Principles of Virology, Volume 2. S. Jane Flint

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.

BOX 2.2

      EXPERIMENTS

       Dermal damage increases immunity and host survival

      When it was still in use, the smallpox vaccine was delivered by a bifurcated (two-pronged) needle in a process referred to as scarification. Vaccination resulted in local damage to the skin and a subsequent (though quickly re solved) lesion in most individuals that often left a lifelong scar. Until recently, it was not appreciated that the scarification process itself was an important component of the vaccine’s efficacy. Experiments using the smallpox-related virus vaccinia virus showed that intra dermal inoculation of the virus into rabbits resulted in lethal disease by 8 days after infection, whereas delivery by scarification led to a protective host response and animal survival. Scarified rabbits also responded immunologically earlier than those inoculated by the intradermal route. Moreover, scarification in the absence of virus, followed immediately by a same-site intradermal challenge with virus, resulted in significant protection to the infected rabbits. This dramatic difference can be attributed to the rapid induction of a nonspecific host response caused by the scarification wound itself. Scarification damages skin cells and the underlying epidermis, inducing the release of cytokines and chemokines that help direct the host’s immune response to the site of infection and restrict the dissemination of the virus throughout the host.

       Rice AD, Adams MM, Lindsey SF, Swetnam DM, Manning BR, Smith AJ, Burrage AM, Wallace G, MacNeill AL, Moyer RW. 2014. Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. J Virol 88:7753–7763.

Figure 2.6 Sites of viral entry in the respiratory tract. (Left) A detailed view of the respiratory epithelium. A layer of mucus, produced by goblet cells, is a formidable barrier to virus particle attachment. Virus particles that traverse this layer may reproduce in ciliated cells or pass between them, reaching another