Anthony A. Nash

Mechanisms of Cell and Tissue Damage

n n Many infections are associated with damage inflicted either directly or indirectly by invading pathogens. Although some infections do not result in host damage, it is often a natural consequence of the activities of virulence factors produced by the pathogens in order to facilitate survival, and proliferation in the host or onward transmission to another host. The damage often manifests itself as the symptoms of disease which can be useful for diagnosis and for informing appropriate treatments. A wide array of different types of toxins which cause damage to the host are produced by different bacterial pathogens. Here we provide examples of well-characterised toxins and describe their mechanisms of action, and potential function with regard to pathogenesis. In addition we describe indirect damage to the host in the form of inflammation or immunopathology, typically the result of the hosts own immune response. Finally, we discuss diarrhoea as a special case and list some of the major pathogens and the toxins associated with this devastating disease.n n

Attachment to and Entry of Microorganisms into the Body

This chapter describes several attachment and entry procedures applied by the microorganisms to enter the body of the host. The conjunctiva and the alimentary, respiratory and urinogenital tracts offer pathways for infection by microorganisms. Penetration of these surfaces is more easily accomplished than in the case of the intact outer skin. A number of antimicrobial devices have been developed in evolution to deal with this danger and also special cleansing systems to keep the conjunctiva and respiratory tract clean enough to carry out their particular function. In order to colonize or penetrate these bodily surfaces, microorganisms must first become attached to these surfaces. The microorganisms enter the host body through four ways: by specific mechanisms of attachment or simply by penetrating the body surface, by a biting arthropod, through wounds cuts or damage and impairment of defenses at the body surface, and finally by a local or general defect in body defenses.

Recovery from Infection

n n This chapter addresses the factors involved in recovery from infection. Antibody and cellular responses (CMI) are considered. The mechanisms by which antibodies neutralise viruses/prevent infection are described, as is the involvement of antibody in bacterial and protozoal diseases. The role of CMI in recovery from specific bacterial, protozoal and viral infections is considered. The mechanisms of cell killing by cytotoxic T-cells is described and the role of NK cells and macrophages in pathogen clearance is discussed, as is the role of inflammation. Mechanisms by which the complement system acts and its role in vivo is discussed, as is the interferon response. Recovery from S. typhimurium is used to illustrate the multimechanistic nature of recovery. The role of temperature in recovery and pathogen factors that induce fever are considered. Tissue repair mechanisms are discussed, as is finally resistance to infection.n n

Host and Microbial Factors Influencing Susceptibility

This chapter focuses on some of the host and microbial factors influencing susceptibility to disease. These factors include genetic factors in the microorganism, genetic factors in the host, hormonal factors, and stress. The microorganisms ability to infect a given host is genetically determined and many microorganisms infect only one particular host species. Pathogenicity or virulence is also a function of the microbial genome. Virulence is being increasingly recognized to depend on coordinated expression of numerous genes, whose products mediate adherence, antiphagocytic activity, immune evasion, production of toxins, etc. Susceptibility to infectious disease is always influenced and is sometimes determined by the genetic constitution of the host. Inflammation makes an important contribution to tissue damage and pathology in infectious disease and injected corticosteroids (or ACTH) have a pronounced anti-inflammatory effect; their therapeutic use in infectious diseases depending on a reduction in the inflammatory pathological components at sites of infection. Increased circulating levels of corticosteroid hormones are necessary for a successful host response to infectious disease. A host of miscellaneous factors, such as smoking, seasonal changes mental state, influence the course of infectious diseases.

Failure to Eliminate Microbe

This chapter discusses the various factors that contribute to the failure of host defense mechanism in eliminating microbes. One way of looking at persistent infections is to regard them as failures of the host defense mechanisms which are designed to eliminate invading microorganisms from tissues. Persistent infections usually represent a secondary event, following on from an initial acute infection. In certain acute infections the patient appears to recover, but there is later a relapse. Many of the severe infections causing illness and death in communities (poliomyelitis, plague, yellow fever, cholera) are not persistent and the microorganisms are eliminated from the body after recovery. Persistent infections are often important from the microbes point of view, enabling it to be maintained in small or isolated host communities. Persistent infections also generally present problems in the development of vaccines. They are becoming relatively more important, both for the individual and for the community, as the nonpersistent infections are eliminated by public health measures and by vaccination. Not only may they reactivate and cause troublesome infections in immunocompromised or immunosuppressed patients, but some of them can cause malignant tumors.

Early Stages of Infection After Pathogen Entry

n n In this chapter, we describe the early stages of the pathogenic cycle involving entry into the host. For example, some bacteria may enter into epithelial cells, proliferate and then spread at the epithelial surface before being transmitted to another host. Some pathogens then migrate past the epithelial layer to deeper tissues causing invasive infections. Examples of some of the major bacterial, viral and fungal pathogens affecting the epithelial surfaces in the body are provided. The body produces a strong inflammatory immune response to pathogens at the epithelial surface. An introduction to the components of the inflammatory response including the phagocytic cells and the lymphatic system is provided. In addition, the nutritional requirements for invading bacteria including the importance of iron is discussed.n n

Encounter of Microbes with Phagocytic Cells

In this chapter we describe the key events associated with phagocytosis, a critical immune activity required for host innate resistance to infection. In response to phagocytosis, microbial pathogens have evolved a myriad of ways to interfere with this process and avoid killing. In fact, some bacteria have evolved the capacity to survive and proliferate within phagocytic cells. We provide selected examples of the different mechanisms involved in pathogen avoidance of phagocytosis, and also discuss how defects in phagocytic cells can predispose to infection.

Chapter 6 – The Immune Response to Infection

This chapter describes the role of the innate and adaptive immune responses during infection. It highlights the importance of Pattern Recognition Receptor (PRR) in signalling cytokine production and the activation and proliferation of the macrophages, NK cells and dendritic cells (DCs). DCs provide the key link between the innate and adaptive immune systems by processing and presenting microbial antigens via the MHC system to CD8+ T cytotoxic and T helper lymphocytes. CD4+ T helper (Th) cells are defined by the cytokines they produce and their effector and regulatory function in vivo. An important function of Th cells is to provide help for B cell proliferation and maturation, for the proliferation of cytotoxic T cells and for activating macrophages at sites of infection. The significance of antibody and T cells in the immune response to selected pathogens is presented. In addition, sections on NK cells and the complement system have been updated.

Chapter 5 – The Spread of Microbes Through the Body

This chapter addresses the mechanisms by which pathogens spread through the body from the initial site of infection and the host and pathogen factors which influence that spread. Localised spread across mucosal or epithelial surfaces is considered and factors which allow spread beyond this initial event briefly introduced. The two main routes of spread throughout the body, via the lymphatic system and the blood are discussed. The factors which influence recognition of the pathogen by antigen-presenting cells and uptake into the lymphatic system, and the outcome of this interaction, i.e. clearance of the pathogen or further spread, are discussed in relation to the cell type encountered and pathogen factors. Once the pathogen enters the blood and spreads throughout the body, the interactions with two key cell types, vascular endothelial cells and reticuloendothelial cells are discussed. Spread via nerves, infection of tissues and pleura and the generation of rashes are also discussed.

Chapter 7 – Microbial Strategies in Relation to the Immune Response

This chapter addresses the mechanisms by which pathogens evade the host immune responses. The concepts of induced tolerance and energy are discussed and this continues into coverage of the induction of a generalised immunosuppression by pathogens. Strategies used by the pathogen to evade an immune response, e.g. restricted expression of antigens, the structure of the bacterial cell wall, infection of sites where the immune response is ineffficient, the avoidance of the interferon response and the induction of inappropriate immune responses, e.g. non-neutralising antibodies and the Th1/TH2 balance are discussed. Finally antigenic variation both within the host (e.g. HIV, Trypanosomes) and the population (influenza) are discussed.