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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.
Infectious disease can be devastating, and sometimes fatal, to the host. In this part of the chapter we will briefly examine the stages of infection, and the various types of infectious agents.
The process of infection can be broken down into stages, each of which can be blocked by different defense mechanisms. In the first stage, a new host is exposed to infectious particles shed by an infected individual. The number, route, mode of transmission, and stability of an infectious agent outside the host determines its infectivity. Some pathogens, such as anthrax, are spread by spores that are highly resistant to heat and drying, while others, such as the human immunodeficiency virus (HIV), are spread only by the exchange of bodily fluids or tissues because they are unable to survive as infectious agents outside the body.
The first contact with a new host occurs through an epithelial surface. This may be the skin or the internal mucosal surfaces of the respiratory, gastro-intestinal, and urogenital tracts. After making contact, an infectious agent must establish a focus of infection. This involves adhering to the epithelial surface, and then colonizing it, or penetrating it to replicate in the tissues (Fig. 10.2, left-hand panels). Many microorganisms are repelled at this stage by innate immunity. We have discussed the innate immune defense mediated by epithelia and by phagocytes and complement in the underlying tissues in Chapter 2. Chapter 2 also discusses how NK cells are activated in response to intracellular infections, and how a local inflammatory response and induced cytokines and chemokines can bring more effector cells and molecules to the site of an infection while preventing pathogen spread into the blood. These innate immune responses use a variety of germline-encoded receptors to discriminate between microbial and host cell surfaces, or infected and normal cells. They are not as effective as adaptive immune responses, which can afford to be more powerful on account of their antigen specificity. However, they can prevent an infection being established, or failing that, contain it while an adaptive immune response develops.
Infections and the responses to them can be divided into a series of stages. These are illustrated here for an infectious microorganism entering across an epithelium, the commonest route of entry. The infectious organism must first adhere to epithelial (more. )
Only when a microorganism has successfully established a site of infection in the host does disease occur, and little damage will be caused unless the agent is able to spread from the original site of infection or can secrete toxins that can spread to other parts of the body. Extracellular pathogens spread by direct extension of the focus of infection through the lymphatics or the bloodstream. Usually, spread by the bloodstream occurs only after the lymphatic system has been overwhelmed by the burden of infectious agent. Obligate intracellular pathogens must spread from cell to cell; they do so either by direct transmission from one cell to the next or by release into the extracellular fluid and reinfection of both adjacent and distant cells. Many common food poisoning organisms cause pathology without spreading into the tissues. They establish a site of infection on the epithelial surface in the lumen of the gut and cause no direct pathology themselves, but they secrete toxins that cause damage either in situ or after crossing the epithelial barrier and entering the circulation.
Most infectious agents show a significant degree of host specificity, causing disease only in one or a few related species. What determines host specificity for every agent is not known, but the requirement for attachment to a particular cell-surface molecule is one critical factor. As other interactions with host cells are also commonly needed to support replication, most pathogens have a limited host range. The molecular mechanisms of host specificity comprise an area of research known as molecular pathogenesis, which falls outside the scope of this book.
While most microorganisms are repelled by innate host defenses, an initial infection, once established, generally leads to perceptible disease followed by an effective host adaptive immune response. This is initiated in the local lymphoid tissue, in response to antigens presented by dendritic cells activated during the course of the innate immune response (Fig. 10.2, third and fourth panels). Antigen-specific effector T cells and antibody-secreting B cells are generated by clonal expansion and differentiation over the course of several days, during which time the induced responses of innate immunity continue to function. Eventually, antigen-specific T cells and then antibodies are released into the blood and recruited to the site of infection (Fig. 10.2, last panel). A cure involves the clearance of extracellular infectious particles by antibodies and the clearance of intracellular residues of infection through the actions of effector T cells.
After many types of infection there is little or no residual pathology following an effective primary response. In some cases, however, the infection or the response to it causes significant tissue damage. In other cases, such as infection with cytomegalovirus or Mycobacterium tuberculosis, the infection is contained but not eliminated and can persist in a latent form. If the adaptive immune response is later weakened, as it is in acquired immune deficiency syndrome (AIDS), these diseases reappear as virulent systemic infections. We will focus on the strategies used by certain pathogens to evade or subvert adaptive immunity and thereby establish a persistent infection in the first part of Chapter 11.
In addition to clearing the infectious agent, an effective adaptive immune response prevents reinfection. For some infectious agents, this protection is essentially absolute, while for others infection is reduced or attenuated upon reexposure.
The agents that cause disease fall into five groups: viruses, bacteria, fungi, protozoa, and helminths (worms). Protozoa and worms are usually grouped together as parasites, and are the subject of the discipline of parasitology, whereas viruses, bacteria, and fungi are the subject of microbiology. In Fig. 10.3, the classes of microorganisms and parasites that cause disease are listed, with typical examples of each. The remarkable variety of these pathogens has caused the natural selection of two crucial features of adaptive immunity. First, the advantage of being able to recognize a wide range of different pathogens has driven the development of receptors on B and T cells of equal or greater diversity. Second, the distinct habitats and life cycles of pathogens have to be countered by a range of distinct effector mechanisms. The characteristic features of each pathogen are its mode of transmission, its mechanism of replication, its pathogenesis or the means by which it causes disease, and the response it elicits. We will focus here on the immune responses to these pathogens.
A variety of microorganisms can cause disease. Pathogenic organisms are of five main types: viruses, bacteria, fungi, protozoa, and worms. Some common pathogens in each group are listed in the column on the right.
Infectious agents can grow in various body compartments, as shown schematically in Fig. 10.4. We have already seen that two major compartments can be defined—intracellular and extracellular. Intracellular pathogens must invade host cells in order to replicate, and so must either be prevented from entering cells or be detected and eliminated once they have done so. Such pathogens can be subdivided further into those that replicate freely in the cell, such as viruses and certain bacteria (species of Chlamydia and Rickettsia as well as Listeria), and those, such as the mycobacteria, that replicate in cellular vesicles. Viruses can be prevented from entering cells by neutralizing antibodies whose production relies on TH2 cells (see Section 9-14), while once within cells they are dealt with by virus-specific cytotoxic T cells, which recognize and kill the infected cell (see Section 8-21). Intravesicular pathogens, on the other hand, mainly infect macrophages and can be eliminated with the aid of pathogen-specific TH1 cells, which activate infected macrophages to destroy the pathogen (see Section 8-26).
Pathogens can be found in various compartments of the body, where they must be combated by different host defense mechanisms. Virtually all pathogens have an extracellular phase where they are vulnerable to antibody-mediated effector mechanisms. However, intracellular (more. )
Many microorganisms replicate in extracellular spaces, either within the body or on the surface of epithelia. Extracellular bacteria are usually susceptible to killing by phagocytes and thus pathogenic species have developed means of resisting engulfment. The encapsulated gram-positive cocci, for instance, grow in extracellular spaces and resist phagocytosis by means of their polysaccharide capsule. This means they are not immediately eliminated by tissue phagocytes on infecting a previously unexposed host. However, if this mechanism of resistance is overcome by opsonization by complement and specific antibody, they are readily killed after ingestion by phagocytes. Thus, these extracellular bacteria are cleared by means of the humoral immune response (see Chapter 9).
Different infectious agents cause markedly different diseases, reflecting the diverse processes by which they damage tissues (Fig. 10.5). Many extracellular pathogens cause disease by releasing specific toxic products or protein toxins (see Fig. 9.23), which can induce the production of neutralizing antibodies (see Section 9-14). Intracellular infectious agents frequently cause disease by damaging the cells that house them. The specific killing of virus-infected cells by cytotoxic T cells thus not only prevents virus spread but removes damaged cells. The immune response to the infectious agent can itself be a major cause of pathology in several diseases (see Fig. 10.5). The pathology caused by a particular infectious agent also depends on the site in which it grows; Streptococcus pneumoniae in the lung causes pneumonia, whereas in the blood it causes a rapidly fatal systemic illness.
Pathogens can damage tissues in a variety of different ways. The mechanisms of damage, representative infectious agents, and the common names of the diseases associated with each are shown. Exotoxins are released by microorganisms and act at the surface (more. )
As we learned in Chapter 2, for a pathogen to invade the body, it must first bind to or cross the surface of an epithelium. When the infection is due to intestinal pathogens such as Salmonella typhi, the causal agent of typhoid fever, or Vibrio cholerae, which causes cholera, the adaptive immune response occurs in the specialized mucosal immune system associated with the gastrointestinal tract, as described later in this chapter. Some intestinal pathogens even target the M cells of the gut mucosal immune system, which are specialized to transport antigens across the epithelium, as a means of entry.
Many pathogens cannot be entirely eliminated by the immune response. But neither are most pathogens universally lethal. Those pathogens that have persisted for many thousands of years in the human population are highly evolved to exploit their human hosts, and cannot alter their pathogenicity without upsetting the compromise they have achieved with the human immune system. Rapidly killing every host it infects is no better for the long-term survival of a pathogen than being wiped out by the immune response before it has had time to infect another individual. In short, we have learned to live with our enemies, and they with us. However, we must be on the alert at all times for new pathogens and new threats to health. The human immunodeficiency virus that causes AIDS serves as a warning to mankind that we remain constantly vulnerable to the emergence of new infectious agents.
The mammalian body is susceptible to infection by many pathogens, which must first make contact with the host and then establish a focus of infection in order to cause infectious disease. To establish an infection, the pathogen must first colonize the skin or the internal mucosal surfaces of the respiratory, gastrointestinal, or urogenital tracts and then overcome or bypass the innate immune defenses associated with the epithelia and underlying tissues. If it succeeds in doing this, it will provoke an adaptive immune response that will take effect after several days and will usually clear the infection. Pathogens differ greatly in their lifestyles and means of pathogenesis, requiring an equally diverse set of defensive responses from the host immune system.
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