Cedric Mims

The Encounter of the Microbe with the Phagocytic Cell

Summary In summary, the encounter between the microorganism and the phagocytic cell is a central feature of infection and pathogenicity. Phagocytes are designed to ingest, kill and digest invaders, and the course of the infection depends on the success with which this is carried out. Virulent microorganisms have developed a great variety of devices for countering or avoiding the antimicrobial action of phagocytes. Although substances produced by or present on microbes may at first sight appear to have a useful function, not all will prove to be of practical importance in the infected host. Studies on microbial killing and digestion in phagocytes are still poorly understood, but it is important to conceive logically of the ways in which microorganisms can avoid being ingested, killed and digested. Most viruses do not infect phagocytes, and the exceptions do so by endocytosis or fusion, not phagocytosis.

The Spread of Microbes through the Body

This chapter describes several methods through which the microbes spread in the host body. Direct spread occurs to organs and tissues below the body surfaces, extending the focus of infection and sometimes accounting for striking complications. Several microbial factors – such as some soluble substances and enzymes – help in the promotion of direct spread. The spread of the microbes can also occur through lymphatics blood and various other pathways. Microbes in tissue fluids enter lymphatic capillaries rather than blood capillaries, and are transported to the nearest lymph node. A rich lymphatic network lies below the epithelium in the nasopharynx, mouth, and lung; microorganisms traversing these epithelia enter cervical and pulmonary lymph nodes. The blood is the most effective vehicle of all for the spread of microbes through the body, particularly the blood tissue junctions. In small vessels – such as capillaries and sinusoids – where blood flows slowly, there is an opportunity for the microorganism to be arrested and to establish infection in neighboring tissues. Some of the other pathways of microbial spread include cerebrospinal fluid (CSF), pleural and peritoneal cavities, and peripheral nerves.

12 – Vaccines and How they Work

Publisher Summary This chapter discusses the general principles of vaccines, its complications and side effects, and the development of new vaccines. Effective resistance to infection or disease depends on the vaccine having certain properties – such as inducing the right type of immune resistance, inducing an immune response in the right place, inducing an immune response to the right antigens, and immunity to toxins. Virulent microorganisms are inactivated to make killed vaccine. If inactivation has been incompletely carried out, vaccination introduces infection. Nonmicrobial antigens in vaccines can cause allergic responses. Large numbers of killed salmonellas are present in the vaccine for typhoid, and this vaccine therefore contains large amounts of endotoxin, which can present toxicity. Live vaccines often cause illness in children with immunodeficiencies. Several procedures for the development of synthetic peptides as vaccines also have been described. Successful new vaccines will come from encouraging laboratory advances in immunology and biotechnology and at the same time attending to practical problems, such as vaccine supply, quality testing, licensing, and financing.

8 – Mechanisms of Cell and Tissue Damage

Publisher Summary Cell damage has profound effects if it is the endothelial cells of small blood vessels that are involved. When bacteria invade tissues, they almost inevitably cause some damage, and this is also true for fungi and protozoa. Cell and tissue damage are sometimes due to the direct local action of the microorganism and microbial toxins. They either interfere with the transcription, translation, and DNA synthesis or change the permeability of the cell membrane. Some of the indirect damage brought about by these microbes is through inflammation and immune responses. Host cells are destroyed or blood vessels injured as a direct result of the action of microbes or their toxins. Inflammatory materials are liberated from necrotic cells, whatever the cause of the necrosis. Also many bacteria themselves liberate inflammatory products and certain viruses cause living infected cells to release inflammatory mediators. The expression of the immune response necessarily involves a certain amount of inflammation, cell infiltration, lymph node swelling, even tissue destruction. Sometimes they are very severe, leading to serious disease or death, but at other times they play a minimal part in the pathogenesis of disease. Other indirect mechanisms of damage include stress, hemorrhage, placental infection, and tumors.

Preface to the Fifth Edition

When preparing the first edition of this book, more than ten years ago, we tried to accomplish two objectives: it should be useful as an advanced graduate textbook, but also as a reference work for research. With each new edition we have to decide how the book can be improved further. Of course, it is less and less possible to describe the growing area comprehensively. If we included everything that we like, the book would grow beyond a single volume. Since the book is used for many courses, now even sometimes at undergraduate level, we thought that adding some classical material might be more useful than including a selection of the latest results. In this edition, we added a proof of Cayley’s formula, more details on blocking flows, the new faster b-matching separation algorithm, an approximation scheme for multidimensional knapsack, and results concerning the multicommodity max-flow min-cut ratio and the sparsest cut problem. There are further small improvements in numerous places and more than 60 new exercises. Of course, we also updated the references to point to the most recent results and corrected some minor errors that were discovered. We would like to thank Takao Asano, Maxim Babenko, Ulrich Brenner, Benjamin Bolten, Christoph Buchheim, Jean Fonlupt, András Frank, Michael Gester, Stephan Held, Stefan Hougardy, Hiroshi Iida, Klaus Jansen, Alexander Karzanov, Levin Keller, Alexander Kleff, Niko Klewinghaus, Stefan Knauf, Barbara Langfeld, Jens Maßberg, Marc Pfetsch, Klaus Radke, Rabe von Randow, Tomás Salles, Jan Schneider, Christian Schulte, András Sebő, Martin Skutella, Jácint Szabó, and Simon Wedeking for valuable feedback on the previous edition. We are pleased that this book has been received so well, and further translations are on their way. Editions in Japanese, French, Italian, German, Russian, and Chinese have appeared since 2009 or are scheduled to appear soon. We hope that our book will continue to serve its purpose in teaching and research in combinatorial optimization.

11 – Host and Microbial Factors Influencing Susceptibility

Publisher Summary 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.

10 – Failure to Eliminate Microbe

Publisher Summary 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.

2 – Attachment to and Entry of Microorganisms into the Body

Publisher Summary 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.

3 – Events Occurring Immediately After the Entry of the Microorganism

Publisher Summary This chapter discusses the events and responses that follow immediately after the entry of an organism in a host cell. The first activity that could be observed is the growth of the epithelial cells. At the site of entry into the body, microorganisms that are shed directly to the exterior multiply in the epithelial surface producing a spreading infection in the epithelium. Certain microorganisms spread through the body to reach susceptible target organs after free microorganism particles have entered vessels below the skin or intestinal epithelium. The infected host has a variety of defenses that operate without delay, before the immune response comes into action. However, many microbes have strategies for interfering with these defenses. After traversing the epithelial cell layer, a microorganism encounters the basement membrane. After reaching the subepithelial tissues they are exposed to three important host defense systems: the tissue fluids, the lymphatic system leading to the lymph nodes, and phagocytic cells. In addition to being able to resist host defense mechanisms, a pathogenic organism—be it an obligate intracellular, facultative intracellular, or extracellular pathogen—must also overcome the problem of obtaining essential nutrients if it is to be successful.

Chapter 8 – HOW MICROBES CAUSE DISEASE

This chapter describes the mechanisms by which a microbe causes disease. Many microbes release substances into the body as they multiply. Some of these substances are formed as part of the microbes strategy, because they interfere with host defenses. These substances are called toxins and they have a dramatic damaging action on the host. The diseases tetanus, diphtheria, and cholera are caused by toxic molecules (toxins) formed by the infecting bacteria. The microbe on its own does the damage to the body. Many microbes do little or no direct damage to cells or tissues, and the disease is largely due to the hosts own immune and inflammatory response to the infection. The same response that is needed for defense against parasites can damage normal tissues once it is unleashed. Immune inflammation means the arrival of phagocytes and lymphocytes at the site of infection, and this entails swelling and pain. It can be severe and it can last a long time, becoming chronic, but it is a vital part of defense. Immune damage well beyond the call of duty, however, takes place when the focused response directed against the Invader also reacts with and damages host tissues. This happens in autoimmune diseases. Tuberculosis, leprosy and glandular fever (EB virus infection) provide good examples where immunopathology seems to account for most of the disease.