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Chapter 18 : Immunity to Bacterial Infections

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Abstract:

The molecular biology revolution of the last half of the 20th century led to major advances in the understanding of the molecular and cellular bases for the ways in which bacteria cause diseases, and this century similarly saw the development of numerous important vaccines to prevent serious bacterial infections. Virulence factors can disrupt host cellular function due to secreted toxins or toxic bacterial metabolites. Studies of the effect of antibody and complement in the serum talk about the protective immunity against extracellular bacterial pathogens. Convincing data demonstrating that immunoglobulin A (IgA) has a major role in resistance to infection in vivo are limited. However, it is obvious that preventing bacterial entry and attachment would be the most effective mechanism of immunity, attacking the infectious inocula early on and limiting the development of disease. Bacterial pathogens usually enter our bodies through the mucosal and skin surfaces, including the respiratory, ocular, gastrointestinal, and genitourinary tracts. Skin can be an important site of bacterial colonization, particularly for staphylococci, and direct inoculation of pathogens into the host via or through the skin is always a risk factor for subsequent disease. The most effective antigens for obtaining protective immunity due to antibody and complement activation are bacterial surface structures. The anthrax outbreak that occurred in the United States in the fall of 2001 generated a strong interest in further understanding how the bacterial agents of bioterrorism cause disease and how the public can be protected.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18

Key Concept Ranking

Bacterial Proteins
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Bacterial Pathogenesis
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Infection and Immunity
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Antibacterial Agents
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Figures

Image of Figure 18.1
Figure 18.1

Gram stains showing gram-positive and gram-negative bacteria. A sp.; ; a sp.; .

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.2
Figure 18.2

Certain conditions can cause bacteria to preferentially infect some host tissues. The figure highlights several organs and tissues and lists several bacterial species that can demonstrate a preference for each tissue.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.3
Figure 18.3

Steps of bacterial infection. Infection begins with attachment of the bacterium to a host tissue. Persistence and growth of the bacterium at this site are termed . Invasion of the bacterium into deeper host tissues, together with the elaboration of toxic substances by the bacterium, can result in injury to host cells and tissues (p. 429). Inflammation at the site of invasion can be initiated by antibody binding to bacteria, by complement activation on the bacterial surface, or by wound healing mechanisms such as the plasmin system or the kinin system (p. 430). In all of these cases, components C3 to C5 of the complement system can be activated to generate soluble split products called (fragments C3a, C4a, and C5a) that alter vascular permeability and activate local macrophages and neutrophils. A picture of a “hypothetical” bacterium showing different factors that promote colonization, entry, and then progression to disease (p. 430). Alginate can promote colonization by adhering to host tissues. LPS and the pilus promote persistence of the bacterium by creating resistance to complement and phagocytosis, respectively. The type III secretion system is used by the bacterium to deliver bacterial enzymes and toxins into host cells. Many bacteria secrete toxins that can injure host tissues or diminish host immune responses. Such toxins may include signaling proteins, proteases, and superantigens.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.4
Figure 18.4

Mechanisms of immunity to extracellular bacteria mediated by antibodies. For gram-negative bacteria, binding of antibodies and complement can result in opsonization via Fc receptors or CR expressed by macrophages or neutrophils . Antibody binding can also activate complement via the classical pathway, resulting in membrane attack complex (MAC) formation and opsonization via complement receptors. Antibodies bound to the bacterium can also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) as neutrophils bearing Fc receptors and CR release proteases, nucleases, lipases, and reactive oxygen intermediates (ROIs) . (B) For gram-positive bacteria, MAC formation is ineffective in killing bacteria due to the presence of the thick bacterial cell wall; however, opsonization and ADCC are still effective.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.5
Figure 18.5

Mechanisms of immunity to intracellular bacteria mediated by cell-mediated immunity. Bacterial antigens present in the cytoplasm of an infected host cell can be processed via the endogenous presentation pathway and presented to CD8+CTLs on MHC class I. Bacterial antigens present in endosomes of an infected host cell can be processed via the exogenous presentation pathway and presented to CD4 CTLs on MHC class II. Bacterial antigens present on the surface of an infected cell can be bound by antibodies and targeted for killing by NK cells using ADCC. Some CD4 T cells that recognize bacterial antigens complexed with MHC class II may be TH1 cells, which may be capable of initiating a DTH reaction resulting in the activation of macrophages, which may kill bacteria and infected host cells via proteases and reactive oxygen intermediates (ROIs).

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.6
Figure 18.6

Schematic structure of the gram-positive bacterial cell wall. The wall consists of a peptidoglycan layer composed of liner copolymers of -acetylglucosamine and -acetylmuramic acid, cross-linked to each other by oligopeptide cross bridges. Teichoic acids and lipoteichoic acids (anchored at -acetylmuramic acid and in the plasma membrane, respectively) are thought to play a role in regulating the breakdown of the cell wall that occurs during cell division.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.7
Figure 18.7

Peptidoglycan. The schematic structure of the peptidoglycan layer of the cell wall of shows the polysaccharide backbone composed of alternating -acetylmuramic acid (MurAc) and acetylglucosamine (GlcNAc) residues linked β-1,4 with a tetrapeptide bridge emanating from the MurAc residue and composed of L-alanine (L-Ala), D-glutamate (D-Glu), L-lysine (L-Lys), and D-alanine (D-Ala). The tetrapeptide bridges are then cross-linked with a pentaglycine peptide [(Gly)5]. Variations in peptidoglycan structure are common among gram-positive bacteria.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.8
Figure 18.8

Teichoic acids. Representation of the structures of teichoic acids found in the cell walls of gram-positive bacteria. A generic structure for teichoic acids . This is a repeat unit of the three-carbon sugar glycerol linked to each other by phosphate groups and is referred to as a glycerol teichoic acid. Variations in this basic structure are frequently found, such as the use of ribitol, a five-carbon sugar alcohol, in place of glycerol. The teichoic acid of contains a glucose-glycerol disaccharide linked via phosphate groups whereas the teichoic acid of is a glucose--acetylglucosamine disaccharide linked by phosphate groups. Teichoic acids are linked directly to -acetylmuramic acid in the peptidoglycan. This type of teichoic acid uses ribitol (Rib) instead of glycerol and is coupled via an amino sugar and phosphate groups (coupling unit) to -acetylmuramic acid in the peptidoglycan. The structure of lipoteichoic acid from , showing the linkage of a typical glycerol-teichoic acid to a glycolipid through a glucose disaccharide. The lipid is then anchored in the bacterial cytoplasmic membrane.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.9
Figure 18.9

Bacterial capsules. Electron micrographs of the capsule surrounding the outer cell wall layer of a gram-positive and a gram-negative bacterium are shown. The outer capsule layer is visualized with specific antibodies raised to the purified antigen. The antibody binding to the capsule has been detected with a secondary IgG conjugated to ferritin, producing an electron-dense black dot where the secondary antibody binds to the primary antibody bound to the capsule. The capsule was made sufficiently electron dense with antibody to the capsule alone to see the fuzzy outer layer of variable thickness.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.10
Figure 18.10

Schematic representation of the outer surface structure of a gram-negative bacterium. The characteristic structure of the gram-negative bacterial surface is a double membrane with the space between the membranes, called the periplasm, containing a thin cell wall composed of peptidoglycan. Both membranes contain numerous integral and peripheral proteins that carry out numerous functions, including transport of molecules across the membranes. The outer membrane is anchored to the cell wall by lipoproteins that are embedded in the outer membrane and are covalently coupled to the cell wall. The outer leaflet consists entirely of LPS rather than phospholipid (for clarity, the diagram shows only two LPS molecules). The LPS composition of the outer membrane renders the bacterial surface resistant to phospholipases. The hydrophobic anchor of LPS is a unique molecule called lipid A.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.11
Figure 18.11

Schematic representation of the LPS found in the outer membrane of gram-negative bacteria. Man, mannose; Rha, rhamnose; Gal, galactose; GlcNAc, -acetylglucosamine; Glc, glucose; Hep, L-glycero-D-mannoheptose; KDO, 2-keto-3 deoxyoctonate; GlcN, glucosamine. The precise monosaccharide composition of the LPS core and O side chain varies among bacterial species and serovars.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.12
Figure 18.12

Transmission electron micrograph of a piliated strain of . Each cell possesses hundreds of pili (small arrows), which promote aggregation of the bacteria. Also visible is a flagellum (large, open arrows) that is folded under the cell. Flagella are longer and have a larger diameter than pili. In this example, there is only one flagellum, known as a polar flagellum, as it emerges from the cell at one end, or pole.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.13
Figure 18.13

Schematic drawings of the separate domains of exotoxin A, separately oriented to give illustrative views: domain I including residues 1 to 252 and 365 to 404; domain II including residues 253 to 364; and domain III beginning at residue 405. The dotted lines in domain III indicate regions where electron density is difficult to trace. Reprinted from V. S. Allured et al., 1320–1324, 1986. The mechanism of action of exotoxin A. The toxin binds to nicotinamide adenine dinucleotide (NAD) and releases the nicotinamide moiety to leave ADP-ribose on the toxin The toxin then approaches active elongation factor 2 (EF-2) and catalyzes the transfer of the ADP-ribose to EF-2, resulting in a cessation of protein synthesis in the eukaryotic cell

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.14
Figure 18.14

Bacteria evade complement-mediated killing by a number of mechanisms. The presence of capsule or calyx outside the bacterial cell can prevent activated complement components (such as C3b) from attaching to the bacterial cell wall or outer membrane. The presence of long or bulky surface components (green) on the surface of the bacterium can prevent complement receptors on phagocytes from binding activated complement components (such as C3b) that are attached to the bacterial surface. Expression of certain surface proteins (for example, a CD59-related protein produced by ) diverts the activation of the MAC away from the bacterial membrane. Bacteria express some enzymes (such as elastase) that can cleave, inactivate, or cause the disassembling of the activated complement components. The outer membrane may be resistant to insertion of the C5b67 complex. Secreted inhibitors of complement (SIC) bind to complement complexes C5b67 and C5b678, preventing membrane insertion.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.15
Figure 18.15

Diagram of the biofilm-maturation pathway of Unattached cells that approach a surface may attach. Attached cells will proliferate on a surface and use specific functions to actively grow into microcolonies. The high-density microcolonies differentiate into mature biofilms using an intercellular communication mechanism called quorum sensing. Quorum sensing is mediated by small soluble molecules called . Most autoinducers are homoserine lactones such as -butanoyl-l-homoserine lactone and -(3-hydroxy-7--tetradecanoyl)-l-homoserine lactone. Mechanism of quorum sensing. As bacteria grow, they simultaneously produce a transcriptional regulator (R) and a biosynthetic enzyme (I) that synthesizes the homoserine lactone (HSL). The HSL diffuses out of the bacterial cell As the bacterial cell density increases to a critical point, the concentration of extracellular HSL will exceed that of the intracellular HSL, and the HSL will begin to accumulate in the bacterial cells and bind to R. The HSL-R complex can bind to a genetic response element thus activating transcription of critical bacterial genes Panel A is reprinted with permission from M. R. Parsek and E. P. Greenberg, 8789–8793, 2000.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.16
Figure 18.16

Effects of Yops proteins on inhibition of the inflammatory response needed to resist infection. Normally, proinflammatory factors such as bacterial LPS, bound to the LBP, interact with receptor CD14 and coreceptor from the Toll-like family. This leads to phosphorylation cascades (tyrosine kinases and mitogen-activated protein kinase kinase [MAPKK]), resulting in the activation of mitogen-activated protein kinases (MAPKs) and of the IκB kinase (IKK) kinase, which acts on the inhibitor of NF-κB (IκB). Phosphorylation of (IκB) is followed by its degradation, and NF-κB migrates to the nucleus and activates transcription of proinflammatory cytokines, including TNF-α. Two of the translocated Yop proteins, termed YopP (in ) or YopJ (in ), prevent the activation of the two phosphorylation cascades and thus block the release of TNF-α. This Yop protein also induces macrophage apoptosis through the activities of the caspase (Casp) proteins. Reprinted with permission from G. R. Cornelis, 8778–8783, 2000.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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Image of Figure 18.17
Figure 18.17

Some of the molecular factors involved in the pathogenesis of infection. The YadA homotrimeric protein anchored to the outer membrane of the bacterium serves as an adhesin, allowing the bacterium to bind to host molecules such as collagen, fibronectin, and mucus. YadA also inhibits complement activation by the classical pathway. species secretes a superantigen called YPM (-derived mitogen) that may promote bacterial survival in the host by impairing immune function. The interaction of host macrophages with gram-negative bacteria usually results in activation of the macrophage when TLR4 on the macrophage surface binds bacterial LPS. TLR4 signaling proceeds via the MAPK pathway. prevents macrophage activation through the YopJ protein, which is delivered into the macrophage cytoplasm by the bacterial type III secretion apparatus, and inhibits the MAPK pathway. The type III secretion apparatus is composed of Ysc and translocator proteins. YopH is another protein that is delivered into the macrophage cytoplasm by the type III secretion apparatus. YopH inhibits phagocytosis by disrupting cytoskeletal elements.

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
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References

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1. Grandvaux, N.,, B. R. tenOever,, M. J. Servant,, and J. Hiscott. 2002. The interferon antiviral response: from viral invasion to evasion. Curr. Opin. Infect. Dis. 15:259267.
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6. Russell, J. H.,, and T. J. Ley. 2002. Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol. 20:323370.
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10. Zinkernagel, R. M. 2002. Anti-infection immunity and autoimmunity. Ann. N. Y. Acad. Sci. 958:36.

Tables

Generic image for table
Table 18.1

Innate immune effectors mediating resistance to bacterial infection

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
Generic image for table
Table 18.2

Bacterial pathogens that can escape humoral immune mechanisms, survive intracellularly, and require activated phagocytes or CTLs for successful elimination

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
Generic image for table
Table 18.3

Common extracellular bacterial pathogens that are cleared by humoral immune effectors and examples of their common disease manifestations

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18
Generic image for table
Table 18.4

Microorganisms classified according to their potential threat of bioterrorism and biowarfare

Citation: Pier G. 2004. Immunity to Bacterial Infections, p 425-452. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch18

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