Immunology (Lippincott Illustrated Reviews Series) 2nd Edition
Chapter 5: Innate Immune Function
PAMP-PRR engagement activates phagocytes. Binding of PAMPs on microbial surfaces by PRRs on the surfaces of phagocytes activates the phagocytes to ingest and degrade the microbes.
If microbes should penetrate the body’s first line of defense—the mechanical, chemical, and biological barriers—the innate immune system provides the second line of defense (the first immunologic line of defense) against infection. Because its components are always in an activated or near-activated state, responses by the innate immune system occur much faster than those of the adaptive immune system that provides the third line of defense (the second immunologic line of defense). Once the adaptive system becomes involved, the innate and adaptive immune systems often interact with one another to coordinate their activities. To respond quickly, components of the innate immune system are genetically programmed to recognize molecules associated with broad classes of pathogens. Innate immune responses include the rapid destruction of an infectious organism, activation of phagocytic cells, and the localized protective response known as inflammation. In inflammation, innate (and sometimes adaptive) cells and molecules are stimulated to isolate and destroy infectious agents and trigger tissue repair.
The innate immune system uses a limited number of pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs)—conserved, structural features expressed by microbes but not by the host (see Fig. 2.5). Unlike the epitope-specific somatically generated receptors of the adaptive immune system expressed by B and T lymphocytes, genes encoding PRRs are encoded within the genome and require no additional modification. Because the host does not produce PAMPs, the innate immune system is able to discriminate between self and nonself.
A. Pathogen-associated molecular patterns
The innate immune system distinguishes infectious microbes from noninfectious self cells by recognizing a limited number of widely expressed viral and bacterial molecular structures. PAMPs may be sugars, proteins, lipids, nucleic acids, or combinations of these types of molecules. PRRs on phagocytic cells recognize PAMPs either directly or indirectly by cell-surface PRRs or by soluble molecules that engage a microbe prior to cell-surface receptor contact (e.g., complement and complement receptors, discussed later in this chapter). PAMP binding immobilizes the infectious organism and may culminate in its ingestion by phagocytes. In addition, PRR engagement often leads to the activation of the host cell, causing it to alter its activity and increase its secretion of antimicrobial substances (Fig. 5.1).
Two common bacterial products that contain PAMPs are lipopolysaccharide and peptidoglycan. Bacterial lipopolysaccharide (LPS) is a major constituent of the outer cell membrane of gram-negative bacteria. Cell-surface molecules on monocytes, macrophages, dendritic cells, mast cells, and intestinal epithelial cells bear toll-like receptor 4 (TLR4) (see Table 2.2) and other cell-surface molecules that bind LPS.Peptidoglycans are major components of the cell walls of gram-positive bacteria and are recognized by TLR2 receptors on host phagocytic cells (Fig. 5.2). Peptidoglycans are also expressed to a lesser degree and in a slightly different form on gram-negative bacteria. As a result of receptor engagement, the microbes are ingested and degraded, the macrophage is activated, and cytokine production and inflammation result (see Section IV.A).
Lipopolysaccharide and peptidoglycan structures. Major bacterial PAMPs are found in lipopolysaccharides (carbohydrates 1 lipids) of gram-negative bacteria and in peptidoglycans (carbohydrates 1 proteins) associated with both gram-negative and gram-positive bacteria.
B. Pattern recognition receptors
PRRs are divided into the categories described later and are present as extracellular proteins or as membrane-bound proteins on phagocytic cells in the bloodstream. During recognition of PAMPs, multiple receptors may be simultaneously engaged to mediate internalization, activate the killing of microbes, and induce the production of inflammatory cytokines and chemokines.
1. Toll-like receptors (TLRs) mediate recognition of diverse pathogens. After binding to PAMPs, signal transduction from a TLR to the nucleus leads to enhanced activation of genes encoding cytokines and other molecules involved in antimicrobial activity. The result is synthesis and secretion of the cytokines that promote inflammation and the recruitment of leukocytes to the site of infection.
2. Scavenger receptors are involved in binding of modified low-density lipoproteins, some polysaccharides, and some nucleic acids. They are involved in the internalization of bacteria and in the phagocytosis of host cells undergoing apoptosis.
3. Opsonins are molecules that, when attached to the surface of microbes, make them more attractive to phagocytic cells, thus facilitating microbe destruction. Opsonins bind to microbial surfaces. Receptors for opsonins are present on phagocytic cells, and the subsequent increased phagocytic destruction of microbes is termed opsonization.
C. Markers of abnormal self
An evasive maneuver that microorganisms sometimes employ to avoid recognition by the immune system is to subvert the host cells. Some viruses cause an infected host cell to reduce its expression of MHC class I molecules that are critical to the proper functioning of the adaptive immune system (discussed in Chapters 7 and 10). Similar changes sometimes occur in cells undergoing cancerous transformation. Host cells that become abnormal as a result of such events can alert the immune system to their situation by expressing molecules on their surfaces that act as stress signals. In humans, these include some heat shock proteins and two molecules known as MICA and MICB (Fig. 5.3). These stress signals are detected by various receptors, including some of the TLRs (e.g., TLR2 and TLR4) (see Table 2.2) and the killer activation receptors (KARs) of natural killer (NK) cells (see Section IV.B).
Infection of cells may lead to the surface expression of stress molecules. In response to viral infection, host cells may express stress molecules such as MICA and MICB on their surface and may also reduce their surface expression of MHC class I molecules. These surface changes can be detected by NK cells that seek to eliminate virally infected cells.
III. SOLUBLE DEFENSE MECHANISMS
In addition to the actions of whole cells, the innate immune system employs soluble molecules as weaponry for protection from viral infection, for lytic destruction of microbes, or for increasing the susceptibility of microbes to ingestion by phagocytic cells.
A. Type I interferons
Type I interferons (IFNs) are produced by a subset of dendritic cells (IFN-α), by nonleukocytes such as fibroblasts (IFN-β), and by other cells in response to viral infection (Fig. 5.4). IFN-α and IFN-β are rapidly produced, within 5 minutes, by cells when viral PAMPs interact with certain PRRs. Very little is currently known about the signal transduction pathways responsible for expression and secretion of IFN-α and IFN-β. Secreted type I IFNs induce both virally infected and noninfected cells to activate numerous antiviral defenses including RNA-dependent protein kinase (PKR) and apoptotic (programmed cell death) pathways. In addition, IFN-α and IFN-β influence the activities of macrophages and dendritic cells.
B. Microcidal molecules
Various cells, including epithelial cells, neutrophils, and macrophages, in the skin and mucous membranes secrete cysteine-rich peptides called defensins. These peptides form channels in the cell membranes of bacteria, which cause the influx of certain ions and eventually bacterial death. Other molecules with microcidal functions include cathelicidin, lysozyme, DNases and RNases, and others, as discussed in Chapter 3.
Complement is a collective term for a system of enzymes and proteins that function in both the innate and adaptive branches of the immune system as soluble means of protection against pathogens that evade cellular contact. A series of circulating and self-cell-surface regulatory proteins keep the complement system in check. In the innate immune system, complement can be activated in two ways: via the alternative pathway, in which antigen is recognized by particular characteristics of its surface, or via the mannan-binding lectin (MBL) pathway. Complement can also be activated in the adaptive immune system via the classical pathway that begins with antigen–antibody complexes (which is described in subsequent chapters) (Fig. 5.5). Regardless of the pathway of activation, functions of complement include lysis of bacteria, cells, and viruses; promotion of phagocytosis (opsonization); triggering of inflammation and secretion of immunoregulatory molecules; and clearance of immune complexes from circulation.
Type 1 interferon response to intracellular microbial invasion. Some cells respond to infection by producing and secreting type I interferons that signal adjacent cells to activate their antimicrobial defenses.
Three complement pathways lead to formation of the membrane attack complex.
• Components C1 through C9, B, , and P are native complement (protein) components.
• Fragments of native complement components are indicted by lowercase letter (e.g., C4a, C5b, Bb). Smaller cleavage fragments are assigned the letter “a,” and major (larger) fragments are assigned the letter “b.”
• A horizontal bar above a component or complex indicates enzymatic activity (e.g., ).
1. The alternative pathway is initiated by cell-surface constituents that are recognized as foreign to the host, such as LPS (Fig. 5.6). Various enzymes (e.g., kallikrein, plasmin, elastase) cleave C3, the most abundant (~1300 mg/mL) serum complement component, into several smaller fragments. One of these, the continuously present, short-lived, and unstable C3b fragment, is the major opsonin of the complement system and readily attaches to receptors on cell surfaces (Fig. 5.7).
1. C3b binds Factor B.
2. Factor B in the complex is cleaved by Factor to produce ,
an unstable C3 convertase.
3. Two proteins, C3b inactivator (I) and β1H-globulin (H), function as important negative regulators, making an inactive form of C3b (C3b) to prevent the unchecked overamplification of the alternative pathway.
4. Alternatively, binds properdin (Factor P) to produce stabilized C3 convertase, .
5. Additional C3b fragments join the complex to make , also known as C5 convertase. C5 convertase cleaves C5 into C5a and C5b.
6. C5b inserts into the cell membrane and is the necessary step leading to formation of the membrane attack complex (MAC) and cell lysis.
Alternative pathway of complement activation. Beginning with the binding of C3b to a microbial surface, this pathway results in an amplified production of C3b and formation of a C5 convertase.
Multiple functional roles for complement fragment C3b.
2. The terminal or lytic pathway can be entered from the alternative, mannan-binding lectin, or classical pathway of complement activation. Attachment of C5b to the bacterial membranes initiates formation of the membrane attack complex (MAC) and lysis of the cell (Fig. 5.8). The attachment of C5b leads to the addition of components C6, C7, and C8. C8 provides a strong anchor into the membrane and facilitates the subsequent addition of multiple C9 molecules to form a pore in the membrane. Loss of membrane integrity results in the unregulated flow of electrolytes and causes the lytic death of the cell (Fig. 5.9).
Terminal or membrane attack complex (MAC) of complement. The MAC forms a pore in the surfaces of microbes to which it is attached, causing lytic death of those microbes.
Insertion of the membrane attack complex (MAC) components into a cell membrane. Formation of the MAC requires a sequential addition of several complement components, beginning with C5a and terminating with multiple C9 components, to form the pore in the microbial membrane.
3. Mannan-binding lectin pathway: Lectins are proteins that bind to specific carbohydrates. This pathway is activated by binding of mannan-binding lectin (MBL) to mannose-containing residues of glycoproteins on certain microbes (e.g., Listeria spp., Salmonella spp., Candida albicans). MBL is an acute phase protein, one of a series of serum proteins whose levels can rise rapidly in response to infection, inflammation, or other forms of stress. MBL, once bound to appropriate mannose-containing residues, can interact with MBL-activated serine protease (MASP). Activation of MASP leads to subsequent activation of components C2, C4, and C3 (Fig. 5.10).
4. Anaphylotoxins: The small fragments (C3a, C4a, C5a) generated by the cleavage of C3 and C5 in the alternative pathway and of C3, C4, and C5 in the MBL pathway act as anaphylotoxins. Anaphylotoxins attract and activate different types of leukocytes (Table 5.1). They draw additional cells to the site of infection to help eliminate the microbes. C5a has the most potent effect, followed by C3a and C4a.
D. Cytokines and chemokines
Cytokines are secreted by leukocytes and other cells and are involved in innate immunity, adaptive immunity, and inflammation (Table 5.2). Cytokines act in an antigen-nonspecific manner and are involved in a wide array of biologic activities ranging from chemotaxis to activation of specific cells to induction of broad physiologic changes. Chemokines are a subgroup of cytokines of low molecular weight and particular structural patterns that are involved in the chemotaxis (chemical-induced migration) of leukocytes. The roles of specific cytokines and chemokines are described in the contexts of the immune responses in which they participate (see Section IV.A of this chapter).
Mannan-binding lectin (MBL) pathway of complement activation. The lectin binding pathway is initiated by the binding of certain glycoproteins commonly found on microbial surfaces, and results in the formation of a C3 convertase (that acts to produce C3b) and a C5 convertase (that can lead to MAC formation).
IV. CELLULAR DEFENSE MECHANISMS
In addition to soluble means of defense, the innate immune system employs cellular mechanisms to combat infection. Receptors that recognize ligands from pathogens trigger inflammation and destruction of microbes by phagocytes. In addition, NK cells detect and destroy host cells that have been infected, injured, or transformed. We will discuss each of these cellular actions.
Phagocytosis is the engulfment and degradation of microbes and other particulate matter by cells such as macrophages, dendritic cells, neutrophils, and even B lymphocytes (prior to their activation). These cells are part of the body’s “cleansing” mechanism. They not only defend the body by ingesting microbes, but also remove cellular debris and particulate matter that arise from normal physiologic functions.
Phagocytosis involves cell-surface receptors associated with specialized regions of the plasma membrane called clathrin-coated pits. Dendritic cells use an additional mechanism to sample large amounts of soluble molecules, a process known as macropinocytosis. This process does not involve clathrin. Instead, plasma membrane “ruffles” or projections fold back on the membrane to engulf extracellular fluids in large intracellular vesicles.
1. Recognition and attachment of microbes by phagocytes: Phagocytosis is initiated when a phagocyte binds a cell or molecule that has penetrated the body’s barriers. The binding occurs at various receptors on the phagocyte surface (Fig. 5.11). These include PRRs (including TLRs) that recognize microbe-related molecules, complement receptors (CR) that recognize certain fragments of complement (especially C3b) that adhere to microbial surfaces, Fc receptors that recognize immunoglobulins that have bound to microbial surfaces or other particles (discussed in Chapter 11), scavenger receptors, and others.
Phagocyte receptors. Phagocytosis is initiated when any of several types of receptors on the phagocyte surface recognize an appropriate molecule that indicates the presence of a foreign cell or molecule.
Phagocytosis, phagosome, and phagolysosome formation. A. In phagocytosis, molecules and particles are captured and ingested by receptors associated with membrane regions called clathrin-coated pits. B. In macropinocytosis, protrusions of the plasma membrane capture extracellular fluids whose contents are subsequently ingested. In both cases, the ingested material is degraded in phagolysosomes.
2. Ingestion of microbes and other material: Following attachment to the cell membrane, a microorganism or foreign particle is engulfed by extensions of the cytoplasm and cell membrane called pseudopodia and is drawn into the cell by internalization or endocytosis (Fig. 5.12). In addition to phagocytosis, dendritic cells can extend plasma membrane projections and encircle large amounts of extracellular fluids to form cytoplasmic vesicles independent of cell surface attachment. Once internalized, the bacteria are trapped within phagocytic vacuoles (phagosomes) or cytoplasmic vesicles within the cytoplasm. The attachment and ingestion of microbes trigger changes within the phagocyte. It increases in size, becomes more aggressive in seeking additional microbes to bind and ingest, and elevates production of certain molecules. Some of these molecules contribute to the destruction of the ingested microbes; others act as chemotactic agents and activators for other leukocytes.
3. Destruction of ingested microbes and other materials: Phagosomes, the membrane-bound organelles containing the ingested microbes/materials, fuse with lysosomes to form phagolysosomes. Lysosomes employ multiple mechanisms for killing and degrading ingested matter. These include
• lysosomal acid hydrolases, including proteases, nucleases, and lipases;
• several oxygen radicals, including superoxide radicals (O2–), hypochlorite (HOCl–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) that are highly toxic to microbes. The combined action of these molecules involves a period of heightened oxygen uptake known as the oxidative burst (Fig. 5.13);
Oxidative burst. Phagolysosomes contain enzymes capable of generating free radicals that can efficiently kill microbes.
• nitrous oxide (NO);
• decreased pH; and
• other microcidal molecules.
4. Secretion of cytokines and chemokines: Once activated, phagocytes secrete cytokines and chemokines that attract and activate other cells involved in innate immune responses (see Table 5.2 and Tables 6.2 and 6.3). Cytokines or chemical messengers such as interleukin-1 (IL-1) and interleukin-6 (IL-6) induce the production of proteins that lead to elevation of body temperature. Other cytokines, such as tumor necrosis factor-α (TNF-α), increase the permeability of local vascular epithelia to increase its permeability and enhance the movement of cells and soluble molecules from the vasculature into the tissues. Still others, such as interleukin-8 (IL-8) and interleukin-12 (IL-12), attract and activate leukocytes such as neutrophils and NK cells.
B. Natural Killer Cell Responses
NK cells detect aberrant host cells and target them for destruction (Fig. 5.14). NK cells possess killer activation receptors (KAR) that recognize stress-associated molecules, including MICA and MICB in humans, which appear on the surface of infected and transformed host cells. Binding of KAR to MICA and MICB generates a kill signal. Before proceeding to kill the targeted cells, however, NK cells use killer inhibition receptors (KIR) to assess MHC I molecules on the target cell surface. Some viruses and malignant events often depress expression of these molecules. If insufficient levels of KIR-MHC I binding occurs, the NK cell will kill the target host cell. Sufficient binding by the KIRs will override the KAR kill signal, and the host cell will be allowed to survive.
Components of both the innate and adaptive immune systems may respond to certain antigens to initiate a process known as inflammation. The cardinal signs of inflammation are pain (dolor), heat (calor), redness (rubor), swelling (tumor), and loss of function (functio laesa). Enlarged capillaries that result from vasodilation cause redness (erythema) and an increase in tissue temperature. Increased capillary permeability allows for an influx of fluid and cells, contributing to swelling (edema). Phagocytic cells attracted to the site release lytic enzymes, damaging healthy cells. An accumulation of dead cells and fluid forms pus, whereas mediators released by phagocytic cells stimulate nerves and cause pain. The innate immune system contributes to inflammation by activating the alternative and lectin-binding complement pathways, attracting and activating phagocytic cells that secrete cytokines and chemokines, activating NK cells, altering vascular permeability, and increasing body temperature (Fig. 5.15 and Table 5.2). The adaptive immune system also plays a role in inflammation, which is discussed in Chapter 13.
NK cell recognition by KIR and KAR. NK cells have killer activation receptors (KARs) that recognize stress-associated molecules (e.g., MICA and MICB in humans) on the surface of abnormal host cells. Binding of KAR to MICA and MICB provides a kill signal. NK cells also use killer inhibition receptors (KIRs) to assess MHC I molecules on the target cell surface. If insufficient KIR-MHC I binding occurs, the NK cell will proceed to kill the target host cell. But sufficient binding by KIRs will override the KAR kill signal, sparing the life of the host cell.
Inflammation. Inflammation results from the composite action of several immune responses to infection and injury, and results in pain, heat, redness, and swelling.
• The innate immune system provides a rapid, initial means of defense against infection using genetically programmed receptors that recognize structural features of microbes that are not found in the host.
• Pattern recognition receptors (PRRs) on or in phagocytic cells bind to pathogen-associated molecular patterns (PAMPs). PAMPS are conserved, microbe-specific carbohydrates, proteins, lipids, and/or nucleic acids.
• Common bacterial structures that contain PAMPs include lipopolysaccharides and peptidoglycans.
• PRR binding to PAMPs results in phagocytosis and enzymatic degradation of the infectious organism. PRR engagement can lead to the activation of the host cell and its secretion of antimicrobial substances.
• Toll-like receptors are PRRs that bind specific PAMPs. This binding signals the synthesis and secretion of the cytokines to promote inflammation and recruit leukocytes to the site of infection.
• Scavenger receptors are PRRs that are involved in internalization of bacteria and in the phagocytosis of host cells undergoing apoptosis.
• Opsonins bind to microbes to facilitate their phagocytosis.
• Infected or transformed host cells display stress molecules on their surfaces and sometimes show decreased MHC I expression.
• Stress molecules are recognized by killer activation receptors (KAR) on NK cells. Killer inhibition receptors (KIR) on NK cells assess MHC I molecules on the target cell surface.
• Soluble defense molecules include the type I interferons, defensins, complement, and cytokines.
• Complement is a system of enzymes and proteins that functions in both the innate and adaptive branches of the immune system. In the innate immune system, complement can be activated through either the alternative pathway or the mannan-binding lectin pathway.
• Phagocytosis, a direct mechanism to combat infection, is the engulfment and degradation of microbes by phagocytic cells that secrete cytokines and chemokines to attract and activate other cells of the innate immune system. The oxidative burst, producing several highly reactive oxygen metabolites, and a series of degradation enzymes are important means by which ingested microbes are destroyed.
• The innate immune system contributes to inflammation by activating complement pathways, attracting and activating phagocytic cells that secrete cytokines and chemokines, activating NK cells, altering vascular permeability, and increasing body temperature.
• Cardinal signs of inflammation are pain (dolor ), heat (calor ), redness (rubor), swelling (tumor), and loss of function (functio laesa).
5.1. Pathogen-associated molecular patterns (PAMPs)
A. allow B and T lymphocytes to recognize bacteria and destroy them.
B. are cysteine-rich peptides that form channels in bacterial membranes.
C. are recognized by pattern recognition receptors of the innate immune system.
D. closely resemble host cell surface proteins and sugars.
E. induce secretion of interferons by virally infected host cells.
The answer is C. Pattern recognition receptors of the innate immune system bind structural patterns composed of proteins, sugars, and lipids that are found on microbes but are not found in the human host. This mechanism allows for a rapid and precise recognition of potential pathogens. In contrast, B and T lymphocytes are components of the adaptive immune system in which somatically generated receptors recognize precise molecular details of antigens as opposed to broad structural characteristics found in pathogen-associated molecular patterns.
5.2. A 76-year-old man is diagnosed with Escherichia coli septicemia. The initial immune response to E. coli (gram-negative bacteria) will include
A. binding by LPS-binding proteins and delivery to receptors on macrophages.
B. formation of specific somatically generated receptors to bind E. coli.
C. generation and secretion of specific antibodies to recognize E. coli.
D. production of E. coli–specific cytokines by lymphocytes.
E. stimulation of killer activation receptors on NK cells.
The answer is A. LPS of gram-negative bacteria is recognized by LPS-binding protein in the bloodstream and tissue fluids. The LPS-LPS-binding protein complex is then delivered to the cell membrane of a macrophage, where resident LPS receptors, composed of a complex of proteins (TLR-CD14-MD-2) bind the bacterial LPS. As a result of receptor engagement, the microbes are ingested and degraded, the macrophage is activated, and cytokine production and inflammation result. Actions of somatically generated receptors of B and T cells and of antibodies are part of the adaptive immune response as opposed to the innate response. Cytokines do not have antigen-specific activities, and killer activation receptors on NK cells recognize stress-related molecules on the surfaces of abnormal host cells.
5.3. Double-stranded RNA-dependent protein kinase mediates the action of
D. natural killer cells.
E. type I interferons.
The answer is E. The double-stranded RNA-dependent protein kinase (PKR), a serine/threonine kinase, is a component of host responses to infection and various situations of cellular stress. PKR is a key mediator of interferon (IFN) action, the first line of defense against viral infection. Chemokines are a subgroup of cytokines of low molecular weight that affect chemotaxis of leukocytes. Complement provides a soluble means of protection against pathogens that evade contact with cells of the immune system. Defensins are peptides that form channels in bacterial cell membranes, allowing for increased permeability to certain ions and resulting in death of various bacteria. Natural killer cells detect aberrant host cells and target them for destruction.
5.4. Which of the following are examples of molecules that are expressed on the cell surfaces of human cells that are unhealthy or abnormal?
A. α and β defensins
B. C3 convertase and properdin
C. Cytokines and chemokines
D. Interferon-α and interferon-β
E. MICA and MICB
The answer is E. Defensins increase bacterial cell permeability to certain ions, resulting in death of the bacteria. C3 convertase and properdin are both components of the complement pathway, a soluble means of protection against pathogens that evade contact with cells of the immune system. Cytokines and chemokines are secreted by various leukocytes and by endothelial cells and are involved in innate immunity, adaptive immunity, and inflammation. Cytokines act in an antigen-nonspecific manner and are involved in a wide array of biologic activities, whereas chemokines are a subgroup of cytokines involved in chemotaxis. The type I interferons (interferon-α and interferon-β) are secreted by some virally infected cells in response to the infection.
5.5. The alternative complement pathway is initiated by
A. cell-surface constituents that are recognized as foreign to the host.
B. mannose-containing residues of glycoproteins on certain microbes.
C. stimulation of killer activation receptors on NK cells.
D. the formation of antibody–antigen complexes.
E. toll-like receptor binding to pathogen-associated molecular patterns.
The answer is A. Mannose-containing residues of glycoproteins on certain microbes activate the mannan-binding lectin pathway of complement. Killer activation receptors on NK cells recognize stress-related molecules on the surfaces of abnormal host cells. Antigen–antibody complexes are not required to initiate the alternative complement pathway. Toll-like receptor binding to pathogen-associated molecular patterns stimulates synthesis and secretion of the cytokines to promote inflammation and recruitment of leukocytes to the site of infection.