Epithelial Surfaces Help Prevent Infection

In vertebrates, the skin and other epithelial surfaces, including those lining the lung and gut Figure 25-39), provide a physical barrier between the inside of the body and the outside world. Tight junctions (discussed in Chapter 19) between neighboring cells prevent easy entry by potential pathogens. The interior epithelial surfaces are also covered with a mucus layer that protects these surfaces against microbial, mechanical, and chemical insults; many amphibians and fish also have a mucus layer covering their skin. The slimy mucus coating is made primarily of secreted mucin and other glycoproteins, and it physically helps prevent pathogens from adhering to the epithelium. It also facilitates their clearance by beating cilia on the epithelial cells (discussed in Chapter 22).

Figure 25-39

Epithelial defenses against microbial invasion. (A) Cross section through the wall of the human small intestine, showing three villi. Goblet cells secreting mucus are stained magenta. The protective mucus layer covers the exposed surfaces of the villi. (more...)

The mucus layer also contains substances that kill pathogens or inhibit their growth. Among the most abundant of these are antimicrobial peptides, called defensins, which are found in all animals and plants. They are generally short (12–50 amino acids), positively charged, and have hydrophobic or amphipathic domains in their folded structure. They constitute a diverse family with a broad spectrum of antimicrobial activity, including the ability to kill or inactivate Gram-negative and Gram-positive bacteria, fungi (including yeasts), parasites (including protozoa and nematodes), and even enveloped viruses like HIV. Defensins are also the most abundant protein type in neutrophils (see below), which use them to kill phagocytosed pathogens.

It is still uncertain how defensins kill pathogens. One possibility is that they use their hydrophobic or amphipathic domains to insert into the membrane of their victims, thereby disrupting membrane integrity. Some of their selectivity for pathogens over host cells may come from their preference for membranes that do not contain cholesterol. After disrupting the membrane of the pathogen, the positively-charged peptides may also interact with various negatively-charged targets within the microbe, including DNA. Because of the relatively nonspecific nature of the interaction between defensins and the microbes they kill, it is difficult for the microbes to acquire resistance to the defensins. Thus, in principle, defensins might be useful therapeutic agents to combat infection, either alone or in combination with more traditional drugs.

Human Cells Recognize Conserved Features of Pathogens

Microorganisms do occasionally breach the epithelial barricades. It is then up to the innate and adaptive immune systems to recognize and destroy them, without harming the host. Consequently, the immune systems must be able to distinguish self from nonself. We discuss in Chapter 24 how the adaptive immune system does this. The innate immune system relies on the recognition of particular types of molecules that are common to many pathogens but are absent in the host. These pathogen-associated molecules (called pathogen-associated immunostimulants) stimulate two types of innate immune responses—inflammatory responses (discussed below) and phagocytosis by cells such as neutrophils and macrophages. Both of these responses can occur quickly, even if the host has never been previously exposed to a particular pathogen.

The pathogen-associated immunostimulants are of various types. Procaryotic translation initiation differs from eucaryotic translation initiation in that formylated methionine, rather than regular methionine, is generally used as the first amino acid. Therefore, any peptide containing formylmethionine at the N-terminus must be of bacterial origin. Formylmethionine-containing peptides act as very potent chemoattractants for neutrophils, which migrate quickly to the source of such peptides and engulf the bacteria that are producing them (seeFigure 16-96).

In addition, the outer surface of many microorganisms is composed of molecules that do not occur in their multicellular hosts, and these molecules also act as immunostimulants. They include the peptidoglycan cell wall and flagella of bacteria, as well as lipopolysaccharide (LPS) on Gram-negative bacteria (Figure 25-40) and teichoic acids on Gram-positive bacteria (see Figure 25-4D). They also include molecules in the cell walls of fungi such as zymosan, glucan, and chitin. Many parasites also contain unique membrane components that act as immunostimulants, including glycosylphosphatidylinositol in Plasmodium.

Figure 25-40

Structure of lipopolysaccharide (LPS). On the left is the 3-dimensional structure of a molecule of LPS with the fatty acids shown in yellow and the sugars in blue. The molecular structure of the base of LPS is shown on the right. The hydrophobic membrane (more...)

Short sequences in bacterial DNA can also act as immunostimulants. The culprit is a “CpG motif”, which consists of the unmethylated dinucleotide CpG flanked by two 5′ purine residues and two 3′ pyrimidines. This short sequence is at least twenty times less common in vertebrate DNA than in bacterial DNA, and it can activate macrophages, stimulate an inflammatory response, and increase antibody production by B cells.

The various classes of pathogen-associated immunostimulants often occur on the pathogen surface in repeating patterns. They are recognized by several types of dedicated receptors in the host, that are collectively called pattern recognition receptors. These receptors include soluble receptors in the blood (components of the complement system) and membrane-bound receptors on the surface of host cells (members of the Toll-like receptor family). The cell-surface receptors have two functions: they initiate the phagocytosis of the pathogen, and they stimulate a program of gene expression in the host cell for stimulating innate immune responses. The soluble receptors also aid in the phagocytosis and, in some cases, the direct killing of the pathogen.

Complement Activation Targets Pathogens for Phagocytosis or Lysis

The complement system consists of about 20 interacting soluble proteins that are made mainly by the liver and circulate in the blood and extracellular fluid. Most are inactive until they are triggered by an infection. They were originally identified by their ability to amplify and “complement” the action of antibodies, but some components of complement are also pattern recognition receptors that can be activated directly by pathogen-associated immunostimulants.

The early complement components are activated first. There are three sets of these, belonging to three distinct pathways of complement activation—the classical pathway, the lectin pathway, and the alternative pathway. The early components of all three pathways act locally to activate C3, which is the pivotal component of complement (Figure 25-41). Individuals with a deficiency in C3 are subject to repeated bacterial infections. The early components and C3 are all proenzymes, which are activated sequentially by proteolytic cleavage. The cleavage of each proenzyme in the series activates the next component to generate a serine protease, which cleaves the next proenzyme in the series, and so on. Since each activated enzyme cleaves many molecules of the next proenzyme in the chain, the activation of the early components consists of an amplifying, proteolytic cascade.

Figure 25-41

The principal stages in complement activation by the classical, lectin, and alternative pathways. In all three pathways, the reactions of complement activation usually take place on the surface of an invading microbe, such as a bacterium. C1–C9 (more...)

Many of these cleavages liberate a biologically active small peptide fragment and a membrane-binding larger fragment. The binding of the large fragment to a cell membrane, usually the surface of a pathogen, helps to carry out the next reaction in the sequence. In this way, complement activation is confined largely to the particular cell surface where it began. The larger fragment of C3, called C3b, binds covalently to the surface of the pathogen. Once in place, it not only acts as a protease to catalyze the subsequent steps in the complement cascade, but it also is recognized by specific receptors on phagocytic cells that enhance the ability of these cells to phagocytose the pathogen. The smaller fragment of C3 (called C3a), as well as fragments of C4 and C5 (see Figure 25-41), act independently as diffusible signals to promote an inflammatory response by recruiting phagocytes and lymphocytes to the site of infection.

The classical pathway is activated by IgG or IgM antibody molecules (discussed in Chapter 24) bound to the surface of a microbe. Mannan-binding lectin, the protein that initiates the second pathway of complement activation, is a serum protein that forms clusters of six carbohydrate-binding heads around a central collagen-like stalk. This assembly binds specifically to mannose and fucose residues in bacterial cell walls that have the correct spacing and orientation to match up perfectly with the six carbohydrate-binding sites, providing a good example of a pattern recognition receptor. These initial binding events in the classical and lectin pathways cause the recruitment and activation of the early complement components. In the alternative pathway, C3 is spontaneously activated at low levels, and the resulting C3b covalently attaches to both host cells and pathogens. Host cells produce a series of proteins that prevent the complement reaction from proceeding on their cell surfaces. Because pathogens lack these proteins, they are singled out for destruction. Activation of the classical or lectin pathways also activates the alternative pathway through a positive feedback loop, amplifying their effects.

Membrane-immobilized C3b, produced by any of the three pathways, triggers a further cascade of reactions that leads to the assembly of the late components to form membrane attack complexes (Figure 25-42). These complexes assemble in the pathogen membrane near the site of C3 activation and have a characteristic appearance in negatively stained electron micrographs, where they are seen to form aqueous pores through the membrane (Figure 25-43). For this reason, and because they perturb the structure of the bilayer in their vicinity, they make the membrane leaky and can, in some cases, cause the microbial cell to lyse, much like the defensins mentioned earlier.

Figure 25-42

Assembly of the late complement components to form a membrane attack complex. When C3b is produced by any of the three activation pathways, it is immobilized on a membrane, where it causes the cleavage of the first of the late components, C5, to produce (more...)

Figure 25-43

Electron micrographs of negatively stained complement lesions in the plasma membrane of a red blood cell. The lesion in (A) is seen en face, while that in (B) is seen from the side as an apparent transmembrane channel. The negative stain fills the channels, (more...)

The self-amplifying, inflammatory, and destructive properties of the complement cascade make it essential that key activated components be rapidly inactivated after they are generated to ensure that the attack does not spread to nearby host cells. Deactivation is achieved in at least two ways. First, specific inhibitor proteins in the blood or on the surface of host cells terminate the cascade, by either binding or cleaving certain components once they have been activated by proteolytic cleavage. Second, many of the activated components in the cascade are unstable; unless they bind immediately to either an appropriate component in the cascade or to a nearby membrane, they rapidly become inactive.

Toll-like Proteins Are an Ancient Family of Pattern Recognition Receptors

Many of the mammalian cell-surface pattern recognition receptors responsible for triggering host cell gene expression in response to pathogens are members of the Toll-like receptor (TLR) family. Drosophila Toll is a transmembrane protein with a large extracellular domain consisting of a series of leucine-rich repeats (see Figure 15-76). It was originally identified as a protein involved in the establishment of dorso-ventral polarity in developing fly embryos (discussed in Chapter 21). It is also involved, however, in the adult fly's resistance to fungal infections. The intracellular signal transduction pathway activated downstream of Toll when a fly is exposed to a pathogenic fungus leads to the translocation of the NF-κB protein (discussed in Chapter 15) into the nucleus, where it activates the transcription of various genes, including those encoding antifungal defensins. Another member of the Toll family in Drosophila is activated by exposure to pathogenic bacteria, leading to the production of an antibacterial defensin.

Humans have at least ten TLRs, several of which have been shown to play important parts in innate immune recognition of pathogen-associated immunostimulants, including lipopolysaccharide, peptidoglycan, zymosan, bacterial flagella, and CpG DNA. As with Drosophila Toll family members, the different human TLRs are activated in response to different ligands, although many of them use the NF-κB signaling pathway (Figure 25-44). In mammals, TLR activation stimulates the expression of molecules that both initiate an inflammatory response (discussed below) and help induce adaptive immune responses. TLRs are abundant on the surface of macrophages and neutrophils, as well as on the epithelial cells lining the lung and gut. They act as an alarm system to alert both the innate and adaptive immune systems that an infection is brewing.

Figure 25-44

The activation of a macrophage by lipopolysaccharide (LPS). LPS is bound by LPS-binding protein (LBP) in the blood, and the complex binds to the GPI-anchored receptor CD14 on the macrophage surface. The ternary complex then activates Toll-like receptor (more...)

Molecules related to Toll and TLRs are apparently involved in innate immunity in all multicellular organisms. In plants, proteins with leucine-rich repeats and with domains homologous to the cytosolic portion of the TLRs are required for resistance to fungal, bacterial, and viral pathogens (Figure 25-45). Thus, at least two parts of the innate immune system—the defensins and the TLRs—seem to be evolutionarily very ancient, perhaps predating the split between animals and plants over a billion years ago. Their conservation during evolution indicates the importance of these innate responses in the defense against microbial pathogens.

Figure 25-45

Microbial disease in a plant. These tomato leaves are infected with the leaf mold fungus Cladosporium fulvum. Resistance to this type of infection depends on recognition of a fungal protein by a host receptor that is structurally related to the TLRs. (more...)

Phagocytic Cells Seek, Engulf, and Destroy Pathogens

In all animals, invertebrate as well as vertebrate, the recognition of a microbial invader is usually quickly followed by its engulfment by a phagocytic cell. Plants, however, lack this type of innate immune response. In vertebrates, macrophages reside in tissues throughout the body and are especially abundant in areas where infections are likely to arise, including the lungs and gut. They are also present in large numbers in connective tissues, the liver, and the spleen. These long-lived cells patrol the tissues of the body and are among the first cells to encounter invading microbes. The second major family of phagocytic cells in vertebrates, the neutrophils, are short-lived cells, which are abundant in blood but are not present in normal, healthy tissues. They are rapidly recruited to sites of infection both by activated macrophages and by molecules such as formylmethionine-containing peptides released by the microbes themselves.

Macrophages and neutrophils display a variety of cell-surface receptors that enable them to recognize and engulf pathogens. These include pattern recognition receptors such as TLRs. In addition, they have cell-surface receptors for the Fc portion of antibodies produced by the adaptive immune system, as well as for the C3b component of complement. Ligand binding to any of these receptors induces actin polymerization at the site of pathogen attachment, causing the phagocyte's plasma membrane to surround the pathogen and engulf it in a large membrane-enclosed phagosome (Figure 25-46).

Figure 25-46

Phagocytosis. This scanning electron micrograph shows a macrophage in the midst of consuming five red blood cells that have been coated with an antibody against a surface glycoprotein. (From E.S. Gold et al., J Exp. Med. 190:1849–1856, 1999. © (more...)

Once the pathogen has been phagocytosed, the macrophage or neutrophil unleashes an impressive armory of weapons to kill it. The phagosome is acidified and fuses with lysosomes, which contain lysozyme and acid hydrolases that can degrade bacterial cell walls and proteins. The lysosomes also contain defensins, which make up about 15% of the total protein in neutrophils. In addition, the phagocytes assemble an NADPH oxidase complex on the phagosomal membrane that catalyzes the production of a series of highly toxic oxygen-derived compounds, including superoxide (O₂ ^-), hypochlorite (HOCl, the active ingredient in bleach), hydrogen peroxide, hydroxyl radicals, and nitric oxide (NO). The production of these toxic compounds is accompanied by a transient increase in oxygen consumption by the cells, called the respiratory burst. Whereas macrophages will generally survive this killing frenzy and continue to patrol tissues for other pathogens, neutrophils usually die. Dead and dying neutrophils are a major component of the pus that forms in acutely infected wounds. The distinctive greenish tint of pus is due to the abundance in neutrophils of the copper-containing enzyme myeloperoxidase, which is one of the components active in the respiratory burst.

If a pathogen is too large to be successfully phagocytosed (if it is a large parasite such as a nematode, for example), a group of macrophages, neutrophils, or eosinophils (discussed in Chapter 22) will gather around the invader. They will secrete their defensins and other lysosomal products by exocytosis and will also release the toxic products of the respiratory burst (Figure 25-47). This barrage is generally sufficient to destroy the pathogen.

Figure 25-47

Eosinophils attacking a schistosome larva. Large parasites, such as worms, cannot be ingested by phagocytes. When the worm is coated with antibody or complement, however, eosinophils and other white blood cells can recognize and attack it. (Courtesy of (more...)

Many pathogens have developed strategies that allow them to avoid being ingested by phagocytes. Some Gram-positive bacteria coat themselves with a very thick, slimy polysaccharide coat, or capsule, that is not recognized by complement or any phagocyte receptor. Other pathogens are phagocytosed but avoid being killed; as we saw earlier, Mycobacterium tuberculosis prevents the maturation of the phagosome and thereby survives. Some pathogens escape the phagosome entirely, and yet others secrete enzymes that detoxify the products of the respiratory burst. For such wily pathogens, these first lines of defense are insufficient to clear the infection, and adaptive immune responses are required to contain them.

Activated Macrophages Recruit Additional Phagocytic Cells to Sites of Infection

When a pathogen invades a tissue, it almost always elicits an inflammatory response. This response is characterized by pain, redness, heat, and swelling at the site of infection, all caused by changes in local blood vessels. The blood vessels dilate and become permeable to fluid and proteins, leading to local swelling and an accumulation of blood proteins that aid in defense, including the components of the complement cascade. At the same time, the endothelial cells lining the local blood vessels are stimulated to express cell adhesion proteins (discussed in Chapter 19) that facilitate the attachment and extravasion of white blood cells, including neutrophils, lymphocytes, and monocytes (the precursors of macrophages).

The inflammatory response is mediated by a variety of signaling molecules. Activation of TLRs results in the production of both lipid signaling molecules such as prostaglandins and protein (or peptide) signaling molecules such as cytokines (discussed in Chapter 15), all of which contribute to the inflammatory response. The proteolytic release of complement fragments also contribute. Some of the cytokines produced by activated macrophages are chemoattractants (known as chemokines). Some of these attract neutrophils, which are the first cells recruited in large numbers to the site of the new infection. Others later attract monocytes and dendritic cells. The dendritic cells pick up antigens from the invading pathogens and carry them to nearby lymph nodes, where they present the antigens to lymphocytes to marshal the forces of the adaptive immune system (discussed in Chapter 24). Other cytokines trigger fever, a rise in body temperature. On balance, fever helps the immune system in the fight against infection, since most bacterial and viral pathogens grow better at lower temperatures, whereas adaptive immune responses are more potent at higher temperatures.

Some proinflammatory signaling molecules stimulate endothelial cells to express proteins that trigger blood clotting in local small vessels. By occluding the vessels and cutting off blood flow, this response can help prevent the pathogen from entering the bloodstream and spreading the infection to other parts of the body.

The same inflammatory responses, however, which are so effective at controlling local infections, can have disastrous consequences when they occur in a disseminated infection in the bloodstream, a condition called sepsis. The systemic release of proinflammatory signaling molecules into the blood causes dilation of blood vessels, loss of plasma volume, and widespread blood clotting, which is an often fatal condition known as septic shock. Inappropriate or overzealous inflammatory responses are also associated with some chronic conditions, such as asthma (Figure 25-48).

Figure 25-48

Inflammation of the airways in chronic asthma restricts breathing. Light micrograph of a section through the bronchus of a patient who died of asthma. There is almost total occlusion of the airway by a mucus plug. The mucus plug is a dense inflammatory (more...)

Just as with phagocytosis, some pathogens have developed mechanisms to either prevent the inflammatory response or, in some cases, take advantage of it to spread the infection. Many viruses, for example, encode potent cytokine antagonists that block aspects of the inflammatory response. Some of these are simply modified forms of cytokine receptors, encoded by genes acquired by the viral genome from the host. They bind the cytokines with high affinity and block their activity. Some bacteria, such as Salmonella, induce an inflammatory response in the gut at the initial site of infection, thereby recruiting macrophages and neutrophils that they then invade. In this way, the bacteria hitch a ride to other tissues in the body.

Virus-Infected Cells Take Drastic Measures to Prevent Viral Replication

The pathogen-associated immunostimulants on the surface of bacteria and parasites that are so important in eliciting innate immune responses are generally not present on the surface of viruses. Viral proteins are constructed by the host cell ribosomes, and the membranes of enveloped viruses are composed of host cell lipids. The only unusual molecule associated with viruses is the double-stranded RNA (dsRNA) that is an intermediate in the life cycle of many viruses. Host cells can detect the presence of dsRNA and initiate a program of drastic responses in attempt to eliminate it.

The program occurs in two steps. First, the cells degrade the dsRNA into small fragments (about 21–25 nucleotide pairs in length). These fragments bind to any single-stranded RNA (ssRNA) in the host cell with the same sequence as either strand of the dsRNA fragment, leading to the destruction of the ssRNA. This dsRNA-directed ssRNA destruction is the basis of the technique of RNA interference (RNAi) that is used by researchers to block specific gene expression (discussed in Chapter 8). Second, the dsRNA induces the host cell to produce and secrete two cytokines—interferon α (IFN-α) and interferon β (IFN-β), which act in both an autocrine fashion on the infected cell and a paracrine fashion on uninfected neighbors. The binding of the interferons to their cell-surface receptors stimulates specific gene transcription by the Jak/STAT intracellular signaling pathway (see Figure 15-63), leading to the activation of a latent ribonuclease, which nonspecifically degrades ssRNA. It also leads to the activation of a protein kinase that phosphorylates and inactivates the protein synthesis initiation factor eIF-2, shutting down most protein synthesis in the embattled host cell. Apparently, by destroying most of the RNA it contains and transiently halting most protein synthesis, the cell inhibits viral replication without killing itself. In some cases, however, a cell infected with a virus is persuaded by white blood cells to destroy itself to prevent the virus from replicating.

Natural Killer Cells Induce Virus-Infected Cells to Kill Themselves

Another way that the interferons help vertebrates defend themselves against viruses is by stimulating both innate and adaptive cellular immune responses. In Chapter 24, we discuss how interferons enhance the expression of class I MHC proteins, which present viral antigens to cytotoxic T lymphocytes (see Figure 24-48). Here, we consider how interferons enhance the activity of natural killer cells (NK cells), which are part of the innate immune system. Like cytotoxic T cells, NK cells destroy virus-infected cells by inducing the infected cell to kill itself by undergoing apoptosis. Unlike T cells, however, NK cells do not express antigen-specific receptors. How, then, do they distinguish virus-infected cells from uninfected cells?

NK cells monitor the level of class I MHC proteins, which are expressed on the surface of most vertebrate cells. The presence of high levels of these proteins inhibits the killing activity of NK cells, so that the NK cells selectively kill cells expressing low levels, including both virally-infected cells and some cancer cells (Figure 25-49). Many viruses have developed mechanisms to inhibit the expression of class I MHC molecules on the surface of the cells they infect, in order to avoid detection by cytotoxic T lymphocytes. Adenovirus and HIV, for example, encode proteins that block class I MHC gene transcription. Herpes simplex virus and cytomegalovirus block the peptide translocators in the ER membrane that transport proteasome-derived peptides from the cytosol into the lumen of the ER; such peptides are required for newly-made class I MHC proteins to assemble in the ER membrane and be transported through the Golgi apparatus to the cell surface (see Figure 24-58). Cytomegalovirus causes the retrotranslocation of class I MHC proteins from the ER membrane into the cytosol, where they are rapidly degraded by proteasomes. Proteins encoded by still other viruses prevent the delivery of assembled class I MHC proteins from the ER to the Golgi apparatus, or from the Golgi apparatus to the plasma membrane. By evading recognition by cytotoxic T cells in these ways, however, a virus incurs the wrath of NK cells. The local production of IFN-α and IFN-β activates the killing activity of NK cells and also increases the expression of class I MHC proteins in uninfected cells. The cells infected with a virus that blocks class I MHC expression are thereby exposed and become the victims of the activated NK cells. Thus, it is difficult or impossible for viruses to hide from both the innate and adaptive immune systems simultaneously.

Figure 25-49

A natural killer (NK) cell attacking a cancer cell. The NK cell is the smaller cell on the left. This scanning electron micrograph was taken shortly after the NK cell attached, but before it induced the cancer cell to kill itself. (Courtesy of J.C. Hiserodt, (more...)

Both NK cells and cytotoxic T lymphocytes kill infected target cells by inducing them to undergo apoptosis before the virus has had a chance to replicate. It is not surprising, then, that many viruses have acquired mechanisms to inhibit apoptosis, particularly early in infection. As discussed in Chapter 17, apoptosis depends on an intracellular proteolytic cascade, which the cytotoxic cell can trigger either through the activation of cell-surface death receptors or by injecting a proteolytic enzyme into the target cell (see Figure 24-46). Viral proteins can interfere with nearly every step in these pathways. In some cases, however, viruses encode proteins that act late in their replication cycle to induce apoptosis in the host cell, thereby releasing progeny virus that can infect neighboring cells.

The battle between pathogens and host defenses is remarkably balanced. At present, humans seem to be gaining a slight advantage, using public sanitation measures, vaccines, and drugs to aid the efforts of our innate and adaptive immune systems. However, infectious and parasitic diseases are still the leading cause of death worldwide, and new epidemics such as AIDS continue to emerge. The rapid evolution of pathogens and the almost infinite variety of ways that they can invade the human body and elude immune responses will prevent us from ever winning the battle completely.

Summary

The innate immune responses are the first line of defense against invading pathogens. They are also required to initiate specific adaptive immune responses. Innate immune responses rely on the body's ability to recognize conserved features of pathogens that are not present in the uninfected host. These include many types of molecules on microbial surfaces and the double-stranded RNA of some viruses. Many of these pathogen-specific molecules are recognized by Toll-like receptor proteins, which are found in plants and in invertebrate and vertebrate animals. In vertebrates, microbial surface molecules also activate complement, a group of blood proteins that act together to disrupt the membrane of the microorganism, to target microorganisms for phagocytosis by macrophages and neutrophils, and to produce an inflammatory response. The phagocytic cells use a combination of degradative enzymes, antimicrobial peptides, and reactive oxygen species to kill the invading microorganisms. In addition, they release signaling molecules that trigger an inflammatory response and begin to marshal the forces of the adaptive immune system. Cells infected with viruses produce interferons, which induce a series of cell responses to inhibit viral replication and activate the killing activities of natural killer cells and cytotoxic T lymphocytes.