rel="nofollow" href="#ulink_f48c1ab1-934f-5a98-ae8e-829bf49492d6">Figure 2.3 Infection seen as a series of bottlenecks. In the illustrated case, the viral population enters the host as a diverse quasispecies with sufficient titer to establish infection. After entry, the population may encounter a host barrier (bottleneck) that limits diversity. Individual members within this population (red/yellow) may overcome this bottle neck, reproducing and restoring diversity. As a result, the subsequent viral population in a given tissue may have high diversity but differ in overall consensus sequence from the initial infecting population. Note, for example, the emergence of “new” blue and green viruses not found in the original population. Certain tissues that do not impose such bottle necks may be highly permissive for viral infection (e.g., Tissue 3).
Successful Infections Must Modulate or Bypass Host Defenses
In most mammals, common sites of virus entry include the mucosal linings of the respiratory, alimentary, and urogenital tracts; the outer surfaces of the eyes (conjunctival membranes or cornea); and the skin (Fig. 2.4). Each of these portals is equipped with anatomical or chemical features that limit viral entry and infection.
Skin
The skin is the largest organ of the body, weighing more than 9 kg (20 pounds) in an average adult. It serves obvious protective functions, but is also required for thermoregulation, control of hydration and evaporation, and integration of sensory information. The external surface of the skin, or epidermis, is composed of several layers, including a basal germinal layer of proliferating cells, a granular layer of dying cells, and an outer layer of dead, keratinized cells (Fig. 2.5). This outermost layer is a rather literal coat of armor against viral infection: many virus particles that land on intact skin are inactivated by dehydration, acids, or other inhibitors secreted by commensal microorganisms. Some virus particles are removed from the body when dead cells slough of; many others are washed away by soap and water. However, when the integrity of the dead cell layer is compromised by cuts, abrasions, or punctures (e.g., insect bites and needle sticks), virus particles can access the rich array of live cells beneath the keratinized layer, including epithelial cells, endothelial cells, neuronal processes, and capillaries.
Examples of viruses that can gain entry via the skin include some human papillomaviruses, certain poxviruses (e.g., myxoma virus), and all tick- or mosquito-borne viruses that are transmitted by arthropod injection below the dead cell layer. Even deeper inoculation into the tissue below the dermis can occur by hypodermic needle punctures, body piercing, tattooing, or sexual contact when body fluids are mingled as a result of skin abrasions or ulcerations. Viruses that can gain entry in this manner include hepatitis B and C, human immunodeficiency virus type 1, and the herpesviruses Epstein-Barr virus and cytomegalovirus. Finally, rabies virus can be transmitted by animal bites that penetrate deep into tissue and muscle that are rich with nerve endings. Access to nerve terminals provides an opportunity for infection of motor neurons that ultimately leads to the nerve damage often associated with rabies virus infection. Superficial infections in the epidermis typically remain focalized (e.g., papillomaviruses that cause warts), whereas deeper penetration of viruses in dermal or subdermal tissues can reach nearby blood vessels, lymphatics, and neurons, conduits that enable systemic transmission (Box 2.2).
Figure 2.4 Sites of viral entry into the host. The body is covered with skin, which has a relatively impermeable (dead) outer layer of keratinocytes covering a layer of live epithelial cells rich in capillaries. Breaches in the integrity of the skin may allow viruses (or other microbes) access to this rich source of living cells. Moreover, other portals in the host, present to absorb food or release waste (mouth, urogenital tract, anus), exchange gases (respiratory tract), or interact with the environment (eyes), can also be entry points to allow access of viruses to host tissues.
The body’s response to a breach in the critical barrier formed by the skin is to make rapidly a hard, water-resistant shell over the wound, called a scab. Scabs are more than just the dermis below the site of injury drying and hardening; neutrophils and macrophages are recruited in large numbers to a wound, primarily to engulf bacteria and other pathogens that may benefit from this breach in the skin to infect the host. In addition, macrophages further aid the healing process by producing growth factors that promote cell proliferation. As the air dries the wound area, these formerly useful immune cells become part of the scab as well.
Figure 2.5 Schematic diagram of the skin. The epidermis consists of a layer of dead, keratinized cells over the live epidermal cells. Below this is the basement membrane (basal lamina). Below the basement membrane lies the dermis, which contains blood vessels, lymphatic vessels, fibroblasts, nerve endings, and macrophages. The potential depth reached by the proboscis of a mosquito taking a blood meal is shown. For more on how mosquitos spread viruses, see https://youtu.be/7wsk8a3ze80.
Respiratory Tract
Surfaces exposed to the environment but not covered by skin are lined by living cells and are at risk for infection despite the continuous actions of self-cleansing mechanisms. The most common route of viral entry is through the respiratory tract. In a human lung, there are about 300 million terminal sacs, called alveoli, which function in gaseous exchange between inspired air and the blood. Each sac is in close contact with capillary and lymphatic vessels. The combined surface area of the human lungs is ∼180 m2, approximately the size of a tennis court! At rest, humans inspire ∼6 liters of air per minute. Together, the impressive surface area and large volumes of “miasma” that one inhales each minute imply that foreign particles, such as bacteria, allergens, and viruses, are likely introduced into the lungs with every breath.
Mechanical barriers play a significant role in antiviral defense in the respiratory tract. The tract is lined with a mucociliary blanket consisting of ciliated cells, mucus-secreting goblet cells, and subepithelial mucus-secreting glands (Fig. 2.6). Foreign particles deposited in the nasal cavity or upper respiratory tract are often trapped in mucus, carried to the back of the throat, swallowed, and destroyed in the low-pH environment of the gut (Box 2.3). In the lower respiratory tract, particles trapped in mucus are brought up from the lungs to the throat by ciliary action (Fig. 2.7). Cold temperatures, cigarette smoke, and low humidity cause the cilia to stop functioning effectively, likely accounting for the association of these environmental conditions with increased incidence of respiratory tract infections. When coughing occurs, both the host and the virus benefit; the host expels virus-laden mucus with each productive cough, and the virus is carried out of the host, perhaps to infect another nearby. The lowest portions of the tract, the alveoli, lack cilia or mucus, but macro phages lining the alveoli ingest and destroy virus particles.
EXPERIMENTS
Dermal damage increases immunity and host survival
When
