Exposure to pathogens occurs via different routes. The human skin itself has a surface area of some 20 square feet; the epithelial surfaces that line the airways, gastrointestinal tract, and genital tract present an even more formidable surface area of about 4000 square feet. All these surfaces are exposed on a daily basis to viruses and bacteria in the environment. Some of these bacteria, called commensal bacteria, do not usually cause disease and in fact can be beneficial, helping to provide key nutrients or to maintain healthy skin. It is thought that at any point in time, an adult human may be carrying as much as 3 pounds of microbes, against which most of us do not develop an overt inflammatory reaction. These commensal microbes are not pathogenic as long as they remain on these outer surfaces of the body. If the normal barrier function of the epithelia that compose these surfaces is compromised, however, and these microbes enter the body, they can be pathogenic. Food-borne pathogens and sexually transmitted agents target the epithelia to which they are exposed. The sneeze of a flu-infected individual releases millions of virus particles in aerosolized form, ready for inhalation by a new host. Rupture of the skin, even if only by minor abrasions, or of the epithelial barriers that protect the underlying tissues provides an easy route of entry for pathogens, which then gain access to a rich source of nutrients (for bacteria) and to the cells required for replication (for viruses).

Replication of viruses is confined strictly to the cytoplasm or nuclei of host cells, where viral protein synthesis and replication of the viral genetic material occur. Viruses can then spread to other cells either as free virus particles (virions) released from the initially infected cell or by direct transfer to an adjacent cell (cell-to-cell spreading). Many bacteria can replicate in the extracellular spaces of the body, but some are specialized to invade host cells and survive and reproduce within those cells. Such intracellular bacteria reside either in the membrane-delimited vesicles through which they enter cells by endocytosis or phagocytosis (see Figure 17-19) or in the cytoplasm if they escape from these vesicles. An effective host defense system, therefore, needs to be capable of eliminating not only extracellular viruses and bacteria, but also host cells that harbor these pathogens.

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Parasitic eukaryotes can also cause disease. Some of these parasites, such as the protozoans that cause sleeping sickness (trypanosomes) or malaria (Plasmodium species), have very complex life cycles and have evolved complex countermeasures to avoid destruction by the host’s immune system.