Immune response to chapter 17 Infectious diseases F A PATHOGEN IS TO ESTABLISH AN INFECTION IN A susceptible host, a series of coordinated events must rcumvent both innate and adaptive immunity. One of the first and most important features of host innate immunity is the barrier provided by the epithelial surfaces of the skin and the lining of the gut. The difficulty of penetrat- ing these epithelial barriers ensures that most pathogens never gain productive entry into the host. In addition to pro viding a physical barrier to infection, the epithelia also pro duce chemicals that are useful in preventing infection. The Neisseria gonorrheae Attaching to Urethral Epithelial Cells secretion of gastric enzymes by specialized epithelial cells lowers the pH of the stomach and upper gastrointestinal Viral Infections tract, and other specialized cells in the gut produce antibac terial peptides. a Bacterial Infections a major feature of innate immunity is the presence of the a Protozoan Diseases ormal gut flora, which can competitively inhibit the bind- ing of pathogens to gut epithelial cells. Innate responses can Diseases Caused by Parasitic Worms(Helminths) also block the establishment of infection. For example, the m Emerging Infectious Diseases cell walls of some gram-positive bacteria contain a peptido- glycan that activates the alternative complement pathway resulting in the generation of C3b, which opsonizes bacteria and enhances phagocytosis(see Chapter 13). Some bacteria produce endotoxins such as LPS, which stimulate the pro luction of cytokines such as TNF-ac, IL-1, and IL-6 by nacrophages or endothelial cells. These cytokines can acti- tively or to regulate it so that a branch of the immune system vate macrophages Phagocytosis of bacteria by macrophages is activated that is ineffective against the pathogen Contin and other phagocytic cells is another highly effective line of ual variation in surface antigens is another strategy that nnate defense. However, some types of bacteria that com- enables a pathogen to elude the immune system. This anti- monly grow intracellularly have developed mechanisms that genic variation may be due to the gradual accumulation of allow them to resist degradation within the phagocyte mutations, or it may involve an abrupt change in surface Viruses are well known for the stimulation of innate antigens responses. In particular, many viruses induce the production oth innate and adaptive immune responses to patho of interferons, which can inhibit viral replication by induc- gens provide critical defense, but infectious diseases, which ing an antiviral response. viruses are also controlled by nK have plagued human populations throughout history, still cells As described in Chapter 14, NK cells frequently form cause the death of millions each year. Although widespread he first line of defense against viral infections use of vaccines and drug therapy has drastically reduced enerally, pathogens use a variety of strategies to escape mortality from infectious diseases in developed countries, destruction by the adaptive immune system. Many patho- such diseases continue to be the leading cause of death in the gens reduce their own antigenicity either by growing within Third World. It is estimated that over 1 billion people are host cells, where they are sequestered from immune attack, infected worldwide, resulting in more than 11 million deaths or by shedding their membrane antigens. Other pathogens every year (Figure 17-1). Despite these alarming numbers camouflage themselves by mimicking the surfaces of host estimated expenditures for research on infectious diseases cells, either by expressing molecules with amino acid se- prevalent in the Third World are less than 5%of total health- quences similar to those of host cell-membrane molecules or research expenditures worldwide. Not only is this a tragedy by acquiring a covering of host membrane molecules. Some for these countries, but some of these diseases are begin pathogens are able to suppress the immune response selec- ning to emerge or re-emerge in developed countries. Fc
■ Viral Infections ■ Bacterial Infections ■ Protozoan Diseases ■ Diseases Caused by Parasitic Worms (Helminths) ■ Emerging Infectious Diseases Neisseria gonorrheae Attaching to Urethral Epithelial Cells Immune Response to Infectious Diseases I susceptible host, a series of coordinated events must circumvent both innate and adaptive immunity. One of the first and most important features of host innate immunity is the barrier provided by the epithelial surfaces of the skin and the lining of the gut. The difficulty of penetrating these epithelial barriers ensures that most pathogens never gain productive entry into the host. In addition to providing a physical barrier to infection, the epithelia also produce chemicals that are useful in preventing infection. The secretion of gastric enzymes by specialized epithelial cells lowers the pH of the stomach and upper gastrointestinal tract, and other specialized cells in the gut produce antibacterial peptides. A major feature of innate immunity is the presence of the normal gut flora, which can competitively inhibit the binding of pathogens to gut epithelial cells. Innate responses can also block the establishment of infection. For example, the cell walls of some gram-positive bacteria contain a peptidoglycan that activates the alternative complement pathway, resulting in the generation of C3b, which opsonizes bacteria and enhances phagocytosis (see Chapter 13). Some bacteria produce endotoxins such as LPS, which stimulate the production of cytokines such as TNF-, IL-1, and IL-6 by macrophages or endothelial cells. These cytokines can activate macrophages. Phagocytosis of bacteria by macrophages and other phagocytic cells is another highly effective line of innate defense. However, some types of bacteria that commonly grow intracellularly have developed mechanisms that allow them to resist degradation within the phagocyte. Viruses are well known for the stimulation of innate responses. In particular, many viruses induce the production of interferons, which can inhibit viral replication by inducing an antiviral response. Viruses are also controlled by NK cells. As described in Chapter 14, NK cells frequently form the first line of defense against viral infections. Generally, pathogens use a variety of strategies to escape destruction by the adaptive immune system. Many pathogens reduce their own antigenicity either by growing within host cells, where they are sequestered from immune attack, or by shedding their membrane antigens. Other pathogens camouflage themselves by mimicking the surfaces of host cells, either by expressing molecules with amino acid sequences similar to those of host cell-membrane molecules or by acquiring a covering of host membrane molecules. Some pathogens are able to suppress the immune response selectively or to regulate it so that a branch of the immune system is activated that is ineffective against the pathogen. Continual variation in surface antigens is another strategy that enables a pathogen to elude the immune system. This antigenic variation may be due to the gradual accumulation of mutations, or it may involve an abrupt change in surface antigens. Both innate and adaptive immune responses to pathogens provide critical defense, but infectious diseases, which have plagued human populations throughout history, still cause the death of millions each year. Although widespread use of vaccines and drug therapy has drastically reduced mortality from infectious diseases in developed countries, such diseases continue to be the leading cause of death in the Third World. It is estimated that over 1 billion people are infected worldwide, resulting in more than 11 million deaths every year (Figure 17-1). Despite these alarming numbers, estimated expenditures for research on infectious diseases prevalent in the Third World are less than 5% of total healthresearch expenditures worldwide. Not only is this a tragedy for these countries, but some of these diseases are beginning to emerge or re-emerge in developed countries. For chapter 17
390 PART I The Immune System in Health and Disease and a new drug-resistant strain of Mycobacterium tuberculo- sis is spreading at an alarming rate in the United St: Over age five In this chapter, the concepts described in earlier chapters, ntigenicity( Chapter 3)and immune effector mechanisms Under age five (Chapters 12-16), as well as vaccine development(which will be considered in Chapter 18)are applied to selected infec tious diseases caused by viruses, bacteria, protozoa, and helminths-the four main types of pathogens Viral infections A number of specific immune effector mechanisms, together with nonspecific defense mechanisms, are called into play to eliminate an infecting virus (Table 17-1). At the same time the virus acts to subvert one or more of these mechanisms to AIDs Diarrhea Malaria Measles respiratory diseases prolong its own survival. The outcome of the infection de- infections pends on how effectively the host's defensive mechanisms (including resist the offensive tactics of the virus pneumonia and The innate immune response to viral infection is primar ily through the induction of type I interferons(IFN-c and IFN-B)and the activation of NK cells. Double stranded rna FIGURE 17-1 Leading infectious disease killers. Data collected and (dsRNA) produced during the viral life cycle can induce the compiled by the World Health Organization in 2000 for deaths in expression of IFN-a and IFN-B by the infected cell. Macro- 1998 HIV-infected individuals who died of TB are included among phages, monocytes, and fibroblasts also are capable of AIDS deaths thesizing these cytokines, but the mechanisms that induce the production of type I interferons in these cells are not completely understood. IFN-a and IFN-B can induce an example, some United States troops returned from the Per- antiviral response or resistance to viral replication by bind sian Gulf with leishmaniasis; cholera cases have recently ing to the iFN a/B receptor. Once bound, IFN-a and IFN increased worldwide, with more than 100,000 cases reported activate the JAK-STAT pathway, which in turn induces the in KwaZulu-Natal, South Africa, during the summer of 2001; transcription of several genes. One of these genes encodes an TABLE 1 Mechanisms of humoral and cell-mediated immune responses to virus Response type Effector molecule or cel Activity Humoral Antibody(especially, secretory IgA) Blocks binding of virus to host cells, thus preventing infection or reinfection IgM, and IgA antibody Blocks fusion of viral envelope with host-cells plasma membrane Enhances phagocytosis of viral particles Complement activated by igG or Mediates opsonization by C3b and lysis IgM antibody f enveloped viral particles by membrane- IFN-y secreted by tH or Tc cells Has direct antiviral activity Cytotoxic T lymphocytes(CTLs Kill virus-infected self-cells NK cells and macrophages Kill virus-infected cells by antibody- dependent cell-mediated cytotoxicity(ADCC)
example, some United States troops returned from the Persian Gulf with leishmaniasis; cholera cases have recently increased worldwide, with more than 100,000 cases reported in KwaZulu-Natal, South Africa, during the summer of 2001; and a new drug-resistant strain of Mycobacterium tuberculosis is spreading at an alarming rate in the United States. In this chapter, the concepts described in earlier chapters, antigenicity (Chapter 3) and immune effector mechanisms (Chapters 12–16), as well as vaccine development (which will be considered in Chapter 18) are applied to selected infectious diseases caused by viruses, bacteria, protozoa, and helminths—the four main types of pathogens. Viral Infections A number of specific immune effector mechanisms, together with nonspecific defense mechanisms, are called into play to eliminate an infecting virus (Table 17-1). At the same time, the virus acts to subvert one or more of these mechanisms to prolong its own survival. The outcome of the infection depends on how effectively the host’s defensive mechanisms resist the offensive tactics of the virus. The innate immune response to viral infection is primarily through the induction of type I interferons (IFN- and IFN-) and the activation of NK cells. Double stranded RNA (dsRNA) produced during the viral life cycle can induce the expression of IFN- and IFN- by the infected cell. Macrophages, monocytes, and fibroblasts also are capable of synthesizing these cytokines, but the mechanisms that induce the production of type I interferons in these cells are not completely understood. IFN- and IFN- can induce an antiviral response or resistance to viral replication by binding to the IFN / receptor. Once bound, IFN- and IFN- activate the JAK-STAT pathway, which in turn induces the transcription of several genes. One of these genes encodes an 390 PART IV The Immune System in Health and Disease Deaths in millions 4.0 3.0 2.5 2.0 1.5 1.0 0.5 0 Acute respiratory infections (including pneumonia and influenza) AIDS Malaria Measles Diarrheal TB diseases 3.5 2.3 Over age five 1.1 0.9 1.5 2.2 Under age five FIGURE 17-1 Leading infectious disease killers. Data collected and compiled by the World Health Organization in 2000 for deaths in 1998. HIV-infected individuals who died of TB are included among AIDS deaths. TABLE 17-1 Mechanisms of humoral and cell-mediated immune responses to viruses Response type Effector molecule or cell Activity Humoral Antibody (especially, secretory IgA) Blocks binding of virus to host cells, thus preventing infection or reinfection IgG, IgM, and IgA antibody Blocks fusion of viral envelope with host-cells plasma membrane IgG and IgM antibody Enhances phagocytosis of viral particles (opsonization) IgM antibody Agglutinates viral particles Complement activated by IgG or Mediates opsonization by C3b and lysis IgM antibody of enveloped viral particles by membraneattack complex Cell-mediated IFN- secreted by TH or TC cells Has direct antiviral activity Cytotoxic T lymphocytes (CTLs) Kill virus-infected self-cells NK cells and macrophages Kill virus-infected cells by antibodydependent cell-mediated cytotoxicity (ADCC)
Immune Response to Infectious Diseases CHAPTER 17 IFN-O/B face receptor molecules that enable them to initiate infection by binding to specific host-cell membrane molecules. For example, influenza virus binds to sialic acid residues in cell IFN-a/B receptor membrane glycoproteins and glycolipids; rhinovirus binds to intercellular adhesion molecules(ICAMs); and Epstein-Barr virus binds to type 2 complement receptors on B cells. If anti- body to the viral receptor is produced, it can block infection altogether by preventing the binding of viral particles to host cells. Secretory lgA in mucous secretions plays an important role in host defense against viruses by blocking viral attach- 2-5(A)synthetase Protein kinase ment to mucosal epithelial cells. The advantage of the atten PKR (inactive) +ATP and uated oral polio vaccine, considered in Chapter 18, is that it 25(A) PKR(activated) induces production of secretory IgA, which effectively blocks attachment of poliovirus along the gastrointestinal tract RNAse l RNase l of eF- 2 ation Inactive Actin Viral neutralization by antibody sometimes involves mechanisms that operate after viral attachment to host cells In some cases, antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of Degradation of eIF2-GDP the viral envelope with the plasma membrane. If the induced poly (A)mRNA (nonfunctional ntibody is of a complement-activating isotype, lysis of en- veloped virions can ensue. Antibody or complement can also agglutinate viral particles and function as an opsonizing INHIBITION OF PROTEIN SYNTHESIS agent to facilitate Fc-or C3b-receptor-mediated phagocyte- sis of the viral particles FIGURE 17-2 Induction of antiviral activity by IFN-a and-p. These Cell-Mediated Immunity is Important interferons bind to the IFN receptor, which in turn induces the syn- for Viral Control and clearance thesis of both 2-5(A)synthetase and protein kinase(PKR). The actio can degrade mRNA PKR inactivates the translation initiation factor the spread of a virus in the acute phases of infection, thera. Ithough antibodies have an important role in conta elF-2 by phosphorylating it. Both pathways thus result in the inhibi- not usually able to eliminate the virus once infection has tion of protein synthesis and thereby effectively block viral replication. occurred-particularly if the virus is capable of entering a latent state in which its DNA is integrated into host chromo- somal dnA. Once an infection is established. cell-mediated immune mechanisms are most important in host defense. In enzyme known as 2'-5-oligo-adenylate synthetase [2-5(A) general, CD8 Tc cells and CD4 THl cells are the main com- synthetase], which activates a ribonuclease(RNAse L)that ponents of cell-mediated antiviral defense, although in some degrades viral RNA. Other genes activated by IFN-a/B bind- cases CD4" Tc cells have also been implicated. Activated THl ing to its receptor also contribute to the inhibition of viral cells produce a number of cytokines, including IL-2, IFN-y. replication. For example, IFN-a/B binding induces a specific and tNE, that defend against viruses either directly or indi- protein kinase called dsRNA-dependent protein kinase(PKR), rectly. IFN-y acts directly by inducing an antiviral state in which inactivates protein synthesis, thus blocking viral repli- cells. IL-2 acts indirectly by assisting in the recruitment of cation in infected cells(figure 17-2) CtL precursors into an effector population. Both IL-2 and The binding of IFN-a and IFN-B to NK cells induces lytic IFN-y activate NK cells, which play an important role in host activity, making them very effective in killing virally infected defense during the first days of viral infections untill cells. The activity of nK cells is also greatly enhanced by specific CTL response develops IL-12, a cytokine that is produced very early in a response to In most viral infections, specific CTL activity arises within viral infection 3-4 days after infection, peaks by 7-10 days, and then de- ines. Within 7-10 days of primary infection, most virions Many Viruses are Neutralized by Antibodies have been eliminated, paralleling the development of CTLs CTLs specific for the virus eliminate virus-infected self-cells Antibodies specific for viral surface antigens are often crucial and thus eliminate potential sources of new virus. The role of in containing the spread of a virus during acute infection and Ctls in defense against viruses is demonstrated by the abil in protecting against reinfection. Antibodies are particularly ity of virus-specific Ctls to confer protection for the specifi effective in protecting against infection if they are localized at virus on nonimmune recipients by adoptive transfer. The the site of viral entry into the body. Most viruses express sur- viral specificity of the ctl as well can be demonstrated with
enzyme known as 2-5-oligo-adenylate synthetase [2-5(A) synthetase], which activates a ribonuclease (RNAse L) that degrades viral RNA. Other genes activated by IFN-/ binding to its receptor also contribute to the inhibition of viral replication. For example, IFN-/ binding induces a specific protein kinase called dsRNA-dependent protein kinase (PKR), which inactivates protein synthesis, thus blocking viral replication in infected cells (Figure 17-2). The binding of IFN- and IFN- to NK cells induces lytic activity, making them very effective in killing virally infected cells. The activity of NK cells is also greatly enhanced by IL-12, a cytokine that is produced very early in a response to viral infection. Many Viruses are Neutralized by Antibodies Antibodies specific for viral surface antigens are often crucial in containing the spread of a virus during acute infection and in protecting against reinfection. Antibodies are particularly effective in protecting against infection if they are localized at the site of viral entry into the body. Most viruses express surface receptor molecules that enable them to initiate infection by binding to specific host-cell membrane molecules. For example, influenza virus binds to sialic acid residues in cellmembrane glycoproteins and glycolipids; rhinovirus binds to intercellular adhesion molecules (ICAMs); and Epstein-Barr virus binds to type 2 complement receptors on B cells. If antibody to the viral receptor is produced, it can block infection altogether by preventing the binding of viral particles to host cells. Secretory IgA in mucous secretions plays an important role in host defense against viruses by blocking viral attachment to mucosal epithelial cells. The advantage of the attenuated oral polio vaccine, considered in Chapter 18, is that it induces production of secretory IgA, which effectively blocks attachment of poliovirus along the gastrointestinal tract. Viral neutralization by antibody sometimes involves mechanisms that operate after viral attachment to host cells. In some cases, antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of the viral envelope with the plasma membrane. If the induced antibody is of a complement-activating isotype, lysis of enveloped virions can ensue. Antibody or complement can also agglutinate viral particles and function as an opsonizing agent to facilitate Fc- or C3b-receptor–mediated phagocytosis of the viral particles. Cell-Mediated Immunity is Important for Viral Control and Clearance Although antibodies have an important role in containing the spread of a virus in the acute phases of infection, they are not usually able to eliminate the virus once infection has occurred—particularly if the virus is capable of entering a latent state in which its DNA is integrated into host chromosomal DNA. Once an infection is established, cell-mediated immune mechanisms are most important in host defense. In general, CD8+ TC cells and CD4+ TH1 cells are the main components of cell-mediated antiviral defense, although in some cases CD4+ TC cells have also been implicated. Activated TH1 cells produce a number of cytokines, including IL-2, IFN-, and TNF, that defend against viruses either directly or indirectly. IFN- acts directly by inducing an antiviral state in cells. IL-2 acts indirectly by assisting in the recruitment of CTL precursors into an effector population. Both IL-2 and IFN- activate NK cells, which play an important role in host defense during the first days of many viral infections until a specific CTL response develops. In most viral infections, specific CTL activity arises within 3–4 days after infection, peaks by 7–10 days, and then declines. Within 7–10 days of primary infection, most virions have been eliminated, paralleling the development of CTLs. CTLs specific for the virus eliminate virus-infected self-cells and thus eliminate potential sources of new virus. The role of CTLs in defense against viruses is demonstrated by the ability of virus-specific CTLs to confer protection for the specific virus on nonimmune recipients by adoptive transfer. The viral specificity of the CTL as well can be demonstrated with Immune Response to Infectious Diseases CHAPTER 17 391 IFN-α/β IFN-α/β receptor 2-5(A) synthetase Protein kinase PKR (inactive) ATP 2-5(A) PKR (activated) Inactive RNAse L Degradation of poly(A)mRNA eIF2-GDP (nonfunctional) Phosphorylation of eIF-2 Active RNAse L + ATP and dsRNA INHIBITION OF PROTEIN SYNTHESIS FIGURE 17-2 Induction of antiviral activity by IFN- and -. These interferons bind to the IFN receptor, which in turn induces the synthesis of both 2-5(A) synthetase and protein kinase (PKR). The action of of 2-5(A) synthetase results in the activation of RNAse L, which can degrade mRNA. PKR inactivates the translation initiation factor eIF-2 by phosphorylating it. Both pathways thus result in the inhibition of protein synthesis and thereby effectively block viral replication.
392 PART I The Immune System in Health and Disease adoptive transfer: adoptive transfer of a Ctl clone specific these newly emerging strains leads to repeated epidemics of for influenza virus strain X protects mice against influenza influenza Antigenic variation among rhinoviruses, the causa- virus X but not against influenza virus strain. tive agent of the common cold, is responsible for our inabil ity to produce an effective vaccine for colds. Nowhere is anti- Viruses can evade host defense genic variation greater than in the human immunodeficiency echanisms virus(HIv), the causative agent of AIDS. Estimates suggest that hiv accumulates mutations at a rate 65 times faster thal Despite their restricted genome size, a number of viruses does influenza virus. Because of the importance of AIDS, have been found to encode proteins that interfere at various section of Chapter 19 addresses this disease levels with specific or nonspecific host defenses. Presumably, A large number of viruses evade the immune response by the advantage of such proteins is that they enable viruses to causing generalized immunosuppression. among these are replicate more effectively amidst host antiviral defenses. As he paramyxoviruses that cause mumps, the measles virus, described above, the induction of IFN-a and IFN-B is a Epstein-Barr virus(EBV), cytomegalovirus, and HIV. In major innate defense against viral infection, but some viruses some cases, immunosuppression is caused by direct viral in- have developed strategies to evade the action of IFN-a fection of lymphocytes or macrophages. The virus can then These include hepatitis C virus, which has been shown to either directly destroy the immune cells by cytolytic mecha- overcome the antiviral effect of the interferons by blocking or nisms or alter their function. In other cases, immunosup- inhibiting the action of PKR (see Figure 17-2) pression is the result of a cytokine imbalance. For example, Another mechanism for evading host responses, utilized BV produces a protein, called BCRFl, that is homologous to in particular by herpes simplex viruses(hsv) is inhibition IL-10: like IL-10, BCRFl suppresses cytokine production by of antigen presentation by infected host cells. HSV-1 and the TH1 subset, resulting in decreased levels of IL-2,TNE, and HSV-2 both express an immediate-early protein(a protein IFN-Y synthesized shortly after viral replication) called ICP47, which very effectively inhibits the human transporter mole- Influenza Has Been Responsible for Some cule needed for antigen processing(TAP; see Figure 8-8) of the Worst pandemics in histor Inhibition of TAP blocks antigen delivery to class I MHC re ceptors on HSV-infected cells, thus preventing presentation The influenza virus infects the upper respiratory tract and of viral antigen to CD8* T cells. This results in the trapping major central airways in humans, horses, birds, pigs, and of empty class I MHC molecules in the endoplasmic reticu- even seals In 1918-19, an influenza pandemic(worldwide lum and effectively shuts down a CD8 T-cell response to epidemic)killed more than 20 million people, a toll surpass- HSV-infected cells ing the number of casualties in World War I. Some areas, The targeting of MHC molecules is not unique to HSV. such as Alaska and the Pacific Islands. lost more than half of Other viruses have been shown to down-regulate class I their population during that pandemic MHC expression shortly after infection. Two of the best characterized examples, the adenoviruses and cytomegalo virus(CMv), use distinct molecular mechanisms to reduce PROPERTIES OF THE INFLUENZA VIRUS the surface expression of class I MHC molecules, again in- Influenza viral particles, or virions, are roughly spherical or hibiting antigen presentation to CD8 T cells. Some viruses- ovoid in shape, with an average diameter of 90-100 nm. The CMV, measles virus, and Hiv-have been shown to reduce virions are surrounded by an outer envelope-a lipid bilayer levels of class II MHC molecules on the cell surface, thus acquired from the plasma membrane of the infected host cell blocking the function of antigen-specific antiviral helper during the process of budding Inserted into the envelope are T cells two glycoproteins, hemagglutinin(HA)and neuraminidase Antibody-mediated destruction of viruses requires com- (NA), which form radiating projections that are visible in plement activation, resulting either in direct lysis of the vin electron micrographs(Figure 17-3). The hemagglutinin pro- particle or opsonization and elimination of the virus by jections, in the form of trimers, are responsible for the phagocytic cells. A number of viruses have strategies for evad- attachment of the virus to host cells. There are approximately ing complement-mediated destruction. Vaccinia virus, for 1000 hemagglutinin projections per influenza virion. The example, secretes a protein that binds to the CAb complement hemagglutinin trimer binds to sialic acid groups on host-cell component, inhibiting the classical complement pathway, glycoproteins and glycolipids by way of a conserved amino and herpes simplex viruses have a glycoprotein component acid sequence that forms a small groove in the hemagglu that binds to the C3b complement component, inhibiting tinin molecule Neuraminidase, as its name indicates, cleaves both the classical and alternative pathways N-acetylneuraminic(sialic)acid from nascent viral glyco- a number of viruses escape immune attack by constantly proteins and host-cell membrane glycoproteins, an activity langing their antigens. In the influenza virus, continual that presumably facilitates viral budding from the infected antigenic variation results in the frequent emergence of new host cell. Within the envelope, an inner layer of matrix pro- infectious strains. The absence of protective immunity to tein surrounds the nucleocapsid, which consists of eight dif-
adoptive transfer: adoptive transfer of a CTL clone specific for influenza virus strain X protects mice against influenza virus X but not against influenza virus strain Y. Viruses Can Evade Host Defense Mechanisms Despite their restricted genome size, a number of viruses have been found to encode proteins that interfere at various levels with specific or nonspecific host defenses. Presumably, the advantage of such proteins is that they enable viruses to replicate more effectively amidst host antiviral defenses. As described above, the induction of IFN- and IFN- is a major innate defense against viral infection, but some viruses have developed strategies to evade the action of IFN-/. These include hepatitis C virus, which has been shown to overcome the antiviral effect of the interferons by blocking or inhibiting the action of PKR (see Figure 17-2). Another mechanism for evading host responses, utilized in particular by herpes simplex viruses (HSV) is inhibition of antigen presentation by infected host cells. HSV-1 and HSV-2 both express an immediate-early protein (a protein synthesized shortly after viral replication) called ICP47, which very effectively inhibits the human transporter molecule needed for antigen processing (TAP; see Figure 8-8). Inhibition of TAP blocks antigen delivery to class I MHC receptors on HSV-infected cells, thus preventing presentation of viral antigen to CD8+ T cells. This results in the trapping of empty class I MHC molecules in the endoplasmic reticulum and effectively shuts down a CD8+ T-cell response to HSV-infected cells. The targeting of MHC molecules is not unique to HSV. Other viruses have been shown to down-regulate class I MHC expression shortly after infection. Two of the bestcharacterized examples, the adenoviruses and cytomegalovirus (CMV), use distinct molecular mechanisms to reduce the surface expression of class I MHC molecules, again inhibiting antigen presentation to CD8+ T cells. Some viruses— CMV, measles virus, and HIV—have been shown to reduce levels of class II MHC molecules on the cell surface, thus blocking the function of antigen-specific antiviral helper T cells. Antibody-mediated destruction of viruses requires complement activation, resulting either in direct lysis of the viral particle or opsonization and elimination of the virus by phagocytic cells. A number of viruses have strategies for evading complement-mediated destruction. Vaccinia virus, for example, secretes a protein that binds to the C4b complement component, inhibiting the classical complement pathway; and herpes simplex viruses have a glycoprotein component that binds to the C3b complement component, inhibiting both the classical and alternative pathways. A number of viruses escape immune attack by constantly changing their antigens. In the influenza virus, continual antigenic variation results in the frequent emergence of new infectious strains. The absence of protective immunity to these newly emerging strains leads to repeated epidemics of influenza. Antigenic variation among rhinoviruses, the causative agent of the common cold, is responsible for our inability to produce an effective vaccine for colds. Nowhere is antigenic variation greater than in the human immunodeficiency virus (HIV), the causative agent of AIDS. Estimates suggest that HIV accumulates mutations at a rate 65 times faster than does influenza virus. Because of the importance of AIDS, a section of Chapter 19 addresses this disease. A large number of viruses evade the immune response by causing generalized immunosuppression. Among these are the paramyxoviruses that cause mumps, the measles virus, Epstein-Barr virus (EBV), cytomegalovirus, and HIV. In some cases, immunosuppression is caused by direct viral infection of lymphocytes or macrophages. The virus can then either directly destroy the immune cells by cytolytic mechanisms or alter their function. In other cases, immunosuppression is the result of a cytokine imbalance. For example, EBV produces a protein, called BCRF1, that is homologous to IL-10; like IL-10, BCRF1 suppresses cytokine production by the TH1 subset, resulting in decreased levels of IL-2, TNF, and IFN-. Influenza Has Been Responsible for Some of the Worst Pandemics in History The influenza virus infects the upper respiratory tract and major central airways in humans, horses, birds, pigs, and even seals. In 1918–19, an influenza pandemic (worldwide epidemic) killed more than 20 million people, a toll surpassing the number of casualties in World War I. Some areas, such as Alaska and the Pacific Islands, lost more than half of their population during that pandemic. PROPERTIES OF THE INFLUENZA VIRUS Influenza viral particles, or virions, are roughly spherical or ovoid in shape, with an average diameter of 90–100 nm. The virions are surrounded by an outer envelope—a lipid bilayer acquired from the plasma membrane of the infected host cell during the process of budding. Inserted into the envelope are two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which form radiating projections that are visible in electron micrographs (Figure 17-3). The hemagglutinin projections, in the form of trimers, are responsible for the attachment of the virus to host cells. There are approximately 1000 hemagglutinin projections per influenza virion. The hemagglutinin trimer binds to sialic acid groups on host-cell glycoproteins and glycolipids by way of a conserved amino acid sequence that forms a small groove in the hemagglutinin molecule. Neuraminidase, as its name indicates, cleaves N-acetylneuraminic (sialic) acid from nascent viral glycoproteins and host-cell membrane glycoproteins, an activity that presumably facilitates viral budding from the infected host cell. Within the envelope, an inner layer of matrix protein surrounds the nucleocapsid, which consists of eight dif- 392 PART IV The Immune System in Health and Disease
Immune Response to Infectious Diseases CHAPTER 17 emergence of a new subtype of influenza whose HA and pos sibly also NA are considerably different from that of the virus present in a preceding epidemic. The first time a human influenza virus was isolated was in 1934; this virus was given the subtype designation HONI (where H is hemagglutinin and n is neuraminidase). The LoNi subtype persisted until 1947, when a major antigenic shift generated a new subtype, HINI, which supplanted the previous subt and became prevalent worldwide until 957, when H2N2 emerged. The H2N2 subtype prevailed for the next decade and was replaced in 1968 by H3N2 Antigenic shift in 1977 saw the re-emergence of HIN1. The most recent antigenic shift, in 1989, brought the re-emergence of H3N2, which remained dominant throughout the next several years. o 1 um a 3 However, an HiNi strain re-emerged in Texas in 1995, and current influenza vaccines contain both h3n2 and hini strains. With each antigenic shift, hemagglutinin and neu FIGURE 17-3 Electron micrograph of influenza virus reveals roughly raminidase undergo major sequence changes, resulting in spherical viral particles enclosed in a lipid bilayer with protruding major antigenic variations for which the immune system hemagglutinin and neuraminidase glycoprotein spikes. Courtesy of lacks memory. Thus, each antigenic shift finds the population G Murti, Department of Virology, St Jude Childrens Research Hospital, immunologically unprepared, resulting in major outbreaks of nfluenza, which sometimes reach pandemic proportions ferent strands of single-stranded RNA (ssRNA) associated luting Matrix protein with protein and Rna polymerase(Figure 17-4). Each RNA strand encodes one or more different influenza proteins Lipid bilayer Three basic types of influenza(A, B, and C), can be distin- guished by differences in their nucleoprotein and matrix pro- teins. Type A, which is the most common, is responsible for the major human pandemics. Antigenic variation in hemagglu tinin and neuraminidase distinguishes subtypes of type A in- fluenza virus. According to the nomenclature of the World &/MI. M2WE Health Organization, each virus strain is defined by its animal NAw host of origin(specified, if other than human), geographical NP origin, strain number, year of isolation, and antigenic descrip HAWAWNVM tion of HA and Na Table 17-2). For example, A/Sw/lowa/ PAVMMMA 15/30(HIN1) designates strain-A isolate 15 that arose in swine PBI in lowa in 1930 and has antigenic subtypes 1 of HA and NA. WAS Notice that the H and N spikes are antigenically distinctin thes two strains. There are 13 different hemagglutinins and 9 neu raml inidases among the type a influenza viruses &s. The distinguishing feature of influenza virus is its vari- ity. The virus can change its surface antigens so com pletely that the immune response to infection with the virus 01020304050 that caused a previous epidemic gives little or no protection Nanometers against the virus causing a subsequent epi genic variation results primarily from changes in the hemag. FIGURE 17-4 Schematic representation of influenza structure. The glutinin and neuraminidase spikes protruding from the viral envelope is covered with neuraminidase and hemagglutinin spikes In- envelope(Figure 17-5). Two different mechanisms generate side is an inner layer of matrix protein surrounding the nucleocapsid antigenic variation in HA and NA: antigenic drift and anti- which consists of eight ssRNA molecules associated with nucleopro genic shift. Antigenic drift involves a series of spontaneous tein. The eight RNA strands encode ten proteins: PBl, PB2, PA, HA point mutations that occur gradually, resulting in minor (hemagglutinin), NP(nucleoprotein), NA(neuraminidase),M1, M2 changes in HA and NA Antigenic shift results in the sudden NSl, and NS2
ferent strands of single-stranded RNA (ssRNA) associated with protein and RNA polymerase (Figure 17-4). Each RNA strand encodes one or more different influenza proteins. Three basic types of influenza (A, B, and C), can be distinguished by differences in their nucleoprotein and matrix proteins. Type A, which is the most common, is responsible for the major human pandemics. Antigenic variation in hemagglutinin and neuraminidase distinguishes subtypes of type A influenza virus. According to the nomenclature of the World Health Organization, each virus strain is defined by its animal host of origin (specified, if other than human), geographical origin, strain number, year of isolation, and antigenic description of HA and NA (Table 17-2). For example, A/Sw/Iowa/ 15/30 (H1N1) designates strain-A isolate 15 that arose in swine in Iowa in 1930 and has antigenic subtypes 1 of HA and NA. Notice that the H and N spikes are antigenically distinct in these two strains. There are 13 different hemagglutinins and 9 neuraminidases among the type A influenza viruses. The distinguishing feature of influenza virus is its variability. The virus can change its surface antigens so completely that the immune response to infection with the virus that caused a previous epidemic gives little or no protection against the virus causing a subsequent epidemic. The antigenic variation results primarily from changes in the hemagglutinin and neuraminidase spikes protruding from the viral envelope (Figure 17-5). Two different mechanisms generate antigenic variation in HA and NA: antigenic drift and antigenic shift. Antigenic drift involves a series of spontaneous point mutations that occur gradually, resulting in minor changes in HA and NA. Antigenic shift results in the sudden emergence of a new subtype of influenza whose HA and possibly also NA are considerably different from that of the virus present in a preceding epidemic. The first time a human influenza virus was isolated was in 1934; this virus was given the subtype designation H0N1 (where H is hemagglutinin and N is neuraminidase). The H0N1 subtype persisted until 1947, when a major antigenic shift generated a new subtype, H1N1, which supplanted the previous subtype and became prevalent worldwide until 1957, when H2N2 emerged. The H2N2 subtype prevailed for the next decade and was replaced in 1968 by H3N2. Antigenic shift in 1977 saw the re-emergence of H1N1. The most recent antigenic shift, in 1989, brought the re-emergence of H3N2, which remained dominant throughout the next several years. However, an H1N1 strain re-emerged in Texas in 1995, and current influenza vaccines contain both H3N2 and H1N1 strains. With each antigenic shift, hemagglutinin and neuraminidase undergo major sequence changes, resulting in major antigenic variations for which the immune system lacks memory. Thus, each antigenic shift finds the population immunologically unprepared, resulting in major outbreaks of influenza, which sometimes reach pandemic proportions. Immune Response to Infectious Diseases CHAPTER 17 393 Matrix protein Lipid bilayer Hemagglutinin Neuraminidase Nucleocapsid NS1, NS2 M1, M2 PB2 PB1 PA HA NP NA 0 10 20 30 40 50 Nanometers FIGURE 17-3 Electron micrograph of influenza virus reveals roughly spherical viral particles enclosed in a lipid bilayer with protruding hemagglutinin and neuraminidase glycoprotein spikes. [Courtesy of G. Murti, Department of Virology, St. Jude Children’s Research Hospital, Memphis, Tenn.] FIGURE 17-4 Schematic representation of influenza structure. The envelope is covered with neuraminidase and hemagglutinin spikes. Inside is an inner layer of matrix protein surrounding the nucleocapsid, which consists of eight ssRNA molecules associated with nucleoprotein. The eight RNA strands encode ten proteins: PB1, PB2, PA, HA (hemagglutinin), NP (nucleoprotein), NA (neuraminidase), M1, M2, NS1, and NS2. O.1 m
394 PART I The Immune System in Health and Disease Some influenza a strains and antigenic shift is thought to occur through genetic TABLE 17-2 their hemagglutinin(H)and sortment between influenza virions from humans and from neuraminidase(N) subtype various animals, including horses, pigs, and ducks(Figure 17-6b). The fact that influenza contains eight separate Antigenic strands of ssRNA makes possible the reassortment of the Virus strain designation RNA strands of human and animal virions within a single cell infected with both viruses. Evidence for in vivo genetic Human A/Puerto Rico/8/34 HONT reassortment between influenza a viruses from humans and A/Fort Monmouth/1/47 HINT domestic pigs was obtained in 1971. After infecting a pig A/Singapore/1/57 H2N2 simultaneously with human Hong Kong influenza(H3N2) A/Hong Kong/1/68 H3N2 and with swine influenza(HIN1), investigators were able to A/USSR/80/77 recover virions expressing H3N1. In some cases, an apparent A/Brazil/11/78 HINT antigenic shift may represent the re-emergence of a previous A/Bangkok/1/79 strain that has remained hidden for several decades. In May A/Taiwan/1/86 of 1977, a strain of influenza, A/USSR/77(HIN1), appeared that proved to be identical to a strain that had caused an epi A/Shanghai/16/89 H3N2 demic 27 years earlier. The virus could have been preserved A/Johannesburg/33/95 H3N2 over the years in a frozen state or in an animal reservoir A/Wuhan/359/95 H3N2 When such a re-emergence occurs, the ha and na antigens expressed are not really new; however, they will be seen by A/Hong Kong/156/97 H5N1 the immune system of anyone not previously exposed to that strain(people under the age of twenty-seven in the 1977 Swine HINT epidemic, for example)as if they were new because no mem- A/Sw/Taiwan/70 H3N2 ory cells specific for these antigenic subtypes will exist in the susceptible population. Thus, from an immunologic Horse(equine) A/Eq/Prague/1/56 point of view, the re-emergence of an old influenza A strain A/Eq/Miami/1/63 H3N8 Birds A/Fowl/ Dutch/27 H7N7 A/Turkey/Ontario/68 A/Chicken/Hong Kong/258/97 H5N1 e25 Between pandemic-causing a enic drift, generating minor variations which account for strain differences within a sub type. The immune response contributes to the emergence 品星 of these different influenza strains as individuals infected with a given influenza strain mount an effective immune response, the strain is eliminated. However, the accumula tion of point mutations sufficiently alters the antigenicity of some variants so that they are able to escape immune elimi- nation( Figure 17-6a). These variants become a new strain of influenza, causing another local epidemic cycle. The role of PB2 PBI PA NP HAI NA MI M2 NSI NSZ antibody in such immunologic selection can be demon strated in the laboratory by mixing an influenza strain with a FIGURE 17-5 Amino acid sequence variation in 10 influenza viral monoclonal antibody specific for that strain and then cultur- proteins from two H3N2 strains and one HiN1 strain. The surface ing the virus in cells. The antibody neutralizes all unaltered glycoproteins hemagglutinin(HA1)and neuraminidase(NA)show viral particles and only those viral particles with mutations significant sequence variation; in contrast, the sequences of internal resulting in altered antigenicity escape neutralization and are viral proteins, such as matrix proteins(M1 and M2) and nucleopro- able to continue the infection. Within a short time in culture, tein(NP), are largely conserved. Adapted from G G. Brownlee, 1986, a new influenza strain can be shown to emerge in Options for the Control of Influenza, Alan R. Liss
Between pandemic-causing antigenic shifts, the influenza virus undergoes antigenic drift, generating minor antigenic variations, which account for strain differences within a subtype. The immune response contributes to the emergence of these different influenza strains. As individuals infected with a given influenza strain mount an effective immune response, the strain is eliminated. However, the accumulation of point mutations sufficiently alters the antigenicity of some variants so that they are able to escape immune elimination (Figure 17-6a). These variants become a new strain of influenza, causing another local epidemic cycle. The role of antibody in such immunologic selection can be demonstrated in the laboratory by mixing an influenza strain with a monoclonal antibody specific for that strain and then culturing the virus in cells. The antibody neutralizes all unaltered viral particles and only those viral particles with mutations resulting in altered antigenicity escape neutralization and are able to continue the infection. Within a short time in culture, a new influenza strain can be shown to emerge. Antigenic shift is thought to occur through genetic reassortment between influenza virions from humans and from various animals, including horses, pigs, and ducks (Figure 17-6b). The fact that influenza contains eight separate strands of ssRNA makes possible the reassortment of the RNA strands of human and animal virions within a single cell infected with both viruses. Evidence for in vivo genetic reassortment between influenza A viruses from humans and domestic pigs was obtained in 1971. After infecting a pig simultaneously with human Hong Kong influenza (H3N2) and with swine influenza (H1N1), investigators were able to recover virions expressing H3N1. In some cases, an apparent antigenic shift may represent the re-emergence of a previous strain that has remained hidden for several decades. In May of 1977, a strain of influenza, A/USSR/77 (H1N1), appeared that proved to be identical to a strain that had caused an epidemic 27 years earlier. The virus could have been preserved over the years in a frozen state or in an animal reservoir. When such a re-emergence occurs, the HA and NA antigens expressed are not really new; however, they will be seen by the immune system of anyone not previously exposed to that strain (people under the age of twenty-seven in the 1977 epidemic, for example) as if they were new because no memory cells specific for these antigenic subtypes will exist in the susceptible population. Thus, from an immunologic point of view, the re-emergence of an old influenza A strain 394 PART IV The Immune System in Health and Disease Amino acid change, % NS2 5 Viral proteins PB2 PB1 PA NP HA1 NA M1 M2 NS1 61 69 10 15 20 25 30 FIGURE 17-5 Amino acid sequence variation in 10 influenza viral proteins from two H3N2 strains and one H1N1 strain. The surface glycoproteins hemagglutinin (HA1) and neuraminidase (NA) show significant sequence variation; in contrast, the sequences of internal viral proteins, such as matrix proteins (M1 and M2) and nucleoprotein (NP), are largely conserved. [Adapted from G. G. Brownlee, 1986, in Options for the Control of Influenza, Alan R. Liss.] TABLE 17-2 Some influenza A strains and their hemagglutinin (H) and neuraminidase (N) subtype Antigenic Species Virus strain designation subtype Human A/Puerto Rico/8/34 H0N1 A/Fort Monmouth/1/47 H1N1 A/Singapore/1/57 H2N2 A/Hong Kong/1/68 H3N2 A/USSR/80/77 H1N1 A/Brazil/11/78 H1N1 A/Bangkok/1/79 H3N2 A/Taiwan/1/86 H1N1 A/Shanghai/16/89 H3N2 A/Johannesburg/33/95 H3N2 A/Wuhan/359/95 H3N2 A/Texas/36/95 H1N1 A/Hong Kong/156/97 H5N1 Swine A/Sw/Iowa/15/30 H1N1 A/Sw/Taiwan/70 H3N2 Horse (equine) A/Eq/Prague/1/56 H7N7 A/Eq/Miami/1/63 H3N8 Birds A/Fowl/Dutch/27 H7N7 A/Tern/South America/61 H5N3 A/Turkey/Ontario/68 H8N4 A/Chicken/Hong Kong/258/97 H5N1
Immune Response to Infectious Diseases CHAPTER 17 395 humoral responses, CTLs can play a role in immune re- Virus r Bacterial Infections Immunity to bacterial infections is achieved by means of ntibody unless the bacterium is capable of intracellular growth, in which case delayed-type hypersensitivity has an important role. Bacteria enter the body either through a Human wine number of natural routes( e. g, the respiratory tract, the gas influenza trointestinal tract, and the genitourinary tract) or through normally inaccessible routes opened up by breaks in mucous membranes or skin. Depending on the number of organisms Tip/interface FIGURE 17-6 Two mechanisms generate variations in influenza surface antigens (a) In antigenic drift, the accumulation of point mu- tations eventually yields a variant protein that is no longer recognized by antibody to the original antigen. (b) Antigenic shift may occur by re- assortment of an entire ssrna between human and animal virions in- fecting the same cell. Only four of the eight RNA strands are depict have the same effect as an antigenic shift that generates a Hinge HOST RESPONSE TO INFLUENZA INFECTION a helix Humoral antibody specific for the HA molecule is produced during an influenza infection. This antibody confers protec- tion against influenza, but its specificity is strain-specific and is readily bypassed by antigenic drift. antigenic drift in the HA molecule results in amino acid substitutions in several antigenic domains at the molecule's distal end( Figure 17-7) Two of these domains are on either side of the conserved sialic-acid-binding cleft, which is necessary for binding of virions to target cells. Serum antibodies specific for these two regions are important in blocking initial viral infectivity These antibody titers peak within a few days of infection and then decrease over the next 6 months; the titers then plateau and remain fairly stable for the next several years. This anti body does not appear to be required for recovery from in- fluenza, as patients with agammaglobulinemia recover from FIGURE 17-7 Structure of hemagglutinin molecule Sialic acid on the disease. Instead, the serum antibody appears to play a sig- host cells interacts with the binding cleft, which is bounded by re- nificant role in resistance to reinfection by the same strain. gions-designated the loop and tip/interface--where antigenic drift When serum-antibody levels are high for a particular Ha is prevalent(blue areas). Antibodies to these regions are important molecule, both mice and humans are resistant to infection by in blocking viral infections. Continual changes in amino acid residues virions expressing that HA molecule. If mice are infected in these regions allow the influenza virus to evade the antibody re- with influenza virus and antibody production is experimen- sponse. Small red dots represent residues that exhibit a high degree tally suppressed, the mice recover from the infection but of variation among virus strains. /Adapted from D. C. Wiley et al can be reinfected with the same viral strain In addition to 1987, Nature 289 373. towww.whfreeman.com/immunology95molecularVis Viral Antigens See Introduction and Flu virus Hemagglutinin
can have the same effect as an antigenic shift that generates a new subtype. HOST RESPONSE TO INFLUENZA INFECTION Humoral antibody specific for the HA molecule is produced during an influenza infection. This antibody confers protection against influenza, but its specificity is strain-specific and is readily bypassed by antigenic drift. Antigenic drift in the HA molecule results in amino acid substitutions in several antigenic domains at the molecule’s distal end (Figure 17-7). Two of these domains are on either side of the conserved sialic-acid–binding cleft, which is necessary for binding of virions to target cells. Serum antibodies specific for these two regions are important in blocking initial viral infectivity. These antibody titers peak within a few days of infection and then decrease over the next 6 months; the titers then plateau and remain fairly stable for the next several years. This antibody does not appear to be required for recovery from influenza, as patients with agammaglobulinemia recover from the disease. Instead, the serum antibody appears to play a significant role in resistance to reinfection by the same strain. When serum-antibody levels are high for a particular HA molecule, both mice and humans are resistant to infection by virions expressing that HA molecule. If mice are infected with influenza virus and antibody production is experimentally suppressed, the mice recover from the infection but can be reinfected with the same viral strain. In addition to humoral responses, CTLs can play a role in immune responses to influenza. Bacterial Infections Immunity to bacterial infections is achieved by means of antibody unless the bacterium is capable of intracellular growth, in which case delayed-type hypersensitivity has an important role. Bacteria enter the body either through a number of natural routes (e.g., the respiratory tract, the gastrointestinal tract, and the genitourinary tract) or through normally inaccessible routes opened up by breaks in mucous membranes or skin. Depending on the number of organisms Immune Response to Infectious Diseases CHAPTER 17 395 Antigenic Virus drift Host cell Antigenic shift Human influenza Swine influenza (a) (b) FIGURE 17-6 Two mechanisms generate variations in influenza surface antigens. (a) In antigenic drift, the accumulation of point mutations eventually yields a variant protein that is no longer recognized by antibody to the original antigen. (b) Antigenic shift may occur by reassortment of an entire ssRNA between human and animal virions infecting the same cell. Only four of the eight RNA strands are depicted. Tip/interface Binding cleft Loop Hinge α helix β pleated sheet FIGURE 17-7 Structure of hemagglutinin molecule. Sialic acid on host cells interacts with the binding cleft, which is bounded by regions—designated the loop and tip/interface—where antigenic drift is prevalent (blue areas). Antibodies to these regions are important in blocking viral infections. Continual changes in amino acid residues in these regions allow the influenza virus to evade the antibody response. Small red dots represent residues that exhibit a high degree of variation among virus strains. [Adapted from D. C. Wiley et al., 1981, Nature 289:373.] Go to www.whfreeman.com/immunology Molecular Visualization Viral Antigens See Introduction and Flu Virus Hemagglutinin
396 PART I The Immune System in Health and Disease entering and their virulence, different levels of host defense macrophages to kill ingested pathogens more effectively(see are enlisted. If the inoculum size and the virulence are both Figure 14-15) low, then localized tissue phagocytes may be able to eliminate the bacteria with an innate, nonspecific defense. Larger in- Bacteria Can Effectively Evade Host oculus or organisms with greater virulence tend to induce Defense Mechanisms an adaptive, specific immune response. There are four primary steps in bacterial infection Immune Responses to Extracellular ttachment to host cells and Intracellular Bacteria Can Differ Proliferation Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma Invasion of host tissue cells in regional lymph nodes and the submucosa of the res Toxin-induced damage to host cells piratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular Host-defense mechanisms act at each of these steps, and bacteria. The antibodies act in several ways to protect the many bacteria have evolved ways to circumvent some of these host from the invading organisms, including removal of the host defenses ( Table 17-3) bacteria and inactivation of bacterial toxins(Figure 17-8) Some bacteria have surface structures or molecules that Extracellular bacteria can be pathogenic because they induce enhance their ability to attach to host cells. a number of a localized inflammatory response or because they produce gram-negative bacteria, for instance, have pili (long hairlike toxins. The toxins, endotoxin or exotoxin, can be cytotoxic projections), which enable them to attach to the membrane but also may cause pathogenesis in other ways. An excellent of the intestinal or genitourinary tract(Figure 17-9). Other example of this is the toxin produced by diphtheria, which bacteria, such as Bordetella pertussis, secrete adhesion mole exerts a toxic effect on the cell by blocking protein synthesis. cules that attach to both the bacterium and the ciliated Endotoxins, such as lipopolysaccharides(LPS), are generally epithelial cells of the upper respiratory tract components of bacterial cell walls, while exotoxins, such Secretory IgA antibodies specific for such bacterial struc diphtheria toxin, are secreted by the bacteria. ures can block bacterial attachment to mucosal epithelial Antibody that binds to accessible antigens on the surface cells and are the main host defense against bacterial attach of a bacterium can, together with the C3b component of ment. However, some bacteria(e. g, Neisseria gonorrhoeae, complement, act as an opsonin that increases ph agocytoSIS emo US uenzae, and Neisseria meningiti and thus clearance of the bacterium(see Figure 17-8). In the the igA response by secreting proteases that cleave secretory case of some bacteria-notably, the gram-negative organ IgA at the hinge region; the resulting Fab and Fc fragments isms-complement activation can lead directly to lysis of the have a shortened half-life in mucous secretions and are not organism. Antibody-mediated activation of the complement able to agglutinate microorganisms system can also induce localized production of immune Some bacteria evade the igA response of the host by ffector molecules that help to develop an amplified and changing these surface antigens. In N. gonorrhoeae, for ex more effective inflammatory response. For example, the ample, pilin, the protein component of the pili, has a highly complement split products C3a, C4a, and C5a act as anaphy- variable structure Variation in the pilin amino acid sequence latoxins, inducing local mast-cell degranulation and thus is generated by gene rearrangements of its coding sequence vasodilation and the extravasation of lymphocytes and neu- The pilin locus consists of one or two expressed genes and trophils from the blood into tissue space(see Figure 17-8). 10-20 silent genes. Each gene is arranged into six regions Other complement split products serve as chemotactic fac- called minicassettes. Pilin variation is generated by a process tors for neutrophils and macrophages, thereby contributing of gene conversion, in which one or more minicassettes from to the buildup of phagocytic cells at the site of infection. the silent genes replace a minicassette of the expression gene. Antibody to a bacteria toxin may bind to the toxin and n This process generates enormous antigenic variation, which tralize it; the antibody-toxin complexes are then cleared by may contribute to the pathogenicity of N. gonorrhoeae by phagocytic cells in the same manner as any other antigen- increasing the likelihood that expressed pili will bind firmly antibody complex to epithelial cells. In addition, the continual changes in the While innate immunity is not very effective against intra- pilin sequence allow the organism to evade neutralization cellular bacterial pathogens, intracellular bacteria can acti- by IgA ate NK cells, which, in turn, provide an early defense against Some bacteria possess surface structures that serve to these bacteria. Intracellular bacterial infections tend to in- inhibit phagocytosis. a classic example is Streptococcus pneu duce a cell-mediated immune response, specifically, delayed- moniae, whose polysaccharide capsule prevents phagocytosis type hypersensitivity. In this response, cytokines secreted by very effectively. There are 84 serotypes of S pneumoniae that CD4* T cells are important-notably IFN-Y, which activates differ from one another by distinct capsular polysaccharides Gotowww.whfreeman.com/immunology mation Vaccine Strategies See Pathenogenesis
entering and their virulence, different levels of host defense are enlisted. If the inoculum size and the virulence are both low, then localized tissue phagocytes may be able to eliminate the bacteria with an innate, nonspecific defense. Larger inoculums or organisms with greater virulence tend to induce an adaptive, specific immune response. Immune Responses to Extracellular and Intracellular Bacteria Can Differ Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma cells in regional lymph nodes and the submucosa of the respiratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular bacteria. The antibodies act in several ways to protect the host from the invading organisms, including removal of the bacteria and inactivation of bacterial toxins (Figure 17-8). Extracellular bacteria can be pathogenic because they induce a localized inflammatory response or because they produce toxins. The toxins, endotoxin or exotoxin, can be cytotoxic but also may cause pathogenesis in other ways. An excellent example of this is the toxin produced by diphtheria, which exerts a toxic effect on the cell by blocking protein synthesis. Endotoxins, such as lipopolysaccharides (LPS), are generally components of bacterial cell walls, while exotoxins, such as diphtheria toxin, are secreted by the bacteria. Antibody that binds to accessible antigens on the surface of a bacterium can, together with the C3b component of complement, act as an opsonin that increases phagocytosis and thus clearance of the bacterium (see Figure 17-8). In the case of some bacteria—notably, the gram-negative organisms—complement activation can lead directly to lysis of the organism. Antibody-mediated activation of the complement system can also induce localized production of immune effector molecules that help to develop an amplified and more effective inflammatory response. For example, the complement split products C3a, C4a, and C5a act as anaphylatoxins, inducing local mast-cell degranulation and thus vasodilation and the extravasation of lymphocytes and neutrophils from the blood into tissue space (see Figure 17-8). Other complement split products serve as chemotactic factors for neutrophils and macrophages, thereby contributing to the buildup of phagocytic cells at the site of infection. Antibody to a bacteria toxin may bind to the toxin and neutralize it; the antibody-toxin complexes are then cleared by phagocytic cells in the same manner as any other antigenantibody complex. While innate immunity is not very effective against intracellular bacterial pathogens, intracellular bacteria can activate NK cells, which, in turn, provide an early defense against these bacteria. Intracellular bacterial infections tend to induce a cell-mediated immune response, specifically, delayedtype hypersensitivity. In this response, cytokines secreted by CD4+ T cells are important—notably IFN-, which activates macrophages to kill ingested pathogens more effectively (see Figure 14-15). Bacteria Can Effectively Evade Host Defense Mechanisms There are four primary steps in bacterial infection: ■ Attachment to host cells ■ Proliferation ■ Invasion of host tissue ■ Toxin-induced damage to host cells Host-defense mechanisms act at each of these steps, and many bacteria have evolved ways to circumvent some of these host defenses (Table 17-3). Some bacteria have surface structures or molecules that enhance their ability to attach to host cells. A number of gram-negative bacteria, for instance, have pili (long hairlike projections), which enable them to attach to the membrane of the intestinal or genitourinary tract (Figure 17-9). Other bacteria, such as Bordetella pertussis, secrete adhesion molecules that attach to both the bacterium and the ciliated epithelial cells of the upper respiratory tract. Secretory IgA antibodies specific for such bacterial structures can block bacterial attachment to mucosal epithelial cells and are the main host defense against bacterial attachment. However, some bacteria (e.g., Neisseria gonorrhoeae, Haemophilus influenzae, and Neisseria meningitidis) evade the IgA response by secreting proteases that cleave secretory IgA at the hinge region; the resulting Fab and Fc fragments have a shortened half-life in mucous secretions and are not able to agglutinate microorganisms. Some bacteria evade the IgA response of the host by changing these surface antigens. In N. gonorrhoeae, for example, pilin, the protein component of the pili, has a highly variable structure. Variation in the pilin amino acid sequence is generated by gene rearrangements of its coding sequence. The pilin locus consists of one or two expressed genes and 10–20 silent genes. Each gene is arranged into six regions called minicassettes. Pilin variation is generated by a process of gene conversion, in which one or more minicassettes from the silent genes replace a minicassette of the expression gene. This process generates enormous antigenic variation, which may contribute to the pathogenicity of N. gonorrhoeae by increasing the likelihood that expressed pili will bind firmly to epithelial cells. In addition, the continual changes in the pilin sequence allow the organism to evade neutralization by IgA. Some bacteria possess surface structures that serve to inhibit phagocytosis. A classic example is Streptococcus pneumoniae, whose polysaccharide capsule prevents phagocytosis very effectively. There are 84 serotypes of S. pneumoniae that differ from one another by distinct capsular polysaccharides. 396 PART IV The Immune System in Health and Disease Go to www.whfreeman.com/immunology Animation Vaccine Strategies See Pathenogenesis
Immune Response to Infectious Diseases CHAPTER 17 397 VISUALIZING CONCEPTS ① Toxin neutralization C3b C lysis ④ Anaphylatoxins mediate Chemotaxis C3a, C4a, C5a Mast cell Mediators一 Neutr Macrophage FIGURE 17-8 Antibody-mediated mechanisms for combating increase phagocytosis. (4)C3a, C4a, and C5a, generated by antibody. infection by extracellular bacteria (1)Antibody neutralizes bacterial initiated complement activation, induce local mast cell degranulation, toxins. (2)Complement activation on bacterial surfaces leads to releasing substances that mediate vasodilation and extravasation complement-mediated lysis of bacteria. (3) Antibody and the com- of lymphocytes and neutrophils (5)Other complement split prod plement split product C3b bind to bacteria, serving as opsonins to ucts are chemotactic for neutrophils and macrophages
Immune Response to Infectious Diseases CHAPTER 17 397 VISUALIZING CONCEPTS Mast cell Opsonization and phagocytosis Anaphylatoxins mediate mast cell degranulation Complement–mediated lysis Toxin neutralization C3b C3b C3b C3b C3b C3b Toxin Bacteria Complement activation C3a, C4a, C5a Mediators Extravasation Macrophage Macrophage Neutrophil Lymphocyte 3 5 Chemotaxis 2 4 1 FIGURE 17-8 Antibody-mediated mechanisms for combating infection by extracellular bacteria. (1) Antibody neutralizes bacterial toxins. (2) Complement activation on bacterial surfaces leads to complement-mediated lysis of bacteria. (3) Antibody and the complement split product C3b bind to bacteria, serving as opsonins to increase phagocytosis. (4) C3a, C4a, and C5a, generated by antibodyinitiated complement activation, induce local mast cell degranulation, releasing substances that mediate vasodilation and extravasation of lymphocytes and neutrophils. (5) Other complement split products are chemotactic for neutrophils and macrophages
398 PART I The Immune System in Health and Disease TABLE 17-3 Host immune responses to bacterial infection and bacterial evasion mechanisms Infection proces Host defense Bacterial evasion mechanism Attachment to host Blockage of attachment by Secretion of proteases that cleave secretory igA dimers secretory IgA antibodies neisseria meningitidis, N gonorrhoeae, Haemophilus influenzae Antigenic variation in attachment structures(pili of Proliferation sis(Ab-and fibrin coat)that inhibit phagocytic els aride capsule, M protein, Mechanisms for surviving within phagocytic cells Induction of apoptosis in macrophages( Shigella flexneri Complement-mediated lysis and Generalized resistance of gram-positive bacteria to complement localized inflammatory respons mediated lysis Insertion of membrane-attack complex prevented by long side hain in cell-wall LPS(some gram-negative bacteria) Invasion of host tissues Ab-mediated agglutination Secretion of elastase that inactivates C3a and C5a(Pseudomonas) Toxin-induced damage Neturalization of toxin by antibody Secretion of hyaluronidase, which enhances bacterial invasiveness to host cells uring infection, the host produces antibody against the Mechanisms for interfering with the complement system infecting serotype. This antibody protects against reinfection help other bacteria survive. In some gram-negative bacteria, with the same serotype but will not protect against infection for example, long side chains on the lipid a moiety of the by a different serotype. In this way, S. pneumoniae can cause cell-wall core polysaccharide help to resist complement disease many times in the same individual. On other bacteria, mediated lysis. Pseudomonas secretes an enzyme, elastase such as Streptococcus pyogenes, a surface protein projection that inactivates both the C3a and C5a anaphylatoxins, there called the M protein inhibits phagocytosis. Some pathogenic by diminishing the localized inflammatory reaction staphylococci are able to assemble a protective coat from hos A number of bacteria escape host defense mechanisms by proteins. These bacteria secrete a coagulase enzyme that pre- their ability to survive within phagocytic cells. Some, such as cipitates a fibrin coat around them, shielding them from Listeria monocytogenes, do this by escaping from the phago- phagocytic cells lysosome to the cytoplasm, which is a more favorable environ- ment for their growth. Other bacteria, such as Mycobacterium avium, block lysosomal fusion with the phagolysosome; and some mycobacteria are resistant to the oxidative attack that takes place within the phagolysosome Immune Responses Can Contribute to Bacterial Pathogenesis In some cases, disease is caused not by the bacterial pathogen itself but by the immune response to the pathogen. As described in Chapter 12, pathogen-stimulated overproduce tion of cytokines leads to the symptoms of bacterial septic shock, food poisoning, and toxic-shock syndrome. For in stance, cell-wall endotoxins of some gram-negative bacteria activate macrophages, resulting in release of high levels of IL-l and TNF-a, which can cause septic shock. In staphylo- coccal food poisoning and toxic-shock syndrome, exotoxins produced by the pathogens function as superantigens, which FIGURE17-9 Electron micrograph of Neisseria gonorhoeae at- can activate all T cells that express T-cell receptors with a par- taching to urethral epithelial cells. Pili(P)extend from the gonococ- ticular VB domain(see Table 10-4). The resulting overpro- al surface and mediate the attachment / From M. E. Ward and P J duction of cytokines by activated TH cells causes many of the at.1972.nt.Dis.126601J symptoms of these diseases
During infection, the host produces antibody against the infecting serotype. This antibody protects against reinfection with the same serotype but will not protect against infection by a different serotype. In this way, S. pneumoniae can cause disease many times in the same individual. On other bacteria, such as Streptococcus pyogenes, a surface protein projection called the M protein inhibits phagocytosis. Some pathogenic staphylococci are able to assemble a protective coat from host proteins. These bacteria secrete a coagulase enzyme that precipitates a fibrin coat around them, shielding them from phagocytic cells. Mechanisms for interfering with the complement system help other bacteria survive. In some gram-negative bacteria, for example, long side chains on the lipid A moiety of the cell-wall core polysaccharide help to resist complementmediated lysis. Pseudomonas secretes an enzyme, elastase, that inactivates both the C3a and C5a anaphylatoxins, thereby diminishing the localized inflammatory reaction. A number of bacteria escape host defense mechanisms by their ability to survive within phagocytic cells. Some, such as Listeria monocytogenes, do this by escaping from the phagolysosome to the cytoplasm, which is a more favorable environment for their growth. Other bacteria, such as Mycobacterium avium, block lysosomal fusion with the phagolysosome; and some mycobacteria are resistant to the oxidative attack that takes place within the phagolysosome. Immune Responses Can Contribute to Bacterial Pathogenesis In some cases, disease is caused not by the bacterial pathogen itself but by the immune response to the pathogen. As described in Chapter 12, pathogen-stimulated overproduction of cytokines leads to the symptoms of bacterial septic shock, food poisoning, and toxic-shock syndrome. For instance, cell-wall endotoxins of some gram-negative bacteria activate macrophages, resulting in release of high levels of IL-1 and TNF-, which can cause septic shock. In staphylococcal food poisoning and toxic-shock syndrome, exotoxins produced by the pathogens function as superantigens, which can activate all T cells that express T-cell receptors with a particular V domain (see Table 10-4). The resulting overproduction of cytokines by activated TH cells causes many of the symptoms of these diseases. 398 PART IV The Immune System in Health and Disease TABLE 17-3 Host immune responses to bacterial infection and bacterial evasion mechanisms Infection process Host defense Bacterial evasion mechanisms Attachment to host Blockage of attachment by Secretion of proteases that cleave secretory IgA dimers cells secretory IgA antibodies (Neisseria meningitidis, N. gonorrhoeae, Haemophilus influenzae) Antigenic variation in attachment structures (pili of N. gonorrhoeae) Proliferation Phagocytosis (Ab- and Production of surface structures (polysaccharide capsule, M protein, C3b-mediated opsonization) fibrin coat) that inhibit phagocytic cells Mechanisms for surviving within phagocytic cells Induction of apoptosis in macrophages (Shigella flexneri) Complement-mediated lysis and Generalized resistance of gram-positive bacteria to complementlocalized inflammatory response mediated lysis Insertion of membrane-attack complex prevented by long side chain in cell-wall LPS (some gram-negative bacteria) Invasion of host tissues Ab-mediated agglutination Secretion of elastase that inactivates C3a and C5a (Pseudomonas) Toxin-induced damage Neturalization of toxin by antibody Secretion of hyaluronidase, which enhances bacterial invasiveness to host cells FIGURE 17-9 Electron micrograph of Neisseria gonorrhoeae attaching to urethral epithelial cells. Pili (P) extend from the gonococcal surface and mediate the attachment. [From M. E. Ward and P. J. Watt, 1972, J. Inf. Dis. 126:601.]
