from tissue to tissue means that the immune response is continually playing catch-up: as infection is controlled in the liver, infection of the skin appears. Furthermore, while mice of a certain strain can control the infection and survive, mice of a different strain may not, underscoring the critical involvement of more subtle genetic regulators of immune control.
Just as ectromelia advances through various permissive tissues of the host, the host defenses are deployed in a coordinated, stepwise manner (Fig. 2.2). All surfaces of the mammalian body where pathogens may enter are protected by defensive layers provided by fur, skin, and mucus, or are acidic environments. Once these barriers are crossed and cells become infected, intrinsic cellular defenses including cell-autonomous responses, such as autophagy and cell suicide, are engaged. Because the virus may reproduce faster than an infected cell can control it, the “professional” immune response is also induced, beginning with the early innate response (Chapter 3). Eventually, virus-specific cells of the adaptive response arrive at the site of infection, targeting infected cells and extracellular virus particles for destruction or elimination (Chapter 4).
While this text generally avoids imparting actions to viruses, the impression one may have gained from the ectromelia virus example is that viruses are on a seemingly preordained, step-by-step path to gain access to their target cells of choice (for example, hepatitis viruses in hepatocytes, measles virus in epithelia, or human immunodeficiency virus type 1 in CD4+ T cells). Likewise, one might think that the immune response is deployed in a synchronized and choreographed manner, much like actors performing a play night after night. These impressions would be wrong. As every game of chess is constrained by the same rules, but each game differs in execution and outcome, so too are viral infections and host immunity influenced by random, or stochastic, events. For example, tissues and the immune system may impose bottlenecks on the dissemination of a virus population. The diversity of viral populations enables some particles to pass through the bottleneck, while others are lost as the virus spreads (Chapter 10). Such bottlenecks include not only access to tissues but also immune restriction (Fig. 2.3). The stochastic view does not reject the idea that infections generally follow a predictable course, but rather adds random elements to the consequences of each step that could affect the speed of viral transmission throughout the host, the immunological control of the virus, or the magnitude of illness experienced by the infected host.
Figure 2.1 Ectromelia virus infection of mice. Infection begins with a break in the skin, allowing the virus to access susceptible and permissive cells, with ensuing local viral reproduction and dissemination via the lymphatics within 1 to 2 days of exposure. Experimentally, virus can be injected into the footpad. Primary viremia occurs when the virus is released into the bloodstream, permitting infection of the spleen, liver, and other organs, greatly amplifying the number of viral particles within the host. Secondary viremia occurs as a consequence of release of virus from these organs, resulting in infection of distal sites of the skin. In certain inbred strains, as well as in wild mice, a severe rash may develop. Adapted from Fenner F et al. 1974. The Biology of Animal Viruses (Academic Press, New York, NY), with permission.
Initiating an Infection
Three requirements must be met to ensure successful infection of an individual host: a sufficient number of infectious virus particles must be available to initiate infection; the cells at the site of infection must be physically accessible to the virus, susceptible (bear receptors for entry),and permissive (contain intracellular gene products needed for viral reproduction);and local antiviral defenses must be absent or, at least initially, quiescent.
The first requirement imposes a substantial barrier to any infection and represents a significant limitation in the transmission of virus from host to host. Free virus particles face both a harsh environment and rapid dilution that can reduce their concentration. To remain infectious, viruses that are spread in contaminated water and sewage must remain stable in the presence of osmotic shock, pH changes, and sunlight. Aerosol-dispersed virus particles must remain hydrated and sufficiently concentrated to infect the next host. These requirements account for why respiratory viruses spread most successfully in populations in which individuals are in close contact and in which the time that a virus particle is outside of a host is minimized. In contrast, viruses that are spread by biting insects, contact with mucosal surfaces, or other means of direct contact, including contaminated needles, have little or no environmental exposure; the virus is transmitted directly, for example, from mosquito to human.
Even after transmission from one host to another, infection may fail simply because the concentration of infectious virus particles is too low. For example, in principle, a single West Nile virion delivered by an infected mosquito should be able to initiate an infection, but host physical and immune defenses, coupled with the complexity of the infection process itself, usually require the presence of many infectious particles for an infection to begin. In the case of West Nile virus, the inoculum may not gain access to the bloodstream, or blood-borne proteins may degrade or otherwise prevent infection of target cells. One can envision many paths to failure: the virus particle may adhere to a dead or dying cell, become attached to nonsusceptible cells by nonspecific protein-protein interactions, be swept away in the bloodstream, get stuck in mucus, or be degraded within a lysosome upon entry into a target cell.
In addition, populations of viruses often contain defective particles that are not capable of completing an infectious cycle. Such particles can be produced by incorporation of errors during virus genome replication or by interactions with inhibitory compounds in the environment. The ratio of infectious to defective virus particles in a preparation can be calculated by dividing the number of infectious particles (de fined using a plaque assay; Volume I, Chapter 2) by the total number of particles in a sample. Total particles, infectious and noninfectious, are classically determined using electron microscopy, although less arduous and equally quantitative strategies now exist. Some viruses, such as many bacteriophages, have a very low ratio (that is, virtually all particles are infectious), while other particle-to-PFU ratios, including those for poliovirus and some papillomaviruses, approach 1,000 or 10,000, respectively. Why these ratios differ so radically is not known, but the main point should be clear: not every virus particle that binds to a susceptible and permissive cell can induce all the steps needed to produce progeny virus particles, and even those that can may be thwarted at any step of the viral reproductive cycle.
Figure 2.2 The coordinated host response to infection. In healthy individuals, anatomical and chemical barriers are in place to prevent or repel infection by microbes. When viruses successfully bypass these defenses, intrinsic responses are engaged. These responses already exist in the infected cell, poised to respond without the need for new transcription or translation. Within hours following exposure, cellular components of the innate immune response, including professional antigen-presenting cells, neutrophils, and natural killer cells, migrate to the site of infection. These infiltrating cells, as well as the infected cells themselves, produce soluble proteins (chemokines and cytokines) that serve as beacons for the eventual recruitment of T and B cells. CRISPRs, clustered regularly interspaced short palindromic repeats.
