Principles of Virology, Volume 2. S. Jane Flint
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many of these “anti-host response” strategies (Box 2.1) are aimed at the body’s first line of protection: the physical barriers to infection.
For comments and a personal account related to the chapter topic, see the interview with Dr. Neal Nathanson: http://bit.ly/Virology_Nathanson.
An Overview of Infection and Immunity
A Game of Chess Played by Masters
Infection by viruses is often described in terms associated with warfare. There are opposing forces, each equipped with weapons to defeat the other. Once the battle ensues, each side fights with maxi mum force until a victor emerges. A more fitting metaphor to define the events pursuant to a viral infection would be a game of chess played by two masters. For each action, there follows a counter action. Powerful tactics, such as induction of the adaptive immune response, may take many “moves” to be put into action . As one thinks about infection and immunity, it is imperative to bear in mind that we have coevolved with many of the viruses that infect us today. Such coevolution implies that, at a population level, both host and virus will survive. On an individual level, however, the consequence of infection is dictated by the host species and immune fitness, the dose and strain of virus, and numerous environmental parameters (Chapter 1).
The pathogenesis of ectromelia virus, the agent of mousepox, highlights how the outcome of infection is affected by some of these variables (Fig. 2.1). Ectromelia virus is shed in the feces of its natural mouse host and gains access to naïve mice via small abrasions in the footpad. Therefore, the first hurdle to be overcome is penetration of dead skin, which serves as an inhospitable barrier against infection. There is no guarantee that a mouse in a cage with infected feces will become infected. Virus particles must come in physical contact with permissive and susceptible cells for infection to occur, necessitating some disruption of the skin to allow access of the virus to live cells. Once the virus has gained entry, local reproduction in the epidermis and dermis of the footpad takes place. Within a day after exposure, the virus moves to draining lymph nodes, enters the bloodstream, and can be found in the spleen and liver by 3 days after infection. Thereafter, the virus continues to spread throughout the host, causing massive inflammation and severe skin lesions by 10 to 11 days after exposure.
PRINCIPLES Barriers to infection
Three requirements must be met to ensure successful infection of an individual host: a sufficient number of infectious virus particles, access of these particles to susceptible and permissive cells, and uneducated or dampened local antiviral defenses.
Common sites of virus entry include the respiratory, alimentary, and urogenital tracts; the outer surface of the eyes (conjunctival membranes or cornea); and the skin.
Each of these portals is equipped with anatomical or chemical features that limit viral entry and infection.
Spread beyond the site of infection depends on the initial viral dose, the presence of viral receptors on other cells, and the relative rates of immune induction and release of infectious virus particles.
Disseminated infections typically occur through the bloodstream, although some viruses can be transported by the peripheral nervous system.
Effective transmission of virus particles from one host to another depends on the site of shedding and the concentration of released particles.
Viral transmission to a new host usually occurs through body fluids, including respiratory aerosols and secretions, blood, saliva, semen, urine, and milk.
TERMINOLOGY
Is it evasion or modulation?
From the online Merriam-Webster Dictionary:
Evade: to elude by dexterity
Modulate: to adjust to or keep in proper measure or proportion
The phrase “immune evasion” pervades the virology literature. It is intended to describe the viral mechanisms that thwart host immune defense systems. However, this phrase is imprecise and even misleading. The term “evasion” implies that host defenses are ineffective, similar to a bank robber evading capture by a hapless police force. In reality, a virus does not necessarily need to be invisible to the host response throughout its reproduction cycle; it simply must delay or defer detection for a time sufficient to produce progeny virus particles. If viruses really could evade the immune system, we might not be here discussing such semantic issues.
Perhaps a more accurate term to describe viral gene products that delay or frustrate host defenses is “immune modulators.” The principle is that, given the speed of viral reproduction, an infection can be successful even if host defenses are suppressed only transiently or partially.
From the moment of ectromelia virus entry, the host mounts a response to counteract the virus. The impact of such countermeasures is revealed by the effects of specific immune deficiencies, which lead to different kinds of disease. If the mouse lacks CD8+ T lymphocytes, a major immune cell population critical for destroying virus-infected cells, it will die of extensive liver destruction by 4 to 5 days after infection. If instead the host lacks the potent antiviral cytokine interferon gamma, the virus may be controlled in the liver, even though death will occur by 10 to 12 days after infection as a consequence of uncontrolled viral reproduction in the skin. Even in mice with intact immune responses, viral movement 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