Infectious agents and how they cause disease (2024)

10-1. The course of an infection can be divided into several distinctphases

The process of infection can be broken down into stages, each of which can beblocked by different defense mechanisms. In the first stage, a new host isexposed to infectious particles shed by an infected individual. The number,route, mode of transmission, and stability of an infectious agent outside thehost determines its infectivity. Some pathogens, such as anthrax, are spread byspores that are highly resistant to heat and drying, while others, such as thehuman immunodeficiency virus (HIV), are spread only by the exchange of bodilyfluids or tissues because they are unable to survive as infectious agentsoutside the body.

The first contact with a new host occurs through an epithelial surface. This maybe the skin or the internal mucosal surfaces of the respiratory,gastro-intestinal, and urogenital tracts. After making contact, an infectiousagent must establish a focus of infection. This involves adhering to theepithelial surface, and then colonizing it, or penetrating it to replicate inthe tissues (Fig. 10.2, left-handpanels). Many microorganisms are repelled at this stage by innate immunity. Wehave discussed the innate immune defense mediated by epithelia and by phagocytesand complement in the underlying tissues in Chapter 2. Chapter2 also discusses how NK cells are activated in response tointracellular infections, and how a local inflammatory response and inducedcytokines and chemokines can bring more effector cells and molecules to the siteof an infection while preventing pathogen spread into the blood. These innateimmune responses use a variety of germline-encoded receptors to discriminatebetween microbial and host cell surfaces, or infected and normal cells. They arenot as effective as adaptive immune responses, which can afford to be morepowerful on account of their antigen specificity. However, they can prevent aninfection being established, or failing that, contain it while an adaptive immune response develops.

Only when a microorganism has successfully established a site of infection in thehost does disease occur, and little damage will be caused unless the agent isable to spread from the original site of infection or can secrete toxins thatcan spread to other parts of the body. Extracellular pathogens spread by directextension of the focus of infection through the lymphatics or the bloodstream.Usually, spread by the bloodstream occurs only after the lymphatic system hasbeen overwhelmed by the burden of infectious agent. Obligate intracellularpathogens must spread from cell to cell; they do so either by directtransmission from one cell to the next or by release into the extracellularfluid and reinfection of both adjacent and distant cells. Many common foodpoisoning organisms cause pathology without spreading into the tissues. Theyestablish a site of infection on the epithelial surface in the lumen of the gutand cause no direct pathology themselves, but they secrete toxins that causedamage either in situ or after crossing the epithelial barrierand entering the circulation.

Most infectious agents show a significant degree of host specificity, causingdisease only in one or a few related species. What determines host specificityfor every agent is not known, but the requirement for attachment to a particularcell-surface molecule is one critical factor. As other interactions with hostcells are also commonly needed to support replication, most pathogens have alimited host range. The molecular mechanisms of host specificity comprise anarea of research known as molecular pathogenesis, which falls outside the scopeof this book.

While most microorganisms are repelled by innate host defenses, an initialinfection, once established, generally leads to perceptible disease followed byan effective host adaptive immune response. This is initiated in the locallymphoid tissue, in response to antigens presented by dendritic cells activatedduring the course of the innate immune response (Fig. 10.2, third and fourth panels). Antigen-specificeffector T cells and antibody-secreting B cells are generated by clonalexpansion and differentiation over the course of several days, during which timethe induced responses of innate immunity continue to function. Eventually,antigen-specific T cells and then antibodies are released into the blood andrecruited to the site of infection (Fig.10.2, last panel). A cure involves the clearance of extracellularinfectious particles by antibodies and the clearance of intracellular residuesof infection through the actions of effector T cells.

After many types of infection there is little or no residual pathology followingan effective primary response. In some cases, however, the infection or theresponse to it causes significant tissue damage. In other cases, such asinfection 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 systemicinfections. We will focus on the strategies used by certain pathogens to evadeor subvert adaptive immunity and thereby establish a persistent infection in thefirst part of Chapter 11.

In addition to clearing the infectious agent, an effective adaptive immune response prevents reinfection. For some infectious agents, this protection isessentially absolute, while for others infection is reduced or attenuated uponreexposure.

10-2. Infectious diseases are caused by diverse living agents that replicate intheir hosts

The agents that cause disease fall into five groups: viruses, bacteria, fungi,protozoa, and helminths (worms). Protozoa and worms are usually grouped togetheras parasites, and are the subject of the discipline of parasitology, whereasviruses, bacteria, and fungi are the subject of microbiology. In Fig. 10.3, the classes of microorganismsand parasites that cause disease are listed, with typical examples of each. Theremarkable variety of these pathogens has caused the natural selection of twocrucial features of adaptive immunity. First, the advantage of being able torecognize a wide range of different pathogens has driven the development ofreceptors on B and T cells of equal or greater diversity. Second, the distincthabitats and life cycles of pathogens have to be countered by a range ofdistinct effector mechanisms. The characteristic features of each pathogen areits mode of transmission, its mechanism of replication, its pathogenesis or themeans by which it causes disease, and the response it elicits. We will focushere on the immune responses to these pathogens.

Infectious agents can grow in various body compartments, as shown schematicallyin Fig. 10.4. We have already seen thattwo major compartments can be defined—intracellular and extracellular.Intracellular pathogens must invade host cells in order to replicate, and somust either be prevented from entering cells or be detected and eliminated oncethey have done so. Such pathogens can be subdivided further into those thatreplicate freely in the cell, such as viruses and certain bacteria (species ofChlamydia and Rickettsia as well asListeria), and those, such as the mycobacteria, thatreplicate in cellular vesicles. Viruses can be prevented from entering cells byneutralizing antibodies whose production relies on TH2 cells (seeSection 9-14), while once withincells they are dealt with by virus-specific cytotoxic T cells, which recognizeand kill the infected cell (see Section8-21). Intravesicular pathogens, on the other hand, mainly infectmacrophages and can be eliminated with the aid of pathogen-specificTH1 cells, which activate infected macrophages to destroy thepathogen (see Section 8-26).

Many microorganisms replicate in extracellular spaces, either within the body oron the surface of epithelia. Extracellular bacteria are usually susceptible tokilling by phagocytes and thus pathogenic species have developed means ofresisting engulfment. The encapsulated gram-positive cocci, for instance, growin extracellular spaces and resist phagocytosis by means of their polysaccharidecapsule. This means they are not immediately eliminated by tissue phagocytes oninfecting a previously unexposed host. However, if this mechanism of resistanceis overcome by opsonization by complement and specific antibody, they arereadily killed after ingestion by phagocytes. Thus, these extracellular bacteriaare cleared by means of the humoral immune response (see Chapter 9).

Different infectious agents cause markedly different diseases, reflecting thediverse processes by which they damage tissues (Fig. 10.5). Many extracellular pathogens cause disease by releasingspecific toxic products or protein toxins (see Fig. 9.23), which can induce the production of neutralizingantibodies (see Section 9-14).Intracellular infectious agents frequently cause disease by damaging the cellsthat 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 inseveral diseases (see Fig. 10.5). Thepathology caused by a particular infectious agent also depends on the site inwhich it grows; Streptococcus pneumoniae in the lung causespneumonia, whereas in the blood it causes a rapidly fatal systemic illness.

As we learned in Chapter 2, for apathogen to invade the body, it must first bind to or cross the surface of anepithelium. When the infection is due to intestinal pathogens such asSalmonella typhi, the causal agent of typhoid fever, orVibrio cholerae, which causes cholera, the adaptive immune response occurs in the specialized mucosal immune system associated with thegastrointestinal tract, as described later in this chapter. Some intestinalpathogens even target the M cells of the gut mucosal immune system, which arespecialized to transport antigens across the epithelium, as a means ofentry.

Many pathogens cannot be entirely eliminated by the immune response. But neitherare most pathogens universally lethal. Those pathogens that have persisted formany thousands of years in the human population are highly evolved to exploittheir human hosts, and cannot alter their pathogenicity without upsetting thecompromise they have achieved with the human immune system. Rapidly killingevery host it infects is no better for the long-term survival of a pathogen thanbeing wiped out by the immune response before it has had time to infect anotherindividual. In short, we have learned to live with our enemies, and they withus. However, we must be on the alert at all times for new pathogens and newthreats to health. The human immunodeficiency virus that causes AIDS serves as awarning to mankind that we remain constantly vulnerable to the emergence of newinfectious agents.

Summary

The mammalian body is susceptible to infection by many pathogens, which mustfirst make contact with the host and then establish a focus of infection inorder to cause infectious disease. To establish an infection, the pathogen mustfirst colonize the skin or the internal mucosal surfaces of the respiratory,gastrointestinal, or urogenital tracts and then overcome or bypass the innateimmune defenses associated with the epithelia and underlying tissues. If itsucceeds in doing this, it will provoke an adaptive immune response that willtake effect after several days and will usually clear the infection. Pathogensdiffer greatly in their lifestyles and means of pathogenesis, requiring anequally diverse set of defensive responses from the host immune system.