartments of the body, in alveoli, subepithelial tissues, sinusoids of the lymph nodes, free in plasma, and above all in the sinusoids of the liver, spleen, and bone marrow Together with dendritic cells and B lymphocytes, macrophages are antigen-processing and antigen-presenting cells and therefore play a pivotal role in initiation ol the primary immune response (see Chapter 8). The antiviral action of macrophages depends on the age and genetics of the host and the site of their origin in the body; indeed, even in a given site there are subpopulations of macrophages that differ in susceptibility. Their state of activation is also important. The kinds of interactions that may occur between macrophages and virions are described in relation to those found in the sinusoids of the liver, the Kupffer cells, in Fig. 6-5.

Differences in virus-macrophage interactions may account for differences in the virulence of virus strains and differences in host resistance. Already efficient phagocytes, macrophages have Fc receptors and C3 receptors in their plasma membrane, which enhance their ability to ingest virions when these are coated with antibody or complement. If macrophages are susceptible, however, as with dengue viruses, (.his can lead to infection rather than inac-livation, and the antibody may enhance rather than prevent infection.

Role of Vascular Endothelial Cells

The vascular endothelium with its basement membrane and tight cell junctions constitutes the blood-tissue interface, and for particles such as virions often a barrier. Parenchymal invasion by circulating virions depends on localization in the endothelial cells of capillaries and venules, where blood flow is slowest and the barrier is thinnest. Virions may move passively between or through endothelial cells and basement membrane, or they may inlect endothelial cells and "grow" through this barrier. This subject has been most intensively studied in relation to viral invasion of the central nervous

Na^al arid oraf mucous membranes

Hepatitis Virus Spreading Organism

Fig. 6-4 Spread of virions through the body in human viral infections, indicating sites of replication and important routes of shedding of various viruses (Modified from C A MimsandD O White, "Viral Pathogenesis and Immunology " Blackweil, Oxford, 1984 )

Na^al arid oraf mucous membranes

Fig. 6-4 Spread of virions through the body in human viral infections, indicating sites of replication and important routes of shedding of various viruses (Modified from C A MimsandD O White, "Viral Pathogenesis and Immunology " Blackweil, Oxford, 1984 )

system (see below), but it also applies to secondary invasion of the skin, pulmonary epithelium, salivary gland epithelium, intestinal epithelium, kidney, and placenta.

Maintenance of Viremia

Neurotropic viruses reach the central nervous system only when the viremia is of adequate magnitude and duration, something that is also a prerequisite if blood-sucking arthropods are to be infected. Because virions circulat-

Fig. 6-5 Types of interactions between viruses and macrophages, exemplified by the Kupffer cells lining a sinusoid in the liver (1) Macrophages may fail to phagocy lose virions, for example, in Venezuelan equine encephalitis virus infection this is an important factor favoring piolonged viremia (2) Virions may be phagocytosed and destroyed. Because the macrophage system is so efficient, viremia with such viruses can be maintained only if virions entei the blood as fast as they are removed. (3) Virions may be phagocytosed and (hen passively transferred to adjacent cells (hepatocytes in (he liver) If, like Rift Valley fever or hepatitis B viruses, the virus replicates in these cells it can cause clinical hepatitis, and the virus produced m the liver can produce a high level of viremia (4) Virions may be phagocylosed by macrophages and (hen replicate in them With some viruses, such as lactate dehydrogenase virus in mice, only macrophages are infected (4A), and progeny virions enhance the viremia, which reaches an extremely high level More commonly (4U), as in yellow fever, virus replicates in both macrophages and hepatic cells, producing severe hepatitis, (Modified from C A Minis and O O White, "Viral Pathogenesis and Immunology." Blackwell, Oxford, 1984 )

Fig. 6-5 Types of interactions between viruses and macrophages, exemplified by the Kupffer cells lining a sinusoid in the liver (1) Macrophages may fail to phagocy lose virions, for example, in Venezuelan equine encephalitis virus infection this is an important factor favoring piolonged viremia (2) Virions may be phagocytosed and destroyed. Because the macrophage system is so efficient, viremia with such viruses can be maintained only if virions entei the blood as fast as they are removed. (3) Virions may be phagocytosed and (hen passively transferred to adjacent cells (hepatocytes in (he liver) If, like Rift Valley fever or hepatitis B viruses, the virus replicates in these cells it can cause clinical hepatitis, and the virus produced m the liver can produce a high level of viremia (4) Virions may be phagocylosed by macrophages and (hen replicate in them With some viruses, such as lactate dehydrogenase virus in mice, only macrophages are infected (4A), and progeny virions enhance the viremia, which reaches an extremely high level More commonly (4U), as in yellow fever, virus replicates in both macrophages and hepatic cells, producing severe hepatitis, (Modified from C A Minis and O O White, "Viral Pathogenesis and Immunology." Blackwell, Oxford, 1984 )

ing in the blood are continuously removed by macrophages, viremia can be maintained only il there is a continuing introduction of virus into the blood from infected tissues, or if there is impairment of the macrophages Circulating leukocytes can themselves constitute a site for viral replication, but viremia is usually maintained by infection of the parenchymal cells of organs like the liver, spleen, lymph nodes, and bone marrow. In some infections the viremia is partly maintained by infection of endothelial cells. Striated and smooth muscle cells may be an important site of replication of some enteroviruses, togaviruses, and rhabdoviruses; virions are transferred to the blood via the lymph.

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