Figure 3-10 Overview of T-cell activation that is central to cell-mediated immunity.

Figure 3-10 Overview of T-cell activation that is central to cell-mediated immunity.

and avoid damage to vital tissues and organs that can result from the presence of infectious agents.


Given the complexities of the human host's defense systems, it is no wonder that microbial strategies designed to survive these systems are equally complex. Before considering the microorganism's perspective, a number of definitions and terms must be considered.

Colonization and Infection

Many of our body surfaces are colonized with a wide variety of microorganisms without apparent detriment. In contrast, an infection involves the growth and multiplication of microorganisms that result in damage to the host. The extent and severity of the damage depend on many factors, including the microorganism's ability to cause disease, the body site of the infection, and the general health of the person infected. Disease results when the infection produces notable changes in human physiology that are often associated with damages to one or more of the body's organ systems.

Pathogens and Virulence

Microorganisms that cause infections and/or disease are called pathogens, and the characteristics that enable them to cause disease are referred to as virulence factors. Most virulence factors protect the organism against host attack or mediate damaging effects on host cells. The terms pathogenicity and virulence reflect the degree to which a microorganism is capable of causing disease. An organism of high pathogenicity is very likely to cause disease when encountered, whereas an organism of low pathogenicity is much less likely to cause infection. When disease does occur, highly virulent organisms often severely damage the human host. The degree of severity diminishes with diminishing virulence of the microorganism.

Because host factors play a role in the development of infectious diseases, the distinction between a pathogen and nonpathogen, or colonizer, is not always dear. For example, many organisms that colonize our skin usually do not cause disease (i.e., exhibit low pathogenidty) under normal circumstances. However, when damage to the skin occurs (Box 3-4), or when the skin is disrupted in some other way, these organisms can gain access to deeper tissues and establish an infection.

Organisms that only cause infection when one or more of the host's defense mechanisms are disrupted or malfunction are known as opportunistic pathogens, and the infections they cause are referred to as opportunistic infections. On the other hand, several pathogens known to cause serious infections can be part of a person's normal flora and never cause disease in that person. However, the same organism can cause life-threatening infection when transmitted to other persons. The reasons for these inconsistendes are not fully understood, but such widely different results undoubtedly involve complex interactions between microorganism and human. Recognizing and separating pathogens from nonpathogens presents one of the greatest challenges in interpreting diagnostic microbiology laboratory results.

Microbial Virulence Factors

Virulence factors provide microorganisms with the capadty to avoid host defenses and damage host cells, tissues, and organs in a number of ways. Some virulence factors are specific for certain pathogenic genera or species and substantial differences exist in the way bacteria, viruses, parasites, and fungi cause disease. Of importance, knowledge of a microorganism's capacity to cause specific types of infections plays a major role in developing the diagnostic microbiology procedures used for isolating and identifying microorganisms (see Part VII for more information regarding diagnosis by organ system).

Attachment. Whether humans encounter microorganisms via the air, through ingestion, or by direct contact, the first step of infection and disease development (a process referred to as pathogenesis) is microbial attachment to a surface (exceptions being instances in which the organisms are directly implanted by trauma or other means into deeper tissues).

Many of the microbial factors that facilitate attachment of pathogens are the same as those used by nonpathogen colonizers (Box 3-3). The difference between pathogens and colonizers is that pathogens do not always stop at colonization. Also, many pathogens are not part of the normal microbial flora so that their successful attachment also requires that they outcompete colonizers for a place on the body's surface. Often medical interventions such as the overuse of antimicrobial agents that can destroy much of the normal flora tilt the competition in favor of the invading organism.

Invasion. Once surface attachment has been secured, microbial invasion into subsurface tissues and organs (i.e., infection) is accomplished by traumatic factors such as those listed in Box 3-4, or by the direct action of an organism's virulence factors. Some microorganisms produce factors that force mucosal surface phagocytes (M cells) to ingest them and then release them unharmed into the tissue below the mucosal surface. Other organisms, such as staphylococci and streptococci, are not so subtle. These organisms produce an array of enzymes (e.g,, hyaluronidases, nucleases, collagenases) that hydrolyze host proteins and nucleic acids that destroy host cells and tissues. This destruction allows the pathogen to "burrow" through minor openings in the outer surfaces and through deeper tissues. Once a pathogen has penetrated the body surface, strategies that allow microbial survival of the host's inflammatory and immune responses must be used. Alternatively, some pathogens cause disease from their site of attachment without further penetration. For example, in diseases such as diphtheria and whooping cough, the bacteria produce toxic substances that destroy surrounding tissues but the organisms themselves generally do not penetrate the mucosal surface they inhabit.

BOX 3-7 Microbial Strategies lor Surviving Inflammation


Inhibit ability of phagocyte to ingest by producing capsule Avoid phagocyte-mediated killing by; Inhibiting phagosome-lysosome fusion Bang resistant to destructive agents (e.g„ lysozyme) released bylysosomes Actlwly and rapidly multiplying within phagocyte Releasing toxins and enzymes that damage or kill phagocyte AVOID EFFECTS OF THE COMPLEMENT SYSTEM: Use capsule to hide surface molecules that would otherwise activate the complement system Produce substances that inhibit the processes Involved in complement activation Produce substances that destroy specific complement proteins

Survival Against Inflammation. If a pathogen is to survive, the action of phagocytes and the complement components of inflammation must be avoided or controlled (Box 3-7), Some organisms, such as Streptococcus pneumoniae, a common cause of bacterial pneumonia and meningitis, avoid phagocytosis by producing a large capsule that inhibits the phagocytic process. Other pathogens may not be able to avoid phagocytosis but are not effectively destroyed and are able to survive within phagocytes. This is the case for Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Still other pathogens use toxins and enzymes to attack and destroy phagocytes before the phagocytes attack and destroy them.

The defenses offered by the complement system depend on a series of biochemical reactions triggered by spedfic microorganism molecular structures. Therefore, microbial avoidance of complement activation requires that the infecting agent either mask its activating molecules (e.g., via production of a capsule that covers bacterial surface antigens) or produce substances (e.g., enzymes) that disrupt critical biochemical components of the complement pathway.

Any single microorganism may produce various virulence factors and several may be expressed simultaneously, For example, while trying to avoid phagocytosis, an organism may also be excreting other enzymes and toxins that help destroy and penetrate tissue, and be producing other factors designed to interfere with the immune response. Microorganisms may also use host systems to their own advantage. For example, the lymphatic and blood circulation system used to carry pathogens away from the site of infection can also be used by surviving pathogens to become dispersed throughout the body,

Survival Against the Immune System. Microbial strategies to avoid the defenses of the immune system

BOX 3-8 Microbial Strategies for Surviving the _Immune System__

  • Pathogen multiplies and invades so quickly that damage to host is complete before immune response can be fully activated, or organism^ virulence is so great that the immune response is insufficient
  • Pathogen invades and destroys cells involved in the immune response
  • Pathogen survives, unrecognized, in host cells and avoids detection by Immune system
  • Pathogen covers its antigens with a capsule so that an immune response is not activated
  • Pathogen changes antigens so that Immune system is constantly fighting a primary encounter (i.e., the memory of the immune system is neutralized)
  • Pathogen produces enzymes (proteases) that directly destroy or inactivate antibodies are outlined in Box 3-8. Again, a pathogen can use more that one strategy to avoid immune-mediated defenses, and microbial survival does not necessarily require devastation of the immune system. The pathogen may merely need to "buy" time to reach a saife area in the body or to be transferred to the next susceptible host. Also, microorganisms can avoid much of the immune response if they do not penetrate the surface layers. This strategy is the hallmark of diseases that are caused by microbial toxins.

Microbial Toxins. Toxins are biochemically active substances that are released by microorganisms and have a particular effect on host cells. Microorganisms use toxins to help them establish infections and multiply within the host. Alternatively, a pathogen may be restricted to a particular body site from which toxins are released to cause widespread problems throughout the body. Toxins also can cause human disease in the absence of the pathogens that produced them. This common mechanism of food poisoning that involves ingestion of preformed bacterial toxins is referred to as intoxication, a notable example of which is botulism.

Endotoxins and exotoxins are the two general types of bacterial toxins (Box 3-9), Endotoxins are released by gram-negative bacteria and can have devastating effects on the body's metabolism, the most serious being endotoxic shock, which often results in death. The effects of exotoxins produced by grampositive bacteria tend to be more liiriited and specific than the effects of gram-negative endotoxins. The activities of exotoxins range from those enzymes produced by many staphylococci and streptococci that augment bacterial invasion by damaging host tissues and cells to those that have highly specific activities (e.g., diphtheria toxin that inhibits protein synthesis

BOX 3-9 Summary of Bacterial Toxins endotoxins

  • General toxin common to almost all gram-negative bacteria
  • Composed of lipopolysaccharide portion of cell envelope
  • Released when gram-negative bacterial cell is destroyed
  • Effects on host include:

Disruption of dotting, causing clots to form throughout body (i.e., disseminated intravascular coagulation [DICJ -Fever

Activation of complement and immune systems Circulatory changes that lead to hypotension, shock, and death exotoxins

  • Most commonly associated with gram-positive bacteria
  • Produced and released by living bacteria; do not require bacterial death for release
  • Specific toxins target specific host cells; the type of toxin varies with the bacterial species
  • Some kill host cells and help spread bacteria in tissues (e.g., enzymes that destroy key biochemical tissue components or specifically destroy host cell membranes)
  • Some destroy or interfere with the specific intracellular activities (e.g., interruption of protein synthesis, interruption of internal cell signals, or interruption of neuromuscular system)

or the cholera toxin that interferes with host cell signals). Examples of other highly active and specific toxins are those that cause botulism and tetanus by interfering with neuromuscular functions.

Genetics of Virulence: Pathogenicity Islands

The evolution and dissemination of many of the virulence factors discussed is now known to be largely facilitated by what are referred to as pathogenicity islands (PAIs). These are mobile genetic elements that contribute to the change and spread of virulence factors among bacterial populations of a variety of species. These genetic elements are thought to have evolved from lysogenic bacteriophages and plasmids and are spread by horizontal gene transfer (see Chapter 2 for information about bacterial genetics). PAIs are typically comprised of one or more virulence-associated genes and "mobility" genes (i.e., integrases and transposases) that mediate movement between various genetic elements (e.g., plasmids and chromosomes) and among different bacterial strains. In essence, PAIs facilitate the dissemination of virulence capabilities among bacteria in a manner similar to the mechanism diagrammed in Figure 2-10, which also facilitates dissemination of antimicrobial resistance genes (see Chapter II).

The existence and function of PAIs must be kept in mind whenever considering the virulence factors discussed in this chapter and when considering pathogenesis in each bacterial organism discussed in Part m. It is important to appreciate how widely disseminated this genetic mechanism is among medically important bacteria. For example, PAIs have

Figure 3-11 Possible outcomes of infections and infectious diseases.

Host factors:

  • General state of health
  • Integrity of surface defenses
  • Capacity for inflammatory and immune response
  • Level of immunity
  • Impact of medical intervention f


Microbial factors:

  • Level of virulence
  • Number of organisms introduced into host
  • Body sites pathogen targets for invasion

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