396 PART I The Immune System in Health and Disease entering and their virulence, different levels of host defense macrophages to kill ingested pathogens more effectively(see are enlisted. If the inoculum size and the virulence are both Figure 14-15) low, then localized tissue phagocytes may be able to eliminate the bacteria with an innate, nonspecific defense. Larger in- Bacteria Can Effectively Evade Host oculus or organisms with greater virulence tend to induce Defense Mechanisms an adaptive, specific immune response. There are four primary steps in bacterial infection Immune Responses to Extracellular ttachment to host cells and Intracellular Bacteria Can Differ Proliferation Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma Invasion of host tissue cells in regional lymph nodes and the submucosa of the res Toxin-induced damage to host cells piratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular Host-defense mechanisms act at each of these steps, and bacteria. The antibodies act in several ways to protect the many bacteria have evolved ways to circumvent some of these host from the invading organisms, including removal of the host defenses ( Table 17-3) bacteria and inactivation of bacterial toxins(Figure 17-8) Some bacteria have surface structures or molecules that Extracellular bacteria can be pathogenic because they induce enhance their ability to attach to host cells. a number of a localized inflammatory response or because they produce gram-negative bacteria, for instance, have pili (long hairlike toxins. The toxins, endotoxin or exotoxin, can be cytotoxic projections), which enable them to attach to the membrane but also may cause pathogenesis in other ways. An excellent of the intestinal or genitourinary tract(Figure 17-9). Other example of this is the toxin produced by diphtheria, which bacteria, such as Bordetella pertussis, secrete adhesion mole exerts a toxic effect on the cell by blocking protein synthesis. cules that attach to both the bacterium and the ciliated Endotoxins, such as lipopolysaccharides(LPS), are generally epithelial cells of the upper respiratory tract components of bacterial cell walls, while exotoxins, such Secretory IgA antibodies specific for such bacterial struc diphtheria toxin, are secreted by the bacteria. ures can block bacterial attachment to mucosal epithelial Antibody that binds to accessible antigens on the surface cells and are the main host defense against bacterial attach of a bacterium can, together with the C3b component of ment. However, some bacteria(e. g, Neisseria gonorrhoeae, complement, act as an opsonin that increases ph agocytoSIS emo US uenzae, and Neisseria meningiti and thus clearance of the bacterium(see Figure 17-8). In the the igA response by secreting proteases that cleave secretory case of some bacteria-notably, the gram-negative organ IgA at the hinge region; the resulting Fab and Fc fragments isms-complement activation can lead directly to lysis of the have a shortened half-life in mucous secretions and are not organism. Antibody-mediated activation of the complement able to agglutinate microorganisms system can also induce localized production of immune Some bacteria evade the igA response of the host by ffector molecules that help to develop an amplified and changing these surface antigens. In N. gonorrhoeae, for ex more effective inflammatory response. For example, the ample, pilin, the protein component of the pili, has a highly complement split products C3a, C4a, and C5a act as anaphy- variable structure Variation in the pilin amino acid sequence latoxins, inducing local mast-cell degranulation and thus is generated by gene rearrangements of its coding sequence vasodilation and the extravasation of lymphocytes and neu- The pilin locus consists of one or two expressed genes and trophils from the blood into tissue space(see Figure 17-8). 10-20 silent genes. Each gene is arranged into six regions Other complement split products serve as chemotactic fac- called minicassettes. Pilin variation is generated by a process tors for neutrophils and macrophages, thereby contributing of gene conversion, in which one or more minicassettes from to the buildup of phagocytic cells at the site of infection. the silent genes replace a minicassette of the expression gene. Antibody to a bacteria toxin may bind to the toxin and n This process generates enormous antigenic variation, which tralize it; the antibody-toxin complexes are then cleared by may contribute to the pathogenicity of N. gonorrhoeae by phagocytic cells in the same manner as any other antigen- increasing the likelihood that expressed pili will bind firmly antibody complex to epithelial cells. In addition, the continual changes in the While innate immunity is not very effective against intra- pilin sequence allow the organism to evade neutralization cellular bacterial pathogens, intracellular bacteria can acti- by IgA ate NK cells, which, in turn, provide an early defense against Some bacteria possess surface structures that serve to these bacteria. Intracellular bacterial infections tend to in- inhibit phagocytosis. a classic example is Streptococcus pneu duce a cell-mediated immune response, specifically, delayed- moniae, whose polysaccharide capsule prevents phagocytosis type hypersensitivity. In this response, cytokines secreted by very effectively. There are 84 serotypes of S pneumoniae that CD4* T cells are important-notably IFN-Y, which activates differ from one another by distinct capsular polysaccharides Gotowww.whfreeman.com/immunology mation Vaccine Strategies See Pathenogenesisentering and their virulence, different levels of host defense are enlisted. If the inoculum size and the virulence are both low, then localized tissue phagocytes may be able to eliminate the bacteria with an innate, nonspecific defense. Larger in￾oculums or organisms with greater virulence tend to induce an adaptive, specific immune response. Immune Responses to Extracellular and Intracellular Bacteria Can Differ Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma cells in regional lymph nodes and the submucosa of the res￾piratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular bacteria. The antibodies act in several ways to protect the host from the invading organisms, including removal of the bacteria and inactivation of bacterial toxins (Figure 17-8). Extracellular bacteria can be pathogenic because they induce a localized inflammatory response or because they produce toxins. The toxins, endotoxin or exotoxin, can be cytotoxic but also may cause pathogenesis in other ways. An excellent example of this is the toxin produced by diphtheria, which exerts a toxic effect on the cell by blocking protein synthesis. Endotoxins, such as lipopolysaccharides (LPS), are generally components of bacterial cell walls, while exotoxins, such as diphtheria toxin, are secreted by the bacteria. Antibody that binds to accessible antigens on the surface of a bacterium can, together with the C3b component of complement, act as an opsonin that increases phagocytosis and thus clearance of the bacterium (see Figure 17-8). In the case of some bacteria—notably, the gram-negative organ￾isms—complement activation can lead directly to lysis of the organism. Antibody-mediated activation of the complement system can also induce localized production of immune effector molecules that help to develop an amplified and more effective inflammatory response. For example, the complement split products C3a, C4a, and C5a act as anaphy￾latoxins, inducing local mast-cell degranulation and thus vasodilation and the extravasation of lymphocytes and neu￾trophils from the blood into tissue space (see Figure 17-8). Other complement split products serve as chemotactic fac￾tors for neutrophils and macrophages, thereby contributing to the buildup of phagocytic cells at the site of infection. Antibody to a bacteria toxin may bind to the toxin and neu￾tralize it; the antibody-toxin complexes are then cleared by phagocytic cells in the same manner as any other antigen￾antibody complex. While innate immunity is not very effective against intra￾cellular bacterial pathogens, intracellular bacteria can acti￾vate NK cells, which, in turn, provide an early defense against these bacteria. Intracellular bacterial infections tend to in￾duce a cell-mediated immune response, specifically, delayed￾type hypersensitivity. In this response, cytokines secreted by CD4+ T cells are important—notably IFN-, which activates macrophages to kill ingested pathogens more effectively (see Figure 14-15). Bacteria Can Effectively Evade Host Defense Mechanisms There are four primary steps in bacterial infection: ■ Attachment to host cells ■ Proliferation ■ Invasion of host tissue ■ Toxin-induced damage to host cells Host-defense mechanisms act at each of these steps, and many bacteria have evolved ways to circumvent some of these host defenses (Table 17-3). Some bacteria have surface structures or molecules that enhance their ability to attach to host cells. A number of gram-negative bacteria, for instance, have pili (long hairlike projections), which enable them to attach to the membrane of the intestinal or genitourinary tract (Figure 17-9). Other bacteria, such as Bordetella pertussis, secrete adhesion mole￾cules that attach to both the bacterium and the ciliated epithelial cells of the upper respiratory tract. Secretory IgA antibodies specific for such bacterial struc￾tures can block bacterial attachment to mucosal epithelial cells and are the main host defense against bacterial attach￾ment. However, some bacteria (e.g., Neisseria gonorrhoeae, Haemophilus influenzae, and Neisseria meningitidis) evade the IgA response by secreting proteases that cleave secretory IgA at the hinge region; the resulting Fab and Fc fragments have a shortened half-life in mucous secretions and are not able to agglutinate microorganisms. Some bacteria evade the IgA response of the host by changing these surface antigens. In N. gonorrhoeae, for ex￾ample, pilin, the protein component of the pili, has a highly variable structure. Variation in the pilin amino acid sequence is generated by gene rearrangements of its coding sequence. The pilin locus consists of one or two expressed genes and 10–20 silent genes. Each gene is arranged into six regions called minicassettes. Pilin variation is generated by a process of gene conversion, in which one or more minicassettes from the silent genes replace a minicassette of the expression gene. This process generates enormous antigenic variation, which may contribute to the pathogenicity of N. gonorrhoeae by increasing the likelihood that expressed pili will bind firmly to epithelial cells. In addition, the continual changes in the pilin sequence allow the organism to evade neutralization by IgA. Some bacteria possess surface structures that serve to inhibit phagocytosis. A classic example is Streptococcus pneu￾moniae, whose polysaccharide capsule prevents phagocytosis very effectively. There are 84 serotypes of S. pneumoniae that differ from one another by distinct capsular polysaccharides. 396 PART IV The Immune System in Health and Disease Go to www.whfreeman.com/immunology Animation Vaccine Strategies See Pathenogenesis