The front line of host defense (2024)

2-1. Infectious agents must overcome innate host defenses to establish a focus ofinfection

Our bodies are constantly exposed to microorganisms present in the environment,including infectious agents that have been shed from infected individuals.Contact with these microorganisms may occur through external or internalepithelial surfaces: the respiratory tract mucosa provides a route of entry forairborne microorganisms, the gastrointestinal mucosa for microorganisms in foodand water; insect bites and wounds allow micro-organisms to penetrate the skin;and direct contact between individuals offers opportunities for infection of theskin and reproductive mucosa (Fig.2.2).

In spite of this exposure, infectious disease is fortunately quite rare. Theepithelial surfaces of the body serve as an effective barrier against mostmicroorganisms, and are rapidly repaired if wounded. Furthermore, most of themicroorganisms that do succeed in crossing the epithelial surfaces areefficiently removed by innate immune mechanisms that function in the underlyingtissues. Thus in most cases these defenses, which we will examine in more detailin subsequent sections, prevent a site of infection from being established. Itis difficult to know how many infections are repelled in this way, because thereare no symptoms of disease. It is clear, however, that the microorganisms that anormal human being inhales or ingests, or that enter through minor wounds, aremostly held at bay or eliminated, since they seldom cause disease.

Infectious disease occurs when a microorganism succeeds in evading oroverwhelming innate host defenses to establish a local site of infection andreplication that allows its further transmission. In some cases, such asathlete’s foot, the initial infection remains local and does not causesignificant pathology. In other cases the infectious agent causes significantpathology as it spreads through the lymphatics or the bloodstream, or as aresult of secreting toxins.

Pathogen spread is often countered by an inflammatory response that recruits moreeffector molecules and cells of the innate immune system from local bloodvessels (Fig. 2.3), while inducingclotting farther downstream so that pathogens cannot spread through the blood.The induced responses of innate immunity act over several days while an adaptiveimmune response gets underway in response to pathogen antigens delivered tolocal lymphoid tissue. Such a response can target specific features of thepathogen and will usually clear the infection and protect the host againstreinfection with the same pathogen.

2-2. The epithelial surfaces of the body are the first defenses againstinfection

Our body surfaces are defended by epithelia, which provide a physical barrierbetween the internal milieu and the external world that contains pathogens.Epithelial cells are held together by tight junctions, which effectively form aseal against the external environment. Epithelia comprise the skin and thelinings of the body’s tubular structures—the gastrointestinal, respiratory, andurinogenital tracts. Infections occur only when the pathogen can colonize orcross through these barriers, and since the dry, protective layers of the skinpresent a more formidable barrier, pathogen entry most often occurs through theinternal epithelial surfaces. The importance of epithelia in protection againstinfection is obvious when the barrier is breached, as in wounds and burns, wheninfection is a major cause of mortality and morbidity. In the absence ofwounding or disruption, pathogens normally cross epithelial barriers by bindingto molecules on internal epithelial surfaces, or establish an infection byadhering to and colonizing these surfaces. This specific attachment allows thepathogen to infect the epithelial cell, or to damage it so that the epitheliumcan be crossed, or, in the case of colonizing pathogens, to avoid beingdislodged by the flow of air or fluid across the epithelial surface. Theinternal epithelia are known as mucosalepithelia because they secrete a viscous fluid called mucus, whichcontains many glycoproteins called mucins. Microorganisms coated in mucus may beprevented from adhering to the epithelium, and in mucosal epithelia such as thatof the respiratory tract, microorganisms can be expelled in the flow of mucusdriven by the beating of epithelial cilia. The efficacy of mucus flow inclearing infection is illustrated by people with defective mucus secretion orinhibition of ciliary movement; they frequently develop lung infections causedby bacteria that colonize the epithelial surface. In the gut, peristalsis is animportant mechanism for keeping both food and infectious agents moving through.Failure of peristalsis is typically accompanied by overgrowth of bacteria withinthe intestinal lumen.

Our surface epithelia are more than mere physical barriers to infection; theyalso produce chemical substances that are microbicidal or inhibit microbialgrowth (Fig. 2.4). For example, theantibacterial enzyme lysozyme is secreted in tears and saliva. The acid pH ofthe stomach and the digestive enzymes of the upper gastrointestinal tract createa substantial chemical barrier to infection. Further down the intestinal tract,antibacterial and antifungal peptides called cryptidins or α-defensins are madeby Paneth cells, which are resident in the base of the crypts in the smallintestine beneath the epithelial stem cells. Related antimicrobial peptides, theβ-defensins, are made by other epithelia, primarily in the skin and respiratorytract. Such antimicrobial peptides play a role in the immune defense of manyorganisms, including insects. They are cationic peptides that are thought tokill bacteria by damaging the bacterial cell membrane. Another type ofantimicrobial protein is secreted into the fluid that bathes the epithelialsurfaces of the lung. This fluid contains two proteins—surfactant proteins A andD—that bind to and coat the surfaces of pathogens so that they are more easilyphagocytosed by macrophages that have left the subepithelial tissues to enterthe alveoli of the lung. Coating of a particle with proteins that facilitate itsphagocytosis is known as opsonization and we will meet several examples of this defensestrategy in this chapter.

In addition to these defenses, most epithelial surfaces are associated with anormal flora of nonpathogenic bacteria that compete with pathogenicmicroorganisms for nutrients and for attachment sites on cells. The normal floracan also produce antimicrobial substances, such as the colicins (anti-bacterialproteins made by Escherichia coli) that prevent colonization byother bacteria. When the nonpathogenic bacteria are killed by antibiotictreatment, pathogenic microorganisms frequently replace them and causedisease.

2-3. After entering tissues, many pathogens are recognized, ingested, and killedby phagocytes

If a microorganism crosses an epithelial barrier and begins to replicate in thetissues of the host, it is, in most cases, immediately recognized by themononuclear phagocytes, or macrophages, that reside in tissues. Macrophages mature continuouslyfrom circulating monocytes that leave the circulation to migrate into tissuesthroughout the body (see Fig. 1.3). Theyare found in especially large numbers in connective tissue, in association withthe gastrointestinal tract, in the lung (where they are found in both theinterstitium and the alveoli), along certain blood vessels in the liver (wherethey are known as Kupffer cells), and throughout the spleen, where they removesenescent blood cells. The second major family of phagocytes—the neutrophils, or polymorphonuclearneutrophilic leukocytes (PMNs or polys)—are short-lived cells that are abundantin the blood but are not present in normal, healthy tissues. Both thesephagocytic cells have a key role in innate immunity because they can recognize,ingest, and destroy many pathogens without the aid of an adaptive immuneresponse. Macrophages are the first to encounter pathogens in the tissues butthey are soon re-inforced by the recruitment of large numbers of neutrophils tosites of infection.

Macrophages and neutrophils recognize pathogens by means of cell-surfacereceptors that can discriminate between the surface molecules displayed bypathogens and those of the host. These receptors, which we will examine in moredetail later, include the macrophage mannose receptor, which is found onmacrophages but not on monocytes or neutrophils, scavenger receptors, which bindmany charged ligands, and CD14, a receptor for bacterial lipopolysaccharide(LPS) found predominantly on monocytes and macro-phages (Fig. 2.5). Pathogens can also interact with macrophagesand neutrophils through receptors for complement borne on these cells. As wewill see in the second part of the chapter, the complement system is activatedrapidly in response to many types of infection, producing complement proteinsthat opsonize the surface of pathogens as they enter the tissues.

Ligation of many of the cell-surface receptors that recognize pathogens leads tophagocytosis of the pathogen, followed by its death inside the phagocyte.Phagocytosis is an active process, in which the bound pathogen is firstsurrounded by the phagocyte membrane and then internalized in a membrane-boundedvesicle known as a phagosome, which becomes acidified. In additionto being phagocytic, macrophages and neutrophils have granules, called lysosomes, that contain enzymes,proteins, and peptides that can mediate an intracellular antimicrobial response.The phagosome fuses with one or more lysosomes to generate aphagolysosome in which the lysosomal contents are released todestroy the pathogen (see Fig. 2.5).

Upon phagocytosis, macrophages and neutrophils also produce a variety of othertoxic products that help kill the engulfed microorganism (Fig. 2.6). The most important of these are hydrogenperoxide (H₂O₂), the superoxide anion(O₂^–), and nitric oxide (NO), which are directly toxicto bacteria. They are generated by lysosomal NADPH oxidases and other enzymes ina process known as the respiratoryburst, as it is accompanied by a transient increase in oxygenconsumption. Neutrophils are short-lived cells, dying soon after they haveaccomplished a round of phagocytosis. Dead and dying neutrophils are a majorcomponent of the pus that forms insome infections; bacteria that give rise to such infections are thus known aspyogenic bacteria. Macrophages,on the other hand, are long-lived and continue to generate new lysosomes.Patients with chronic granulomatous disease have a genetic deficiency of NADPHoxidase, which means that their phagocytes do not produce toxic oxygenderivatives and are less able to kill ingested microorganisms and clear theinfection. People with this defect are unusually susceptible to bacterial andfungal infections, especially in infancy.

Macrophages can make this response immediately on encountering an infectingmicroorganism and this can be sufficient to prevent an infection from becomingestablished. The great cellular immunologist Elie Metchnikoff believed that the innate response ofmacrophages encompassed all host defense and, indeed, it is now clear thatinvertebrates, such as the sea star that he was studying, rely entirely oninnate immunity for their defense against infection. Although this is not thecase in humans and other vertebrates, the innate response of macrophages stillprovides an important front line of host defense that must be overcome if amicroorganism is to establish an infection that can be passed on to a newhost.

A key feature that distinguishes pathogenic from nonpathogenic micro-organisms istheir ability to overcome innate immune defenses. Pathogens have developed avariety of strategies to avoid being immediately destroyed by macrophages. Manyextracellular pathogenic bacteria coat themselves with a thick polysaccharidecapsule that is not recognized by any phagocyte receptor. Other pathogens, forexample mycobacteria, have evolved ways to grow inside macrophage phagosomes byinhibiting fusion with a lysosome. Without such devices, a microorganism mustenter the body in sufficient numbers to simply overwhelm the immediate innatehost defenses and establish a focus of infection.

The second important effect of the interaction between pathogens and tissuemacrophages is activation of macrophages to release cytokines and othermediators that set up a state of inflammation in the tissue and bringneutrophils and plasma proteins to the site of infection. It is thought that thepathogen induces cytokine secretion by signals delivered through some of thereceptors to which it binds, and we will see later how this occurs in responseto LPS. Receptors that signal the presence of pathogens and induce cytokinesalso have another important role. This is to induce the expression of so-calledco-stimulatory molecules on both macrophages and dendritic cells, another type of phagocytic cell presentin tissues, thus enabling these cells to initiate an adaptive immune response(see Section 1-6).

The cytokines released by macrophages make an important contribution both tolocal inflammation and to other induced but nonadaptive responses that occur inthe first few days of a new infection. We will be describing the role ofindividual cytokines in these induced responses in the last part of thischapter. However, since an inflammatory response is usually initiated withinminutes of infection or wounding, we will outline here how it occurs and how itcontributes to host defense.

2-4. Pathogen recognition and tissue damage initiate an inflammatoryresponse

Inflammation plays three essential roles in combating infection. The first is todeliver additional effector molecules and cells to sites of infection to augmentthe killing of invading microorganisms by the front-line macrophages. The secondis to provide a physical barrier preventing the spread of infection, and thethird is to promote the repair of injured tissue, a nonimmunological role thatwe will not discuss further. Inflammation at the site of infection is initiatedby the response of macrophages to pathogens.

Inflammatory responses are operationally characterized by pain,redness, heat, and swelling at the site of an infection, reflecting three typesof change in the local blood vessels. The first is an increase in vasculardiameter, leading to increased local blood flow—hence the heat and redness—and areduction in the velocity of blood flow, especially along the surfaces of smallblood vessels. The second change is that the endothelial cells lining the bloodvessel are activated to express adhesion molecules that promote the binding ofcirculating leukocytes. The combination of slowed blood flow and inducedadhesion molecules allows leukocytes to attach to the endothelium and migrateinto the tissues, a process known as extravasation, which we will describe indetail later. All these changes are initiated by the cytokines produced byactivated macrophages. Once inflammation has begun, the first cells attracted tothe site of infection are generally neutrophils. They are followed by monocytes,which differentiate into more tissue macrophages. In the later stages ofinflammation, other leukocytes such as eosinophils and lymphocytes also enterthe infected site. The third major change in the local blood vessels is anincrease in vascular permeability. Instead of being tightly joined together, theendothelial cells lining the blood vessel walls become separated, leading toexit of fluid and proteins from the blood and their local accumulation in thetissue. This accounts for the swelling, or edema, and pain—as well as the accumulation of plasma proteins thataid in host defense.

These changes are induced by a variety of inflammatory mediators released as aconsequence of the recognition of pathogens. These include the lipid mediatorsof inflammation—prostaglandins,leukotrienes, andplatelet-activating factor (PAF)—which are rapidlyproduced by macrophages through enzymatic pathways that degrade membranephospholipids. Their actions are followed by those of the cytokines andchemokines (chemoattractant cytokines) that are synthesized and secreted bymacrophages in response to pathogens. The cytokine tumor necrosis factor-α (TNF-α), forexample, is a potent activator of endothelial cells.

As we will see in the next part of the chapter, another way in which pathogenrecognition rapidly triggers an inflammatory response is through activation ofthe complement cascade. One of the cleavage products of the complement reactionis a peptide called C5a. C5a is a potent mediator of inflammation, with severaldifferent activities. In addition to increasing vascular permeability andinducing the expression of some adhesion molecules, it acts as a powerfulchemoattractant for neutrophils and monocytes, and activates phagocytes andlocal mast cells, which are in turnstimulated to release granules containing the inflammatory molecule histamineand TNF-α.

If wounding has occurred, the injury to blood vessels immediately triggers twoother protective enzyme cascades. The kinin system is an enzymatic cascade of plasma proteins that istriggered by tissue damage to produce several inflammatory mediators, includingthe vasoactive peptide bradykinin.This causes an increase in vascular permeability that promotes the influx ofplasma proteins to the site of tissue injury. It also causes pain, which,although unpleasant to the victim, draws attention to the problem and leads toimmobilization of the affected part of the body, which helps to limit the spreadof any infectious agents. The coagulationsystem is another enzymatic cascade of plasma enzymes that istriggered following damage to blood vessels. This leads to the formation of aclot, which prevents any microorganisms from entering the bloodstream. Boththese cascades have an important role in the inflammatory response to pathogenseven if wounding or gross tissue injury has not occurred, as they are alsotriggered by endothelial cell activation. Thus, within minutes of thepenetration of tissues by a pathogen, the inflammatory response causes an influxof proteins and cells that will control the infection. It also forms a physicalbarrier to limit the spread of infection and makes the host fully aware of whatis going on.

Summary

The mammalian body is susceptible to infection by many pathogens, which mustfirst make contact with the host and then establish a focus of infection inorder to cause disease. These pathogens differ greatly in their lifestyles, thestructures of their surfaces, and means of pathogenesis, which thereforerequires an equally diverse set of defensive responses from the host immunesystem. The first phase of host defense consists of those mechanisms that arepresent and ready to resist an invader at any time. The epithelial surfaces ofthe body keep pathogens out, and protect against colonization and againstviruses and bacteria that enter through specialized cell-surface interactions,by preventing pathogen adherence and by secreting antimicrobial enzymes andpeptides. Bacteria, viruses, and parasites that overcome this barrier are facedimmediately by tissue macrophages equipped with surface receptors that can bindand phagocytose many different types of pathogen. This, in turn, leads to aninflammatory response, which causes the accumulation of plasma proteins,including the complement components that provide circulating or humoral innateimmunity, as will be described in the next part of the chapter, and phagocyticneutrophils at the site of infection. Innate immunity provides a front line ofhost defense through effector mechanisms that engage the pathogen directly, actimmediately on contact with it, and are unaltered in their ability to resist asubsequent challenge with either the same or a different pathogen. Thesemechanisms often succeed in preventing an infection from becoming established.If not, they are reinforced through the recruitment and increased production offurther effector molecules and cells in a series of induced responses that wewill consider later in this chapter. These induced innate responses often failto clear the infection. In that case, macrophages and other cells activated inthe early innate response help to initiate the development of an adaptive immuneresponse.