Immunology of Infectious Diseases

This chapter summarizes the most important findings on bacterial virulence factors and mechanisms of infection. Gastric infection by the gram-negative bacterium Helicobacter pylori is associated with a number of clinical outcomes including gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and adenocarcinoma of the stomach. A number of gram-negative pathogenic bacteria have evolved specialized systems for the delivery of virulence factors directly into the host cytosol. One such system is the type III secretion system, in which bacterial proteins lacking a typical signal sequence are secreted directly from the bacteria into the cytosol of infected cells. Recent studies of the role of the locus for enterocyte effacement (LEE)-encoded secreted proteins in enteropathogenic Escherichia coli (EPEC) pathogenesis have demonstrated the potential involvement of EspA, EspB, and EspD as structural components of the secretion apparatus. The invasion plasmid antigens (Ipa proteins) orchestrate the cytoskeletal rearrangements necessary for bacterial entry. These proteins also direct many of the other virulence properties of Shigella flexneri, including escape from the phagocytic vacuole and induction of apoptosis of macrophages and resulting inflammation. Apoptosis is normally viewed as an immunologically silent cell death process unaccompanied by inflammation. However, this is clearly not the case for the caspase-1-dependent apoptosis induced by S. flexneri. Obligate intracellular bacterial pathogens like Chlamydia, Rickettsia, and Coxiella species are less well characterized than facultative intracellular pathogens. Finally, the chapter discusses recent progress in understanding the cell biology of Chlamydia infections.

This chapter provides basic knowledge of fungal biology that is necessary for proper comprehension of the intimate mechanisms and strategies that fungi have adopted in causing infections and diseases. Fungal morphogenesis, dimorphism, and phenotypic switching are now beginning to be explored at the molecular and genetic levels. Unlike mammalian cells, fungi possess a multilayered rigid cell wall immediately exterior to the plasmalemma. The major polysaccharides of the cell wall matrix consist of glucans, made up of β-1,6-linked D-glucose residues with β-1,3-linked branches at frequent intervals; mannan, an a-1,6-linked polymer of D-mannose with a-1,2 and a-1,3 branches; chitosans (polymers of glucosamine); and galactans (polymers of galactose). The chapter focuses on various fungal diseases. Adherence to host tissues is considered the pivotal first step in the pathogenesis of fungal infections. Fungi secrete a variety of enzymes, such as proteases, elastases, and phospholipases, which are considered to be major virulence factors. Subversion of host phagocyte receptors by fungal pathogens represents a most successful strategy to escape elimination by the host immune system. Progress toward understanding the epidemiology and pathogenesis of fungal infections has been slow, as has the progress in the area of diagnosis and treatment. There is a need for additional strategies of prevention and treatment of fungal infections. This demands the continuation of studies aimed at the molecular typing of fungi, fungal virulence genes, and host-specific immune reactivity that limit fungal infectivity.

The genetic and morphologic complexity of parasites makes them challenging targets for immunological studies. The chapter focuses on major parasites and the diseases they cause. Toxoplasma infection in humans arises from the consumption of undercooked infected meat or through contact with the feces of an infected cat. The species of Plasmodium that cause disease in humans are, in decreasing order of importance, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale. Trypanosoma brucei is endemic in sub-Saharan Africa, where it is transmitted between humans by blood-feeding tsetse flies. In humans, trematodes live either within the bloodstream or within the lungs or intestine. The most important cestodes that infect humans are Taenia saginata, Taenia solium, and Echinococcus spp. Impaired lymphatic drainage associated with the adult parasites living within the lymph vessels can lead to elephantiasis, a self-explanatory condition in which there is severe swelling of the limb extremities, genitalia, and breasts. The chapter considers few general characteristics of immunity to parasites that deserve special attention, and discusses relationship between immunity and disease. With global warming, there is also an expectation that parasites previously considered to be largely tropical pathogens will move north and south of their traditional areas of endemicity to cause disease in formerly temperate zones. The ready spread of parasitic pathogens is also enhanced by the greater ease of global travel and by the global transportation of food (a factor in outbreaks of foodborne Cyclospora infection in the United States).

There are at least four practical reasons for immunologists to have a good working knowledge of virology. The first is that viruses remain a major cause of human morbidity and mortality and pose a constant potential for causing devastating plagues. Second, viruses are important vectors for vaccines against viral pathogens and nonviral pathogens. Third, viruses are evolution’s gift to gene therapists. Finally, viruses are extremely useful experimental tools and probes for understanding the biology of cells and organisms. The requirement of viral genomes to reach the cytosol provides an early opportunity for recognition by the adaptive immune system in the absence of viral gene expression. Viral penetration of cells has four potential outcomes. First, the cell may be completely inhospitable and the viral proteins and nucleic acids are disposed of with minimal perturbation of the host cells. Second, viral replication initiates but fails to produce infectious progeny, with consequences for the cell ranging from minimal transient perturbations to death. Third, viral replication results in the generation of infectious progeny and cells either are killed immediately or remain persistently infected and continue to function as they produce progeny viruses. Fourth, the virus enters a latent state and essentially disappears until it is triggered to reactivate, with the production of infectious progeny. The chapter focuses on genetic instability of viruses, species specificity, pathogenicity, and vulnerability to immune attack.

The specific immune system includes several unique molecules found only in vertebrates: the immunoglobulins (Ig), the T-cell receptors (TCR), and the class I and class II molecules of the major histocompatibility complex (MHC). This chapter reviews recent evidence from molecular evolutionary studies regarding (i) the origin of the vertebrate immune system and (ii) the molecular mechanisms by which families of immune system genes have been diversified. Many researchers studying innate immunity have proposed that innate immune mechanisms of vertebrates share an evolutionary ancestry with those of invertebrates. The two mechanisms most commonly invoked to explain specific immunity—wholegenome duplication by polyploidization and horizontal gene transfer. Some authors have tried to implicate polyploidization in the origin of vertebrate-specific immunity. The chapter discusses four separate lines of evidence favoring the hypothesis that MHC polymorphism is maintained by a form of balancing selection; thus, unlike the vast majority of genetic polymorphisms of which we are aware, it is not a selectively neutral polymorphism. Defensins are antimicrobial peptides found in mammals; apparently related genes are found in insects, suggesting that the presence of defensins may be one aspect of innate immunity that shows evolutionary continuity between invertebrates and vertebrates. Interestingly, natural selection favoring diversity at the amino acid level is a characteristic not only of the specific immune system but also of some innate immune system genes.

This chapter presents an overview of the role played by phagocytes in anti-infective immunity. It describes the various types and functions of phagocytic cells, the mechanisms they utilize for microbial recognition, uptake, and killing; and their involvement with the adaptive immune system. Where appropriate, the authors demonstrate how pathogens have overcome the various anti-infective phagocyte functions and indicate where these microbial mechanisms have aided the understanding of phagocyte cell biology. Phagocytes can contribute to the generation of autoimmune diseases by presenting microbial epitopes to lymphocytes which are cross-reactive to self molecules. The respiratory burst of phagocytes that culminates in the production of reactive oxygen intermediates is one of the best characterized antimicrobial defenses. A central role of phagocytes, particularly dendritic cells (DC), in the generation of adaptive immunity is that of antigen presentation. Phagocytes play a central role in anti-infective immunity, which is important in all aspects of the immune response.

The host response to pathogens is extraordinarily diverse. Much of the host response centers on the pathogen and the route and extent of the infection. This chapter analyzes some general features of host-pathogen interaction and discusses general principles of them. The chapter is based on a recent one that also dealt with general aspects of innate immunity and considered aspects of innate immunity studied mainly in mice. While many bacterial infections can be controlled, SCID mice do not do well in combating viruses. Infections with common murine pathogens, including viruses, and other pathogens, like Pneumocystis carinii, occasionally develop. The state of cellular activation is limited and cannot be perpetuated unless lymphocytes are present. The innate system recognizes pathogens by way of surface receptors as well as by using circulating blood proteins. A variety of surface molecules, found mostly in macrophages and neutrophils but also in epithelial cells, are involved: some primarily recognize and bind to the pathogen, and others are primarily involved in signaling or in promoting phagocytosis. The production and differentiation of macrophages are under the control of colony-stimulating factors (CSF), of which CSF-1 is the major member. CSF-1 is a protein elaborated by many cells including mesenchymal cells. T-cell responses depend on their recognition of peptides derived from the intracellular processing of protein antigens, an event carried out by the macrophages or DC, major cells of the innate system.

This chapter centers on antimicrobial peptides, effector molecules that generally act by disrupting microbial membranes. When human neutrophils ingest Salmonella enterica serovar Typhimurium in the presence of radioactive iodide, defensins are the most abundant radioiodinated polypeptides in phagocytic vacuoles. Since iodination is produced by the neutrophil’s myeloperoxidase-hydrogen peroxide system, iodinated defensins provide evidence that the neutrophil’s oxidative and nonoxidative systems operate concurrently within the phagosome. Presumably, adverse consequences from the lack of neutrophil defensins in these species are mitigated by the presence of other antimicrobial effector mechanisms, such as NADPH oxidase, inducible nitric oxide synthase, cathelicidins, serprocidins, and other antimicrobial polypeptides. The only known human cathelicidin has been designated hCAP18 or FALL39/LL-37 by the three groups that described its cDNA, gene and peptide forms. Unlike defensins, which are stored in their mature form in the granules of neutrophils, hCAP18/LL-37 is stored as a 16-kDa (140-aminoacid) proform. Individual peptides differ in their antimicrobial spectrum, and early evidence suggests that they sometimes act synergistically with each other or with larger antimicrobial polypeptides. At sites that are more distant from the infected or inflamed locus, lower concentrations of defensins may act as signaling molecules, similarly to chemokines.

Traditionally, the control of parasitic infections was thought to be the exclusive domain of the acquired immune system. However, during the past decade it has been recognized that innate immunity can shape the outcome of the host-parasite encounter. Perhaps the simplest forms of innate immunity are represented by the presence of preexisting, soluble factors that can recognize and destroy invading parasites. Importantly, whereas complement-sensitive epimastigotes fail to express gp160, epimastigotes transfected with gp160 are resistant to complement-mediated lysis. Although innate immunity plays an important role in resistance to acute parasitic infections, the adaptive response is required to provide long-term protective immunity. Understanding the cellular and molecular basis of the mechanisms that underlie innate immunity to parasitic diseases may also provide important information for the rational design of immunotherapies or vaccines. At present there is a paucity of vaccines which protect against parasitic diseases, and understanding how innate immunity initiates the development of long-lived, protective responses to these parasites may provide new approaches to vaccination. Perhaps the best example of how understanding the mechanisms of innate immunity to infection can influence the development of new approaches to deal with parasitic infections is provided by IL-12.

Innate immunity is central to host defense against fungi. For many types of fungal infections, innate immunity is solely responsible for host defense. However, even for fungal infections that require an adaptive immune response for clearance, innate immunity plays a key role in the effective development of adaptive immunity. Several broad effector mechanisms are induced early to combat a fungal infection. Complement, mannose binding protein (MBP), and surfactant proteins promote initial recognition (opsonization) of fungi. The complement pathways are an essential part of the innate response to fungi. Opsonization can also be mediated by MBP via recognition and binding to complex carbohydrates (e.g., D-mannose and N-acetylglucosamine) on fungal surfaces. During pulmonary infections, surfactant proteins may also opsonize fungi and participate in host defense. The cells of the innate immune system possess many immunoregulatory functions, along with potent antifungal effector mechanisms that can be activated by adaptive immunity. The cells of the innate immune system rapidly release cytokines in response to fungal products and binding of opsonized fungi. Fungal infections induce the production of both C-C and C-X-C chemokines. Dendritic cells are the most effective antigen-presenting cells (APC) for stimulating naive T cells and are probably key APC in initiating Th1-type cellmediated immunity against fungi. Fungal virulence factors and secreted or shed fungal products can interfere with a number of innate mechanisms, resulting in a dynamic interaction between microbe and host.

This chapter reviews the current understanding of the induction and function of innate immune responses to viral infections. The focus is on the characteristics unique to or best characterized in the context of viral rather than nonviral infections. This chapter is organized into six sections. The first reviews the literature on induction of innate cytokine proteins during in vivo infections. The second presents the known molecular pathways to cytokine induction. The third is an overview of biochemical pathways activated by key innate cytokines. The last three sections integrate this information to examine functions of innate cytokines in regulating endogenous immune responses, the accessing of innate cytokines by adaptive immune responses, and the contributions of innate cytokines to viral pathogenesis. The ability of IL-6 to induce secretion of glucocorticoids (GCs) and therefore limit the extent of the pathologic inflammatory reactions, as demonstrated in mice infected with murine cytomegalovirus (MCMV), may contribute to such a protective effect. In MCMV infections, MIP-1α is required for induction of an early natural killer (NK)-cell infiltration into livers. It is now clear that systemic proinflammatory cytokines can be part of acute primary responses to some viruses and are likely to contribute to disease during adaptive responses to a number of viral infections.

The extent of the diversity of T-cell responses is much larger than the original Th1/Th2 dichotomy, raising questions about the significance of the original sharply defined Th1 and Th2 phenotypes, the extent of diversity of T-cell cytokine patterns, the information used by the immune system to decide which type of response to induce, the signals that induce differentiation into these and other phenotypes in vivo, and the extent to which differentiation and continued differentiation occur during normal responses. The study of functional heterogeneity within the CD4+ T-cell population with regard to infectious disease was prompted by studies in the early 1970s on the development of humoral and cell-mediated immunity to pathogens and experimental antigens. In addition, IFN-γ stimulates the production of immunoglobulin G antibodies, which mediate opsonization and phagocytosis of particulate organisms. Th1 responses are also associated with viral infections; a direct role for CD4 cells in viral clearance has not been demonstrated for most viruses, but Th1 responses may support the expansion of CD8+ antiviral effectors. The authors expect that T cells expressing non- Th1, non-Th2 patterns may be essential for other diseases and that the crucial differences between the immune responses may be subtle. The requirement for multiple effector phenotypes is almost certainly due to the intensive interplay between the host response and each pathogen, driving the evolution of complex host defense strategies and equally complex evasion and interference tactics by the pathogen.

This chapter focuses on the principles of immune memory. It is divided into four parts: (i) a historical perspective of vaccination, (ii) an overview of protective immunity to microbes, (iii) a discussion of the current models of memory T- and B-cell differentiation, and (iv) an overview of the mechanisms involved in maintaining immunological memory. Microbial infections usually induce both T- and B-cell long-term memory. The kinetics and anatomic location of antibody production after an acute viral infection are shown. In summary, immunological memory in the B-cell compartment consists of memory B cells and plasma cells: two distinct cell types with different anatomic locations and very different functions. The rapid rise in antibody levels on reinfection is the result of memory B-cell differentiation into new antibody-secreting plasma cells. Since preexisting antibody provides the first line of defense against infection by microbial pathogens, the importance of plasma cells in protective immunity cannot be overstated. In fact, it could be argued that plasma cells may be the single most important cell type in protective immunity to infections. In conclusion, in this chapter an attempt has been made to give an overview of the principles of immunological memory to infection. This remains one of the most exciting areas of immunology and infectious diseases, and there are many challenges ahead.

The distribution of organized mucos-aassociated lymphoid tissues (MALT) in mucosal tissues of the body varies among species, but there are certain consistent patterns. The sequence of events involved in processing and presentation of foreign antigens by professional antigen-presenting cells and the responses and interactions of local lymphocytes that lead to the production of effector and memory cells are likely to be similar in the mucosal and systemic branches of the immune system. Alternatively, dendritic cells (DCs) located in the epithelium over organized MALT, such as those that are abundant in the tonsils, could present antigens either in local MALT or after migration to draining lymph nodes. In addition, the class I-related molecule CD1d is expressed at the basolateral surfaces of intestinal epithelial cells and appears to function as an antigen presenting molecule by interacting with specialized populations of T cells. The possible role of antigen uptake by enterocytes in induction of immune responses or immune tolerance is discussed. The mucosal addressin MadCam-1 (mucosal addressin cell adhesion molecule 1) is preferentially expressed in human and mouse intestinal flat postcapillary venules of the lamina propria and high endothelial venules of organized MALT but not in other mucosal tissues. When microbial pathogens adhere to or invade the epithelial cells that line mucosal surfaces, the cells release proinflammatory cytokines and chemokines and upregulate chemokine receptors and adhesion molecules.

This chapter focuses on the generation and maintenance of the acquired immune response against bacterial pathogens and the pathological effects that may occur if this response is left uncontrolled or actively disregulated. The chapter outlines the general mechanisms of acquired immunity, and then, using specific examples, discusses how various bacterial pathogens induce and modulate this response. Lymphocytes communicate with high endothelial venules via receptor-ligand interactions, which induce lymphocyte transmigration. These adhesion molecules include selectins, integrins, and members of the immunoglobulin (Ig) superfamily. For infections with intracellular bacteria in particular, CD4 T cells dominate both the induction and effector phases of the immune response. Peptides that are presented by major histocompatibility (MHC) class I molecules are generated from endogenous proteins or proteins that are secreted into the cytoplasm. In light of this, CD8 T-cell responses are central to the immune response to viruses. For bacterial infections such as Haemophilus influenzae and Neisseria meningitidis, the capsule elicits significant Ab production but only after 2 years of age. Accordingly, the capsular polysaccharide vaccine initially used against H. influenzae elicited strong Ab-mediated protection only in children older than 2 years. Toxins produced by extracellular bacteria can be divided into exotoxins, which are secreted by the bacteria, and endotoxins, which form an integral part of the outer membrane of gram-negative bacteria and which are released on bacterial lysis.

This chapter focuses primarily on four fungi, Candida albicans, Coccidioides immitis, Cryptococcus neoformans, and Histoplasma capsulatum, but also considers examples from other fungal pathogens. The primary goal in this chapter is to focus on the general principles involved in the acquired immune response to fungi. Major human fungal pathogens and medical conditions predisposing to invasive disease have been discussed in the chapter. For many bacterial and viral pathogens the importance of acquired immunity is evident from the observation that recovery from symptomatic infection results in long-lasting immunity. Nevertheless, for several fungal pathogens, serological skin reactivity surveys indicate that infections are common but clinical disease is rare, consistent with the development of acquired immunity. Hence, the experience with experimental vaccines against fungi indicates that acquired immunity can be protective against fungi and that both arms of the immune system can be effective depending on the antigen used and the fungal pathogen in question. For many fungal pathogens, the effective tissue response to invasion is granulomatous inflammation. Given that an extensive body of evidence indicates an important role for acquired immunity in host defense against fungal pathogens, it is nevertheless important to consider certain caveats with regard to the studies performed in this field.

This chapter covers the acquired immune responses to two types of parasites. The first is the immune response associated with intracellular protozoa, and the principal examples will be Leishmania, Toxoplasma, and Trypanosoma cruzi. The chapter then discusses the immune responses associated with control of helminth infections, particularly focusing on gut-dwelling nematodes. The current model for macrophage activation is that IFN-γ primes cells, and additional signals, such as tumor necrosis factor (TNF), trigger activation of the cell. The relative importance of IL-4 and IL-13 in resistance is also influenced by host genetic background and highlighted by studies in the Trichuris muris system. Here, IL-4KO mice on a C57BL/6 background are uniformly susceptible and develop chronic infections whereas WT mice expel their worm burden. This chapter reviews the effector mechanisms associated with resistance to a select group of parasites, particularly focusing on parasites that illustrate the diversity of effector mechanisms contributing to protective immunity. The immune responses required for eliminating intracellular protozoa are quite different from those required to control gut-dwelling nematodes and can be divided into type 1 and type 2 responses. However, while type 1 or type 2 responses may dominate following infection with intracellular protozoa or gut-dwelling nematodes, respectively, the effector mechanisms required for resistance to any one particular parasite are often tailored to the biological characteristics of that parasite, which in some cases remain to be defined.

The importance of acquired immunity against viruses is demonstrated by the fatal outcome of infections with many viruses (such as vaccinia virus, polyomavirus, and influenza virus) in mice with severe combined immunodeficiency (SCID mice), which lack functional T and B cells. This chapter describes the dynamics of the T- and B-cell responses elicited by virus infections and illustrates the functions and importance of these cells with examples from well-studied viral models. While much emphasis has been placed on ascertaining the relative contributions of either T-cell subset to the resolution of viral infections, the optimal control of infection in vivo usually occurs with cooperation between both sets. Recent technologic advances have furthered one's understanding of the dynamics of T-cell responses elicited by virus infection. A substantial enlargement of the CD8+ cytotoxic T lymphocytes (CTL) compartment is characteristic of the immune response to viral infections. CTL have two separate systems that mediate cytolytic function. The first is the granule exocytosis pathway, and the second is the interaction of Fas ligand (FasL, expressed on T cells) and Fas (expressed on targets). The specificity of Fas-mediated cell death is enhanced by the fact that FasL expression is upregulated following T-cell receptor (TCR) triggering, so that an infected cell expressing viral antigens would more probably receive the death signal than would an uninfected cell. The induction of antiviral antibody responses in immunocompetent normal mice involves complex interactions of antigen-specific activated CD4 T cells and B cells.

This chapter provides a classification of relevant immunopathological reactions depending on the underlying mechanisms leading to tissue damage. The release of mediators such as histamine, leukotrienes, and heparin from mast cells accounts for the anaphylactic reactions to horse serum or to penicillin but is usually not important in the immunopathology of bacterial infections. CD8+ T cells may contribute to host resistance by at least four mechanisms: (i) release of IFN-γ, (ii) lysis of the target cell, (iii) induction of apoptosis of the target cells, and (iv) mediation of direct antimicrobial activity. This chapter provides a brief outline of the immunoprotective and immunopathological features of these mechanisms, using tuberculosis as an example. Cytokines therefore play an important role in immune defense but also contribute to immunopathology and disease. Although tumor necrosis factor (TNF) is crucial to the protective immune response, it also plays a part in the immunopathology of tuberculosis. The typical clinical syndrome, in conjunction with knowledge about the pathophysiology of septic shock, has supported the hypothesis that TNF is released at the onset of antimycobacterial therapy and mediates immunopathology. Mechanistically, one could argue that harmful effects may be ascribed to the biological activity of TNF in affecting vascular endothelium by inducing procoagulant activity, formation of thrombi, and production of nitric oxide synthase, thus causing endarteritis. Rheumatic fever is the most commonly cited example of molecular mimicry in humans.

This chapter focuses primarily on the question of how the balance between immune protection and immune pathology is regulated. A fundamental biological dilemma is that the host has to deal with many different infectious pathogens and, even for a single species of parasite, with different strains. Eosinophils, typically associated with the Th2 response, are involved in immediate hypersensitivity reactions to the filarial worm Onchocerca volvulus. Humans with visceral leishmaniasis have high circulating levels of IL-10, which may partly explain their inability to control the infection. The clinical manifestations of weight loss, hypothermia, hypoglycemia, and increased levels of liver-derived enzymes in the blood, together with hepatic necrosis, suggested that the IL-10 knockout (KO) mice died in response to an overwhelming systemic immune response, resembling that observed during septic shock. Schistosomiasis is caused by one of three major species of helminth parasites, Schistosoma mansoni, S. haematobium, and S. japonicum. Malarial infection provokes high levels of tumor necrosis factor (TNF) and other proinflammatory cytokines as well as causing markedly elevated immunoglobulin production activation of complement and redistribution of lymphocytes from the peripheral circulation to the spleen and other organs. Although our knowledge of cytokines and other immunological mediators has grown enormously in the last 15 years, the current list is undoubtedly a small fraction of the total number of host molecules involved in the pathogenesis of parasitic disease.

This chapter reviews the cycle of virus infection and discusses the anatomic and physiologic defense mechanisms that are situated at each of the common portals of virus entry. The concepts of cell and tissue tropism are central to an understanding of viral pathogenesis, since the lesions and, subsequently, the clinical features resulting from viral infections typically reflect the cellular and tissue localization of these obligate intracellular parasites. Examples of viral receptors and attachment proteins are provided in the chapter. The chapter concludes with a discussion of virus-induced cellular injury, with emphasis on morphologic features of infection, followed by an organ system-based presentation of virologic syndromes. Many virus infections are cytolytic, since the invading virus induces lethal physiologic or morphologic alterations in the host cell. A section of the chapter examines viral disease pathogenesis from the perspective of major organ systems and important disease syndromes that affect them. Syndrome presentation and major organ involvement in viral infections have been discussed in the chapter. The pathogenesis of two common respiratory disease syndromes, acute respiratory distress syndrome (ARDS) and pneumonia are described. The chapter examines viral disease pathogenesis from three general perspectives: from the perspective of basic concepts of infection and transmission, from the perspective of morphologic aspects of cell injury, and from the perspective of major organ systems and disease syndromes that affect them.

This chapter focuses on a few organisms as paradigms of persistence strategies. Programmed rearrangement of genes encoding surface antigens (antigenic variation) is essential for the evasion of adaptive humoral immunity by extracellular, blood-borne pathogens such as the Borrelia spp. that cause relapsing fever (RF) and Lyme disease (LD). Gonorrhea, caused by the gram-negative diplococcus Neisseria gonorrhoeae, is one of the most prevalent sexually transmitted diseases of humans-every year, one million new cases are reported in the United States alone. Variation of several cell surface components of the gonococcus-notably, the pili, outer membrane Opa proteins, and LOS-is controlled by distinct and complex mechanisms. Despite the manifest importance of persistence in the pathogenesis of tuberculosis (TB), little is known about the mechanisms that promote mycobacterial persistence in vivo. Indeed, reactive oxygen intermediates (ROI) detoxification mediated by the KatG catalase is essential for bacterial persistence in mice following induction of adaptive immunity. One of the most familiar and complex types of medically relevant biofilm is dental plaque, comprising hundreds of microbial species. The study of microbial biofilms and their role in persistent infections is still at an early stage. The environmental signals that promote biofilm formation and dissolution and the signals that the bacteria use to communicate with each other are just beginning to be deciphered.

The effects of viral immune evasion proteins can occur outside host cells, in the case of chemokines, cytokines, or cell surface receptors, or inside cells, in the case of signal transduction and antigen presentation pathways. This chapter attempts to summarize examples of viral immune evasion strategies, especially the facets of the immune system frequently targeted by viruses. Human cytomegalovirus (HCMV), human retroviruses, and vaccinia virus incorporate host complement control proteins (CCPs), CD55 and CD59, into the virion envelopes, mediating resistance to complement. The poxviruses variola virus, vaccinia virus (VV), and cowpox virus (CPV) all express CCPs, which were discovered based on sequence similarity to human and mouse CCPs. The ability of viruses to induce IFN gene expression via dsRNA varies greatly, and the viral proteins which have evolved to intercept this dsRNA-dependent activation can function either to block IFN-induced transcription or by neutralizing IFN-induced molecules that establish an antiviral state. The discovery of virus-encoded homologs of IFN regulatory factors (vIRFs) within the genome of human herpesvirus 8 (HHV-8) suggested a mechanism whereby the viral homolog could outcompete cellular IRFs needed for the transcriptional activation of host cell IFN response genes. Inactivation occurs only after direct contact between herpes simplex virus (HSV)-infected fibroblasts and the lymphocytes, not when the lymphocytes are incubated with high concentrations of cell-free virus.

This chapter examines two paradigms of parasite immune evasion during infection: one is a new theme emerging from a classic paradigm of surface antigen variation by extracellular parasites, and the other is a new paradigm of modified antigen recognition of intracellular parasites. A study was published with newer crystal structure data in a broader sequence survey of VSG molecules related by class (the pattern of Cys residues in the N terminus) and type (sequence similarities within the C terminus). The finding of the study was that the amino acid-hypervariable regions existed among different variant surface glycoprotein (VSG) and that some of these were buried within the surface coat. It was proposed that this represented evidence at the primary sequence level for antigenic variation within potential Th-cell epitope sites, and they made the formal hypothesis that antigenic variation by trypanosomes was done to evade host B- and T-cell responses. Additional evidence that VSG-specific Th-cell responses contribute to host resistance has come from a recent unexpected finding. In this work, C57BL/6-Igh-6 mice that lack mature B cells were infected with T. b. rhodesiense LouTat 1. Some parasites reside intracellularly during infection and do not exhibit substantial antigenic variation. In summary, the protozoan parasite Leishmania has developed several powerful strategies to subvert the macrophage signaling system, and this consequently affects the development of protective immune responses to favor parasite survival.

The role of genetic factors in common infectious diseases can be investigated by the analysis of several complementary traits. These traits include clinical phenotypes, which are generally binary (i.e., affected or unaffected); biological phenotypes, such as measures of infection, which may be quantitative (e.g., fecal egg counts in schistosomiasis) or binary (seropositive/seronegative); and measures of the immune response. Sections in this chapter focus on the main findings obtained in studies of susceptibility or resistance to mycobacterial and certain parasitic infections. Tuberculosis and leprosy, the most common human mycobacterial diseases, are caused by Mycobacterium tuberculosis and M. leprae, respectively. Many studies of familial aggregation, twin studies, and segregation analyses have clearly shown that leprosy susceptibility has a significant genetic component. Association studies between leprosy and HLA have provided other lines of evidence for the role of genetic factors in diseases caused by M. leprae. In tuberculoid leprosy, the most consistent results were obtained for HLA-DR2. Segregation analyses on malaria infection levels have been performed in populations from Cameroon and Burkina Faso. Infection levels were assessed by multiple measurements of Plasmodium falciparum parasitemia, and the data were adjusted for factors known to influence parasitemia, such as season, area of residence, and age of the subject.

This chapter presents an overview of the specific mouse loci identified as playing a key role in susceptibility to infection with human bacterial pathogens. The role of natural resistance-associated macrophage protein 1 (Nramp1) in host defenses against clinically relevant strains of Mycobacterium tuberculosis and Mycobacterium leprae was addressed in genetic studies in humans from areas of endemic tuberculosis (The Gambia) and leprosy (South Vietnam) infection, using informative markers derived from the NRAMP1 gene region. Mice bearing naturally occurring (Nramp1D169) or experimentally induced (Nramp1-/-) mutations at Nramp1 are extremely susceptible to intravenous or subcutaneous infection with low doses of S. enterica serovar Typhimurium (103 CFU), with uncontrolled bacterial replication in the spleen and liver of susceptible mice leading to uniform death within 4 to 5 days of infection. Legionella pneumophila induces apoptosis during infection of permissive human macrophages and in alveolar epithelial cell lines. Avirulent L. pneumophila mutants cannot induce either apoptosis or caspase 3 activation, and specific inhibition of caspase 3 activity can block both L. pneumophila-induced apoptosis and cytopathogenicity. Hence, it seems likely that the number of described susceptibility and resistance loci for divergent bacterial infections in the mouse will increase dramatically over the coming years.

This chapter reviews the main steps of the adaptive immune responses and discusses the consequences of genetic polymorphism for the susceptibility to viral infections. It also reviews recent important results obtained with particular viral infections of mice and of humans and concludes with some general remarks on the consequences of these studies for both our fundamental understanding of viral pathogenesis and practical applications to human medicine. Extensive polymorphism of class I and class II molecules, the number of alleles, and their heterozygosity account for the ability to mount efficient immune responses against a large variety of infectious agents. Nevertheless, the modulation of the immune response to viruses by the major histocompatibility complex (MHC) haplotype is well documented for mice and other laboratory animals. The Mx genes and their protein products constitute one of the best-characterized systems of genetically regulated control of viral infections. Importantly, the effect of the Mx1 gene on resistance was not mediated by the adaptive immune responses but was dependent on alpha/beta interferon. A better comprehension of the genetic control of virus infections will help us understand not only how we have evolved but also what we can and cannot achieve with antiviral drugs and vaccines.

Regardless of the theoretical attraction of immune intervention in tuberculosis and although Mycobacterium bovis Bacille Calmette Guérin (BCG) provides a mainstay of global vaccination campaigns, current efforts in tuberculosis control are almost exclusively directed toward implementation of antimicrobial therapy. This chapter reviews the prospects for changing this situation by developing improved immune interventions. BCG provides some hard lessons for would-be developers of new tuberculosis vaccines. On the positive side, it vindicates the concept of vaccination as an approach to tuberculosis control. While precise numbers are hard to obtain, it seems reasonable to extrapolate that BCG has saved the lives of millions of potential victims of childhood tuberculosis. In experimental-animal models, BCG vaccination conforms to this paradigm. In naïve animals, the population of M. tuberculosis increases for several weeks after infection before being brought under the control of the immune response. Mycobacteria provide a potent signal to the innate immune system, with cell wall components triggering scavenger and Toll-like receptors on the cell surface, activating NF-κB transduction pathways leading to secretion of IL-12 and proinflammatory cytokines. If the new vaccine was to be compared to BCG, consideration would also have to be given to the question of withdrawing BCG coverage from part of the trial group, perhaps increasing their risk of potentially fatal childhood tuberculosis. The natural immune response to M. tuberculosis may well have been shaped as much by the evolutionary needs of the microbe as by those of the host.

This chapter reviews concepts and strategies that are being considered for the development of effective immune interventions for the treatment of human immunodeficiency virus (HIV) disease. It is likely that the development of effective immune-based interventions for the treatment of HIV infection will be greatly facilitated by an improved understanding of the fundamental mechanisms of the immunopathogenesis of AIDS. An important challenge for future research efforts will be to discover ways of modulating the host immune response so its beneficial aspects are enhanced without simultaneously increasing its deleterious aspects. Similarly, any attempt to use immunosuppression as an approach to abrogation of the deleterious indirect consequences of HIV infection will need to be done in a way that does not also compromise the beneficial aspects of immunemediated control of HIV replication. The idea of therapeutic vaccination of HIVinfected individuals dates back to the early years of the AIDS epidemic, and clinical trials aimed at augmenting anti-HIV cellular immune responses in infected patients by immunization with the recombinant HIV envelope glycoproteins gp120 and gp160 were first performed in the early 1990s. Recent studies of prophylactic DNA vaccine in macaque models of simian immunodeficiency virus (SIV) infection have shown that DNA vaccines, in combination with cytokines (e.g., interleukin-2 [IL-2]) or followed by boosting with recombinant viral vectors (e.g., an attenuated strain of vaccinia virus known as modified vaccinia Ankara), can induce potent anti-HIV CD4+ and CD8+ T-cell responses and enable substantial control of SIV viremia following experimental challenge with virulent virus strains.