Whether a microbe is a primary or opportunistic pathogen, it must be able to enter a host; find a unique niche; avoid, circumvent, or subvert normal host defenses; multiply; and injure the host. For long-term success as a pathogen, it must also establish itself in the host or somewhere else long enough to eventually be transmitted to a new susceptible host. This competition between the pathogen and the host can be viewed as similar to the more familiar military or athletic struggles—that is, the offense against the defense. The more we learn about bacterial pathogens, the more it seems that the most successful ones not only have an excellent offense; they are also particularly able to confound the host defense.
Pathogens must establish a niche and persist
✺ Success involves offense and confounding host defenses
ENTRY: BEATING INNATE HOST DEFENSES
Each of the portals in the body that communicates with the outside world becomes a potential site of microbial entry. Human and other animal hosts have various protective mechanisms to prevent microbial entry (Table 22–1). A simple, though relatively efficient, mechanical barrier to microbial invasion is provided by the epithelial borders of the internal and external body surfaces. Of these, the skin is the most formidable with its tough keratinized superficial layer. Organisms can gain access to the underlying tissues only by breaks or by way of hair follicles, sebaceous glands, and sweat glands that traverse the stratified layers. The surface of the skin continuously desquamates and thus tends to shed contaminating organisms. The skin also inhibits the growth of most extraneous microorganisms because of low moisture, low pH, and the presence of substances with antibacterial activity. Bacteria have no known mechanism for passing the unbroken skin.
TABLE 22–1Innate Defenses Against Colonization with Pathogens ||Download (.pdf) TABLE 22–1 Innate Defenses Against Colonization with Pathogens
|SITE ||MECHANICAL BARRIER ||CILIATED EPITHELIUM ||COMPETITION BY NORMAL FLORA ||MUCUS ||sIgA ||LYMPHOID FOLLICLES ||LOW PH ||FLUSHING EFFECTS OF CONTENTS ||PERISTALSIS ||SPECIAL FACTORS |
|Skin ||+++ ||– ||+ ||– ||– ||– ||++ ||– ||– ||Fatty acids from action of normal flora on sebum |
|Conjunctiva ||++ ||– ||– ||– ||+ ||– ||– ||+++ ||– ||Lysozyme |
|Oropharynx ||+++ ||– ||+++ ||– ||+ ||Yes ||– ||++ ||– || |
|Upper respiratory tract ||++ ||+ ||+++ ||++ ||++ ||Yes ||– ||++ ||– ||Turbinate baffles |
|Middle ear and paranasal sinusesa ||++ ||+++ ||– ||++ ||? ||– ||– ||+ ||– || |
|Lower respiratory tracta ||++ ||+++ ||– ||++ ||++ ||Yes ||– ||– ||– ||Mucociliary escalator, alveolar macrophages; cough reflex |
|Stomach ||++ ||– ||– ||++ ||– ||– ||+++ ||+ ||+ ||Production of hydrochloric acid |
|Intestinal tract ||++ ||– ||+++ ||+++ ||+++ ||Yes ||– ||+ ||+++ ||Bile; digestive enzymes |
|Vagina ||+++ ||– ||+++ ||+ ||+ ||– ||+++ ||– ||– ||Lactobacillary flora ferments |
|Urinary tracta ||++ ||– ||– ||– ||+ ||– ||+ ||+++ ||– || |
Microbes gain access from the environment
✺ Skin is a major protective barrier
For the internal surfaces a viscous mucin secreted by goblet cells protects the epithelium lining of the respiratory tract, the gastrointestinal tract, and the urogenital system. Microorganisms become trapped in this thick network of protein and polysaccharide and may be swept away before they reach the epithelial cell surface. Secretory IgA (sIgA) secreted into the mucus and other secreted antimicrobials such as lysozyme and lactoferrin aid this cleansing process. Some bacteria excrete an enzyme sIgA protease, which cleaves human sIgA1 in the hinge region to release the Fc portion from the Fab fragment. This enzyme may play an important role in establishing microbial species at the mucosal surface. Ciliated epithelial cells constantly move the mucin away from the lower respiratory tract. In the respiratory tract, particles larger than 5 μm are trapped in this fashion. The epithelium of the intestinal tract below the esophagus is a less efficient mechanical barrier than the skin, but there are other effective defense mechanisms. The high level of hydrochloric acid and gastric enzymes in the normal stomach kill many ingested bacteria. Other bacteria are susceptible to pancreatic digestive enzymes or to the detergent effect of bile salts.
Mucin coats mucosal epithelium
✺ sIgA protease aids survival
Acids and enzymes aid in cleansing
How efficiently bacterial pathogens navigate all these barriers before their initial encounter with their target cell type is in some ways measured by their infecting dose. How many organisms must be given to a host to ensure infection in some proportion of the individuals? Estimates of the infectious doses for several pathogens are shown in Table 22–2. In general, pathogens that have environmental or animal reservoirs can overwhelm innate defenses with large numbers. Those that are amplified by growth in food may also deliver high numbers with or without a reservoir. Pathogens with no reservoir or amplification mechanism must be transmitted human-to-human and thus require the lowest infecting doses. Without this advantage, these pathogens would eventually die out in the population.
TABLE 22–2Dose of Microorganisms Required to Produce Infection in Human Volunteers ||Download (.pdf) TABLE 22–2 Dose of Microorganisms Required to Produce Infection in Human Volunteers
|MICROBE ||ROUTE ||DISEASE-PRODUCING DOSE |
|Salmonella serotype Typhi ||Oral ||105 |
|Shigella spp. ||Oral ||10-1000 |
|Vibrio cholerae ||Oral ||108 |
|V cholerae ||Oral + HCO3– ||104a |
|Mycobacterium tuberculosis ||Inhalation ||1-10 |
✺ Infection is dose-related
ADHERENCE: THE SEARCH FOR A UNIQUE NICHE
The first major interaction between a pathogenic microorganism and its host entails attachment to a eukaryotic cell surface. In its simplest form, adherence requires the participation of two factors: an adhesin on the invading microbe and a receptor on the host cell (Figure 22–1). The adhesin must be exposed on the bacterial surface either alone or in association with appendages like pili. Pili seem to be “sticky” by themselves which may be enhanced by specific adhesin/receptor molecular relationships mediated by molecules at their tips. In gram-negative bacteria, the outer membrane is a major site for adhesins. Most adhesins are proteins, but carbohydrates and teichoic acids may also be involved. The chemical nature of the host receptors is less well known because of the greater difficulty in their isolation (bacteria can be grown by the gallon), but they may be thought of as general or specific. For example, two of the most common receptors, mannose and fibronectin, are widely present on human epithelial cell surfaces. Pili that bind to them can mediate attachment at many sites. Specific receptors are those unique to a particular cell type such as human enterocytes or uroepithelial cells. Where known, these receptors are usually sugar residues that are part of glycolipids or glycoproteins on the host cell surface.
Bacterial attachment. A. The bacterial cell has both adhesive pili and another protein adhesin protruding from its surface. The pili are binding to a receptor present in material covering the cytoplasmic membrane. B. The pili have pulled the organism into closer contact allowing the second adhesin to bind its receptor, which extends from the cytoplasmic membrane through the surface coating.
Adhesin and receptor are required
✺ Pili often bind mannose, fibronectin
Receptors may be specific to host cell type
Many bacteria have more than one mechanism of host cell attachment. In some instances, pili mediate initial attachment, which is followed by a stronger, more specific binding mediated by another protein. This may allow implementation of a second function such as cytoskeleton rearrangement or invasion. Multiple adhesins may also allow bacteria to use one set at the epithelial surface, but a different set when encountering other cell types or the immune system. The role of pili may be more than a simple adhesive one. The pili of Neisseria gonorrhoeae, the cause of gonorrhea, mediate an active twitching motility on the cell surface with the formation of mobile microcolonies (Figure 22–2). Biofilms may also act as an adherence mechanism by binding to catheters, prosthetic devices, or mucosal surfaces.
Pili. Pili extending from a microcolony of Neisseria gonorrhoeae (gonococci) are shown attaching the microvilli of an epithelial cell. The pili actively retract and mediate a movement of the colony across the cell surface called twitching motility. (Photomicrographs kindly provided by Dustin L. Higashi and Magdalene So.)
Many have multiple attachment mechanisms
✺ Biofilms can mediate adherence
Once the bacterial pathogen attaches, it must persist if it is to produce disease. Survival is less complicated if the organism can produce injury without moving from its initial niche. This is the case with some exotoxin-mediated bacterial diseases (diphtheria, whooping cough), but most pathogens must move either into the cell or beyond it. To do so requires a new set of survival strategies which include either multiplying in the intracellular milieu or avoiding the attack of complement and phagocytes in the submucosa.
INVASION: GETTING INTO CELLS
A few bacteria, like viruses, are obligate intracellular pathogens. Other bacteria are facultative intracellular pathogens and can grow as free-living cells in the environment as well as within host cells. Generally, invasive organisms adhere to host cells by one or more adhesins but use a class of molecules, called invasins, which interact with integrins or other families of cell adhesion molecules. The integrins in turn interact with elements of the cell cytoskeleton stimulating modifications which end in uptake of the bacterial cell. Invasive bacteria seem to be exploiting cell uptake mechanisms that are there for other purposes such as nutrition.
✺ Invasins interact with cytoskeleton
Bacteria enter cells initially within a membrane-bound, host-vesicular structure but then follow one of two pathways (Figure 22–3). Some bacteria (Listeria, Shigella) enzymatically lyse the phagosome membrane and escape to the nutrient-rich safe haven of the host cell cytoplasm. These bacteria may continue to multiply there, infect adjacent cells, or move through the cell to the submucosa. Other invasive pathogenic species (Salmonella serotype Typhi, Mycobacterium tuberculosis) remain in the phagosome and replicate even in professional phagocytes. Their survival in this usually perilous location is due to thwarting normal host cell trafficking patterns and avoiding the killing action of the phagolysosome. There are multiple known mechanisms for this including preventing phagosome–lysosome fusion or, if fused, blocking acidification to the optimum pH for digestive enzyme activity. Some bacteria are able to neutralize the phagocytes’ oxidative burst by the production of neutralizing enzymes (catalase, superoxide dismutase).
Bacterial invasion. A. The bacterial cell has an injection secretion system that is injecting multiple proteins into the host cell. Some of these cause cytoskeletal reorganization, which engulfs the bacteria. In the cytosol, the bacteria lyse the vacuolar membrane, escape, and move about. B. A bacterial surface protein binds to the cell surface and induces its own endocytosis. In the cell, some escape (as in A), and others multiply in the phagosome. Another bacterium is seen invading between cells A and B by disrupting intercellular attachment molecules.
Enter phagosome or cytoplasm
✺ Pathogens can block phagosome killing
In gram-negative bacteria with injection secretion systems (types III, IV, VI), a variation on the above scenarios is possible. The secretion systems inject many proteins, some of which disrupt cellular signaling and the cell’s cytoskeleton. The cytoskeleton rearrangements may leave the bacteria tightly bound to an altered surface or trigger invasion. One pathogen even injects its own receptor, which is processed to the outer membrane where it mediates tight binding of its parent bacterial strain.
✺ Injection secretion systems trigger invasion or tight binding
PERSISTING IN A NEW ENVIRONMENT
Bacteria that reach the subepithelial tissues are immediately exposed to the extracellular tissue fluids, which have defined properties that inhibit multiplication of many bacteria. For example, most tissues contain lysozyme in sufficient concentrations to disrupt the cell wall of gram-positive bacteria. Tissue fluid itself is a suboptimal growth medium for most bacteria and is deficient in free iron. In humans the iron not found in hemoglobin is chelated to a series of iron-binding proteins (lactoferrin, transferrin). Because virtually all pathogenic bacteria require iron they have evolved their own set of iron-binding proteins called siderophores which effectively compete with the human proteins for available iron.
Subepithelial environment is different
✺ Siderophores compete for iron sources
Confounding the Immune System
The host immune system evolved in large part because of the selective pressure of microbial attack. To be successful, microbial pathogens must escape this system at least long enough to be transmitted to a new susceptible host or to take up residence within the host in a way that is compatible with mutual coexistence.
Manipulating PAMPs and AMPs
The early warning and response system in which pathogen-associated molecular patterns (PAMPs) are recognized by Toll-like receptors (TLRs) (see Chapter 2) is subject to evasion by successful pathogens. This has been studied in regard to gram-negative bacterial LPS whose pattern is typically detected by TLR-4. In some pathogens (Helicobacter, Legionella, Yersinia) the lipid A (toxic) component of LPS is simply a variant poorly recognized by TLR-4; other pathogens (Salmonella, Pseudomonas) are able to modulate their lipid A pattern. The result of both is a head start by evading a major innate immune mechanism. Modification of lipid A in a way that modifies their surface charge is also a way that gram-negative bacteria escape the action of antimicrobial peptides (AMPs) which attack bacterial membranes by electrostatic force. Gram-positive bacteria may accomplish a similar benefit by altering their cell wall teichoic acids.
✺ LPS modifications disrupt PAMPs and AMPs
A fundamental requirement for many pathogenic bacteria is escape from phagocytosis by macrophages and polymorphonuclear leukocytes. The most common bacterial means of avoiding phagocytosis is an antiphagocytic capsule, which is possessed by almost all principal pathogens that cause pneumonia and meningitis. These polysaccharide capsules of pathogens interfere with effective complement deposition on the bacterial cell surface by binding regulators of C3b that are present in serum. When one of these, serum factor H, is concentrated on the capsular surface, it accelerates the degradation of C3b deposited from the host’s serum. This negates both direct complement injury and makes the receptors recognized by phagocytes unavailable (Figure 22–4). This mechanism is not restricted to polysaccharide capsules. Surface proteins able to bind factor H have the same biologic effect. Antibody directed against the capsular antigen reverses this effect because C3b can then bind in association with IgG. Another mechanism for complement disruption is through surface acquisition of sialic acid, a common component of capsular polysaccharides. Some bacteria are able to incorporate sialic acid from the host on their surfaces with an effect similar to capsules.
Bacterial resistance to opsonophagocytosis. A. Alternate pathway. In the alternate complement pathway, C3b binds to the surface of bacteria, providing a recognition site for professional phagocytes and sometimes causing direct injury. Bacteria with special surface structures such as capsules or protein are able to bind serum factor H to their surface. This interferes with complement deposition by accelerating the breakdown of C3b. B. Classical pathway. Specific antibody binding to an antigen on the surface provides another binding cite for C3b. Phagocyte recognition may occur even if factor H is present.
Polysaccharide capsules and surface proteins may be antiphagocytic
✺ Binding serum factor H to the surface interferes with C3b deposition
One of the most common tactics of pathogens is to produce proteins which induce programmed cell death (apoptosis). This microbial tactic not only inactivates the killing potential of the phagocyte, but also reduces the number of defenders available to inhibit other bacterial invaders. The invading bacteria that induce apoptosis obtain the added benefit that death by apoptosis nullifies the normal cellular signaling processes of cytokine and chemokine signaling of necrotic death.
✺ Apoptosis of phagocytes is induced
Another method by which microorganisms avoid host immune responses is by varying surface antigens. Gonorrhea is a disease in which there appears to be no natural immunity and reinfections are common. In fact, an immune response can be mounted to the pathogenically significant surface pili and outer membrane proteins (OMPs) of N gonorrhoeae, but the organism is continuously varying them. This can happen even in the course of a single acute infection. The genetic mechanism for antigenic variation of pili involves recombination between multiple silent and expressing genes in the gonococcal chromosome. For OMPs multiple genes are turned on and off by the status of a frame-shift mutation. These mechanisms are illustrated in Figure 22–5 and discussed further in Chapter 30. The effect is that when the immune system delivers specific IgG to the site of infection, it will bind its homologous antigen, but a subpopulation with an antigenically different surface can multiply and continue the infection. Therefore, the pathogen escapes immune surveillance. A number of other bacteria and parasites also undergo antigenic variation.
Antigenic variation. Mechanisms for change in the antigenic makeup of both pili and outer membrane Opa proteins of Neisseria gonorrhoeae are shown. A. The chromosome contains multiple unlinked pilin genes, which are either expressing (pilE) or silent (pilS). The expressing gene is transcribing a mature pilin protein subunit. During chromosome replication, one of the pilS genes recombines with one of the pilE genes, donating some of its DNA (red). The new daughter chromosome now produces an antigenically different pilin based on transcription of the donated (red) sequences into protein. B. The chromosome contains multiple Opa genes. Opa 3 and Opa 6 are “on” (producing protein), and the others are “off.” During chromosome replication, replicative slippage in the leader peptide causes a five-base sequence (CTCTT) to be repeated variable numbers of times. Translation of the Opa will remain in-frame only if the number of added CTCTT nucleotides is evenly divisible by three. For the Opa gene in B1, the triplet code for alanine (GCA) is in-frame (9 × 5 = 45. 45 ÷ 3 = 15) but in B3 it is out-of-frame.
Surface antigens can be varied
✺ Antigenically different subpopulations escape immune surveillance
The successful pathogen must survive and multiply in the face of multiple host defenses. Although this is a formidable achievement, by itself it is not enough to cause disease. Disease requires some disruption of host function by the bacteria. Bacterial toxins are the most obvious mechanism of injury and are exported by the secretion systems described in Chapter 21 often along with multiple other virulence factors. In some diseases the only injury appears to be due to the inflammatory response to the invader.
Disease requires injury to the host
The longest known and best studied virulence factors are bacterial exotoxins. They are proteins toxic to the human host which are secreted by the bacteria into the surrounding body fluids. Their action may be local or systemic if absorbed into the bloodstream. These exotoxins usually possess some degree of host cell specificity, which is dictated by the nature of the binding of one or more toxin components to a specific host cell receptor. The distribution of host cell receptors often dictates the degree and nature of the toxicity.
The best-known pathogenic exotoxin theme is represented by the A–B exotoxins. These toxins are divided into two general domains. The B subunit(s) contains the binding specificity of the holotoxin to the host cell. Generally speaking, the B region binds to a specific host cell surface glycoprotein or glycolipid. The specificity of this binding determines the host cell specificity of the toxin. The A (active) subunit, catalyzes an enzymatic reaction characteristic for the toxin. After attachment of the B domain to the host cell surface, the A domain is transported by direct fusion or by endocytosis into the host cell. In the cell, the A unit carries out the enzymatic modification of a protein called its target protein. The most common enzymatic reaction is ADP-ribosylation, which attaches the ADP-ribose moiety from NAD to the target protein. This ADP-ribosylated protein is then unable to carry out its function or behaves abnormally. There are multiple other enzymatic reactions carried out by A–B exotoxins.
✺ B unit binds to cell receptor
✺ A unit acts on target protein
The net effect of the toxin depends on the intracellular function of the target protein and the biologic function of the cell in humans. If it is crucial for the protein-synthesizing apparatus of the cell (diphtheria toxin), protein synthesis ceases and the cell dies (see Figure 1–7). However, cell death is not the inevitable outcome of toxin action. One of the major targets of the ADP-ribosylating A–B toxins are guanine nucleotide-binding proteins (G proteins), which are involved in signal transduction in eukaryotic cells. In this case, the inactivation of the regulatory G protein can inhibit or stimulate some activity of the cell. Cholera toxin inactivates a G protein that downregulates a secretory pathway. If the cell is an intestinal enterocyte, the end result is hypersecretion of electrolytes and diarrhea. Cholera toxin applied to cells from the adrenal gland stimulates steroid production.
Biologic effect depends on function of target protein
Toxin effect may be inhibitory, stimulatory, or fatal
Some exotoxins act directly on the surface of host cells to lyse or to kill them. Many were first observed in the laboratory by their ability to cause hemolysis of erythrocytes. The most common action is to create pores by direct insertion into eukaryotic membranes of a wide range of cells including phagocytes (Figure 22–6). These pore-forming toxins are produced by some of the most aggressive pathogens (S aureus, group A streptococcus, E coli) and cause cellular death by loss of cellular integrity and leakage through the pore. Some are called the RTX (repeats in toxin) group because of a recurrent amino acid sequence in their structure. Another type of membrane-active toxin acts through direct enzymatic activity destroying the integrity of plasma membrane lipids. The α-toxin of Clostridium perfringens is a lecithinase causing hemolysis of RBCs.
Pore-forming exotoxin. The pore protein has inserted itself into the host cell membrane making an open channel. Formation of multiple such pores causes cytoplasmic contents to leave the cell and water to move in. This ultimately leads to cell lysis and death. (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th edition. McGraw-Hill, 2008.)
✺ Insertion in cytoplasmic membrane creates a leaking pore
Many bacteria produce one or more enzymes that are nontoxic per se, but facilitate tissue invasion or help to protect the organism against the body’s defense mechanisms. For example, various bacteria produce collagenase or hyaluronidase or convert serum plasminogen to plasmin, which has fibrinolytic activity. Although the evidence is not conclusive, it is reasonable to assume that these substances may facilitate the spread of infection. Some bacteria also produce deoxyribonuclease, elastase, and many other biologically active enzymes, but their function in the disease process or in providing nutrients for the invaders is uncertain.
Enzymatic actions cause injury, facilitate spread
Some microbial exotoxins have a direct effect on cells of the immune system, and this interaction leads to disease. The most dramatic of these are the toxins causing the toxic shock syndromes of S aureus and group A streptococci. These syndromes are evoked when toxin is produced at an infected site and absorbed into the circulation. These toxins are able to bind directly to class II major histocompatibility complex (MHC) molecules on antigen-presenting cells (without processing) and directly stimulate production of cytokines such as interleukin 1 (IL-1) and tumor necrosis factor (TNF) (Figure 22–7). These molecules are called superantigens because they act as polyclonal stimulators of T cells. This means a significant proportion of all T cells respond by dividing and releasing cytokines, which makes the cytokine release massive enough to cause systemic effects such as shock. When ingested preformed in food, some of these toxins cause diarrhea and vomiting.
Superantigen exotoxin. A superantigen (yellow) is binding to the MHC class II molecular complex outside the groove for antigen presentation. This causes a massive secretion of cytokines.
✺ Superantigens bind directly to MHC II
Cytokines are released from a large proportion of T cells
In many infections caused by gram-negative bacteria, the LPS endotoxin of the outer membrane is a significant component of the disease process. LPS can cause local injury, but the major effects come when gram-negative bacteria enter the bloodstream and circulate. The lipid A portion causes fever through the release of IL-1 and TNF from macrophages and dramatic physiologic effects associated with inflammation. These include hypotension, lowered polymorphonuclear leukocyte and platelet counts from increased margination of these cells to the walls of the small vessels, hemorrhage, and sometimes disseminated intravascular coagulation (DIC) from the activation of clotting factors. Rapid and irreversible shock may follow passage of endotoxin into the bloodstream.
✺ LPS in the bloodstream causes shock, DIC
The term endotoxin comes from the fact that LPS is an inherent structural component of the gram-negative cell wall, not a secreted product of the bacteria. A comparable event with gram-positive and gram-negative bacteria can occur with the release and circulation of peptidoglycan cell wall fragments. This also leads to cytokine release and systemic manifestations. Although the biology is similar, the terms endotoxin or endotoxemia are not used because they have long been reserved for the LPS endotoxin of gram-negative bacteria.
Peptidoglycan fragments are not called endotoxin
Damage Caused by Inflammation and Immune Responses
Many successful pathogens produce disease without using any of the known virulence factors just described. In these instances, injury can still be produced by acute or chronic inflammation or a misdirected immune response triggered by antigenic components of the pathogen.
The normal inflammatory response is a two-edged sword in both acute and chronic infections. Although the enzymes of PMNs are killing the invader, they still cause some damage to host tissues or compromise organ function. Pulmonary alveoli filled with PMNs and macrophages are not effective in the absorption of oxygen. In the closed space of the central nervous system, the swelling caused by inflammation may directly lead to brain injury. In some chronic infections, the pathologic and clinical features are due largely to delayed-type hypersensitivity (DTH) reactions to the organism or its products. In tuberculosis if the host is unable to halt the growth of M tuberculosis by activation of cell-mediated immunity, persistent growth of the pathogen will continue to stimulate DTH-mediated injury.
✺ PMNs cause swelling, occupy space
✺ Prolonged DTH is destructive
Misdirected Immune Responses
Reactions between high concentrations of antibody, soluble microbial antigens, and complement can deposit immune complexes in tissues and cause acute inflammatory reactions and immune complex disease. In poststreptococcal acute glomerulonephritis, for example, the complexes are sequestered in the glomeruli of the kidney, with serious interference in renal function from the resulting complement deposition and tissue reaction. Antibody produced against bacterial antigens can cross-react with certain host tissues and initiates an autoimmune process. This molecular mimicry is felt to be the explanation for poststreptococcal rheumatic fever.
Bacterial antigens trigger autoimmune cross-reactions
Bacteria use pili and surface proteins to adhere to mannose, fibronectin, and other receptors on the surface of epithelial cells.
Cell invasion and cytoskeleton modification are triggered by surface “invasins.” This allows residence in the cytoplasm, progress to adjacent cells or exit to the submucosa.
Survival in professional phagocytes is achieved by multiple mechanisms which defeat steps in their bacterial killing processes.
Survival in the submucosa and beyond requires nutrient scavenging and defense against the innate and adaptive immune systems.
Capsules and surface proteins interfere with complement C3b deposition by binding serum factor H.
Specific humoral immunity is confounded by antigenic variation of surface virulence factors.
Superantigens cause massive cytokine release.
Pore-forming toxins punch holes in cells.
Protein exotoxins catalyze enzymatic reactions which inactivate or disrupt key metabolic processes of the cell. LPS endotoxin causes shock.
Acute and chronic inflammation compromise organ function. Prolonged DTH is destructive.