Infectious Agents and Pathogenesis – serie

Biomedical scientists widely acknowledge that individuals' immune respon­ siveness is important in resistance to infections by microorganisms, including fungi. Because of the devastating acquired immunodeficiency syndrome (AIDS) epidemic, caused by the human immunodeficiency retrovirus, it is now accepted that suppressed immune responses, especially cellular immu­ nity, are important contributors to increased individual susceptibility to opportunistic infections-including infections caused by fungi which were at one time thought to be very lowly or nonpathogenic. Within the last few years, there has been an almost explosive increase in interest and studies concerning the nature and mechanisms of the immune response to fungal infections. Many immunologists who are not well versed in mycology have begun to study the nature and mechanisms of antifungal immunity using a wide variety of newer as well as more conventional immunologic technologies, both in vivo and in vitro. Up to the 1980s, however, there was little interest among basic immunologists concerning fungal immunity. This situation has changed dramatically in the past half decade, mainly because of AIDS.

Presenting the basic concepts and clinical implications of respiratory infection, with special emphasis on the role of the immune system, the field's leading researchers contribute detailed chapters on most of the major pathogenic and opportunistic bacteria, fungi, and viruses. Their work will stimulate new research by microbiologists and immunologists, teach clinicians the interaction between microorganisms and the host, and provide health professionals with information necessary to evaluate public health procedures.

DNA tumor viruses have long been useful experimental models of carcinogenesis and have elucidated several important mechanisms of cell transformation. Re­ search in recent years has shown that human tumors have a multifactorial nature and that some DNA tumor viruses may playa key role in their etiology. The aim of this book is to assess our knowledge of DNA tumor viruses by reviewing animal models, mechanisms of transformation, association with human tumors, and possi­ bilities of prevention and control by vaccination. Animal models of tumor virology have contributed significantly to our under­ standing of the epidemiology and pathogenesis of virus-induced tumors. Bovine papillomaviruses induce papillomas in the intestine of cattle. The papillomas undergo a transition to carcinomas in cows feeding on bracken fern, which pro­ duces a toxin with radiomimetic and immunosuppressive functions. This example of cooperation between a virus and chemical carcinogens parallels the cooperative role of human papillomaviruses (HPVs) and herpes simplex virus type 2 (HSV-2) with environmental carcinogens in the pathogenesis of cervical cancer. Likewise, hepatocarcinomas appearing in woodchucks chronically infected by woodchuck hepatitis virus (WIN) provide strong support for the relationship between hepatitis B virus (HBV) infection and human hepatocellular carcinoma. Also, the fact that WIN DNA integrates closely to cellular oncogenes suggests a possible molecular mechanism for the tumorigenesis induced by HBV.

As we approach the end of this millennium, enteric diseases remain impor­ tant public health problems. In many parts of the world, sanitary measures have advanced little over the last century, although some of the governments in those areas are striving to improve facilities for sanitation and to educate their people in proper handling of food, water, sewage, and other modes of transmission of pathogenic microbes. Even in highly developed countries, outbreaks of diarrheal diseases occur today. Globally, the annual morbidity from enteric infections is estimated at several billion and deaths at several million per year. In this volume, descriptions of some of these diseases, of immunity that results from them, of clinical studies that promote under­ standing of individual and community immunity, of molecular factors of pathogenesis, and/or of advances in vaccine development have been pro­ vided by leading researchers. At present, the application of molecular methods is enhancing the identification of protective antigens of many microorganisms. In addition, new methods for design and delivery of vac­ cines are being devised. Perhaps then more effective tools for reducing at least some of these diseases will be available within the next decade. Lois J. Paradise Herman Friedman Mauro Bendinelli vii Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv LOIS J. PARADISE 1. Indigenous Microorganisms as a Host Defense 1 KENNETH H. WILSON 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Composition of Intestinal Biota. . . . . . . . . . . . . . . . . . . . . . . . 2 3. Molecular Approaches to Determine Composition of the Biota . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 3 4. Role of the Host in Determining the Composition of the Biota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

As a group, rickettsiae, and related bacteria, contain a number of human pathogens that have recently named as causes of 'emerging diseases'. This unique volume offers a thorough and current review of information on the pathogenesis and immune response elicited by members of the genera Rickettsia, Ehrlichia, Coxiella, Orlentia, and Bartonella, in contributions authored by the expert clinicians and researchers who work with these organisms.

Busy clinicians and health practitioners recognize the importance of speedy detection of pathogens to impede the further spread of infection, and to ensure their patients' rapid and complete recovery. This reader-friendly reference is a unique collection of the newest and most effective diagnostic techniques currently in use in clinical and research laboratories. Instructive commentary regarding the application of these often complex methods is provided. This essential text aids readers in selecting the most efficient method, finding the necessary resources, and avoiding the most common pitfalls in implementation.

Although virology and immunology are now considered separate disciplines, history shows that these areas ofinvestigation always overlapped and one cannot really exist without the other. This trend has become particularly significant and fruitful in the past few years in the area of herpesvirus research. The genomes of the most important herpesviruses have been sequenced, a significant portion of their genes have been identified, and many secrets of regulation of gene expr- sion have been unraveled. Now this progress sets the stage for a true revolution in herpesvirus research: analysis of interactions between the host and the virus. Because herpesviruses can induce, suppress, and fool the immune system, the most productive herpesvirologists are also expert immunologists, and the current results ofthis interdisciplinary effort are truly remarkable. Because herpesviruses cause many important human diseases, the devel- ment of vaccines against these agents is a very significant goal. This effort is also very challenging because of the complexity of herpesviruses and the lack of sufficient information about immune responses. The remarkable ability of herpesviruses to escape immune responses is - other feature that brings immunology and virology together. Herpesviruses - code many proteins that interact with and down-regulate some key elements of the immune system. Thisproperty of herpesviruses represents amajor challenge in developing strategies against these viruses. On the positive side, these viral proteins also provide novel tools for analyzing specific immune reactions and molecular mechanisms.

This collection of works brings together experts in the field of human retroviral pathogenesis, vaccine development, and the clinical treatment of AIDS. One of the greatest problems facing the development of an effective vaccine against HIV-1 is the ability of the virus, particularly in the immunogenic envelope glycoprotein, to undergo amino acid hypervariability, thus making a vaccine against one envelope glycoprotein ineffective against other viruses due to their mutability.

Staphylococcus aureus is now acknowledged as being the most important bacterial pathogen of humans. It usually produces localized disease but can be rapidly invasive, spreading through the tissues, invading bone, and seeding the bloodstream to produce a fulminant picture of septic shock, disseminated intravascular coagulation, and rapid death. Moreover, most strains of staph infections are becoming resistant to most antibiotics, thus posing a significant problem for hospitals and health care facilities. This book, a volume in the Infectious Agents and Pathogenesis series, presents chapters by the major researchers in the field.

There is overwhelming evidence that Helicobacter pylori is the major cause of chronic active gastritis and that it may further predispose to peptic ulcers, of which there are several thousand cases in the US each year. The most severe clinical outcomes of H. pylori infection are mucosa-associated lymphoid tissue lymphoma and gastric cancer. Because of these findings, the implications for cancer aetiology are intriguing. This book, a volume in the "Infectious Agents and Pathogenesis" series, presents chapters by major researchers in the field, including Dr. Barry Marshall whose research was responsible for establishing the linking of gastric ulcers with the H. pylori bacterium.

Chlamydia pneumoniae is a bacteria that is most commonly known for causing colds and pneumonia. pneumoniae and atherosclerosis, a clogging of the arteries that causes heart attack and stroke.

The use of recreational drugs of abuse by large numbers of individuals in this country and abroad has aroused serious concerns about the consequences of this activity. For example, it is recognized that marijuana is currently widely used as a recreational drug in the United States as well as other countries. Similarly, abuse of cocaine, especially crack cocaine, is considered to be an epidemic. “The war on drugs” by the US Government was directly aimed at the illicit use of cocaine, marijuana, and opiates as well as other drugs of abuse. Furthermore, alcohol is also considered a major problem of abuse in this country as well as in many other countries. It is estimated there are at least 10 million alcoholics in the United States alone. A signi?cant portion of those hospitalized with infectious diseases are alcoholics. Similarly, there have been many reports of association between marijuana use and increased susceptibility to infection as well as a re- tion between use of opiates and infections. The relationship between drug abuse and increased incidence of various infections has stimulated increased investi- tion of whether and how such drugs affect immune function, especially imp- tant for resistance against infectious agents. During the last decades, a wide variety of studies have shown that drugs of abuse, including marijuana, cocaine, or opiates, as well as alcohol, alter both neurophysiological as well as pathological responses of individuals.

An AIDS vaccine is still elusive and HIV treatment continues to develop multidrug resistance at alarming rates. Because of the similarities between HIV and immune deficiency infections in a variety of animals, it is only natural that scientists use these animals as models to study pathogenesis, treatment, vaccine development and many other aspects of HIV.Part of the series Infectious Agents and Pathogenesis, this volume reviews the immune deficiency virus in a variety of hosts. Pathogenesis, vaccine and drug development, epidemiology, and the natural history of the monkey, mouse, cat, cow, horse, and other animal viruses are detailed and compared to HIV. Also included are chapters on the history and future of animal models, as well as a chapter on ethical and safety considerations in using animal models for AIDS studies.

The threat of bioterrorism has become a major challenge for the twenty-?rst century. However, the potentials of infectious agents as bioweapons have been recognized for centuries. Throughout history there have been attempts to i- tiate infectious disease outbreaks and epidemics during warfare. In the last decade the attention of the biomedical community, as well as governments and the United Nations, has increasingly focused on the threat of bioterr- ism, especially the use of biological and/or chemical weapons against military and civilian populations. As an example, there is now much interest conce- ing microbial infection and bioterrorism in the medical microbiology and - munologycommunities. Thisvolumeaddressessuchconcernsandemphasizes bothbasicandclinicalconcepts,aswellasproblematicimplicationsofinfection by various microbes now recognized as potential bioterrorism agents. The ?rst chapter by Drs. Andrew Canons, Philip Amuso, and Burt And- son from the University of South Florida is an overview of the biotechnology of bioterrorismbothinthepublichealthresponsetopossibleactsofbioterrorism, aswellasfortheconcernsaboutthemisuseofbiotechnology.Thesecondch- ter is a historical perspective of microbial bioterrorism by Dr. Steven Morse, Director of the Bioterrorism Division at the Center for Disease Control and Prevention in Atlanta, GA. This chapter describes in detail historical aspects concerning the early use of biological agents in warfare, development and international conventions to prohibit the use of such weapons, and a brief - scription of important incidents of infectious agents as bioterrorist agents and use during the last few centuries. The next chapter by Dr. Sandra Gompf from the University of South Florida discusses the role of public health physicians and infectious diseases specialists in the control of microbial bioterrorism.

There have been new developments in this field including the publication of three whole genome sequences, the discovery of a developmental cycle and novel cyst-like highly infectious form, and the bacteria have been used as a probe for macrophage cellular function to unravel fundamental new knowledge in the area of cellular biology.

There is currently increasing interest concerning the biology and disease caused by Acinetobacter species. Such interest, however, developed relatively slowly because of the necessity to clarify the confusing taxonomy of these organisms. Much work was needed to identify various species as members of this genus, to recognize their epidemiologic profile, their pathogenic role and their increasing importance as multi-antibiotic resistant organisms. In recent years improvement of genetic approaches, recognition of plasmids, integrons and chromosomal sources of resistance mechanisms aroused interest on the role of Acinetobacters in disease by many microbiologists and clinicians, especially internists and infectious disease specialists. In this regard, physicians are frequently confronted with extremely difficult therapeutic approaches for treatment and prevention of severe nosocomial infections due to multi antibiotic resistant Acinetobacter. Moreover, recent observations of community acquired infections have been reported, especially in patients with various risk factors such as immuno-deficiencies. Also, it is now becoming evident that Acinetobacter infections occur frequently in violent situations such as earthquake or war zones.The mechanisms of Acinetobacter virulence are becoming increasingly clear, providing new insights into their pathogenic role in community acquired infections. It is apparent the time is appropriate for detailed review of the increasing knowledge concerning important new information, both clinical and therapeutic, especially information concerning virulence, resistance mechanisms and typing of Acinetobacter spp. Many new findings are accumulating in almost an exponential manner since publication of previous books on this subject in 1991 and 1996.

There is currently increasing interest concerning the biology and disease caused by Acinetobacter species. Such interest, however, developed relatively slowly because of the necessity to clarify the confusing taxonomy of these organisms. Much work was needed to identify various species as members of this genus, to recognize their epidemiologic profile, their pathogenic role and their increasing importance as multi-antibiotic resistant organisms. In recent years improvement of genetic approaches, recognition of plasmids, integrons and chromosomal sources of resistance mechanisms aroused interest on the role of Acinetobacters in disease by many microbiologists and clinicians, especially internists and infectious disease specialists. In this regard, physicians are frequently confronted with extremely difficult therapeutic approaches for treatment and prevention of severe nosocomial infections due to multi antibiotic resistant Acinetobacter. Moreover, recent observations of community acquired infections have been reported, especially in patients with various risk factors such as immuno-deficiencies. Also, it is now becoming evident that Acinetobacter infections occur frequently in violent situations such as earthquake or war zones.The mechanisms of Acinetobacter virulence are becoming increasingly clear, providing new insights into their pathogenic role in community acquired infections. It is apparent the time is appropriate for detailed review of the increasing knowledge concerning important new information, both clinical and therapeutic, especially information concerning virulence, resistance mechanisms and typing of Acinetobacter spp. Many new findings are accumulating in almost an exponential manner since publication of previous books on this subject in 1991 and 1996.

Staphylococcus aureus is now acknowledged as being the most important bacterial pathogen of humans. It usually produces localized disease but can be rapidly invasive, spreading through the tissues, invading bone, and seeding the bloodstream to produce a fulminant picture of septic shock, disseminated intravascular coagulation, and rapid death. Moreover, most strains of staph infections are becoming resistant to most antibiotics, thus posing a significant problem for hospitals and health care facilities. This book, a volume in the Infectious Agents and Pathogenesis series, presents chapters by the major researchers in the field.

The influence of many drugs of abuse -- licit and illicit -- on immune function has been examined extensively in recent years. Many such substances, including marijuana, cocaine, morphine, and nicotine, have been shown to enhance the disease process by impairing immunologic function. Use of these drugs impairs immunologic functions by suppressing antibody function, decreasing cytokine production, enhancing production and release of IL1, and suppressing IL2 and interferon. Among the viruses known to be effected by these drugs are viruses such as herpes simplex virus and murine retrovirus and bacterial agents such as Staphylococcus, Listeria, Treponema, and Legionella. This volume, part of the Infectious Agents and Pathogenesis series, examines a variety of drugs of abuse and how they affect the immune system.

The threat of bioterrorism has become a major challenge for the twenty-?rst century. However, the potentials of infectious agents as bioweapons have been recognized for centuries. Throughout history there have been attempts to i- tiate infectious disease outbreaks and epidemics during warfare. In the last decade the attention of the biomedical community, as well as governments and the United Nations, has increasingly focused on the threat of bioterr- ism, especially the use of biological and/or chemical weapons against military and civilian populations. As an example, there is now much interest conce- ing microbial infection and bioterrorism in the medical microbiology and - munologycommunities. Thisvolumeaddressessuchconcernsandemphasizes bothbasicandclinicalconcepts,aswellasproblematicimplicationsofinfection by various microbes now recognized as potential bioterrorism agents. The ?rst chapter by Drs. Andrew Canons, Philip Amuso, and Burt And- son from the University of South Florida is an overview of the biotechnology of bioterrorismbothinthepublichealthresponsetopossibleactsofbioterrorism, aswellasfortheconcernsaboutthemisuseofbiotechnology.Thesecondch- ter is a historical perspective of microbial bioterrorism by Dr. Steven Morse, Director of the Bioterrorism Division at the Center for Disease Control and Prevention in Atlanta, GA. This chapter describes in detail historical aspects concerning the early use of biological agents in warfare, development and international conventions to prohibit the use of such weapons, and a brief - scription of important incidents of infectious agents as bioterrorist agents and use during the last few centuries. The next chapter by Dr. Sandra Gompf from the University of South Florida discusses the role of public health physicians and infectious diseases specialists in the control of microbial bioterrorism.

There have been new developments in this field including the publication of three whole genome sequences, the discovery of a developmental cycle and novel cyst-like highly infectious form, and the bacteria have been used as a probe for macrophage cellular function to unravel fundamental new knowledge in the area of cellular biology.

The discovery and concept that Helicobacter pylori is associated with gastric disease including gastric cancer which is one of the most common and frequently lethal forms of malignancy, heralded a new and rapidly expanding field recognizing the emergence of many new pathogens and disease syndromes in clinical medicine, as well as basic infectious disease research. There is now an extensive and widely known literature of how H. pylori is involved in a wide variety of disease syn­ dromes. As summarized in the introductory chapter of this volume, many major advances have been made in diagnosis, both serologic and endoscopic in time of the involvement of this organism in patients with upper GI ailments as well as its presence in those who are not clinically ill. The Introduction describes the rapid development of understanding the role of this organism in disease. The basic bacteriology of H. pylori is then described in the second chapter. Diagnostic tests for detecting H. pylori infection is then highlighted, as well as the role of such infection in gastric cancer. Current knowledge concerning risk factors and peptic ulcer pathology associated with H. pylori is then described. Newer information concerning therapy of H. pylori infection and colonization is described in a subsequent chapter as well as one concerning the effects of anti­ biotics on H. pylori infection. The extensive literature on natural substances with anti-H.

Assembling the latest research by an international group of contributors, this volume covers the epidemiology, pathogenesis, clinical features, and control measures of this elusive microorganism. It will provide a deeper understanding of the pathogen to physicians and surgeons caring for patients infected, or at risk of becoming infected, with Pseudomonas Aeruginosa.

Experts in microbiology and autoimmunity examine the association between microorganisms and the development of specific categories of autoimmune diseases. The opening chapters explore the bacterial induction of diseases considered autoimmune in nature. Subsequent chapters describe the role of viruses in the induction of these diseases and of diseases with an autoimmune component. Specific topics include: the role of streptococcal infection in rheumatic fever and the role of Klebsiella in the development of ankylosing spondylitis.

Tuberculosis once again occupies a special position in the areas of infec­ tious diseases and microbiology. This disease has been important to mankind since even before biblical times. Tuberculosis has been a major cause of morbidity and mortality in humans, especially in highly ur­ banized Europe, until a few decades ago. Indeed, this disease became a center of many novels, plays, and operas, since it appeared to be quite popular to have the heroine dying of "consumption. " Most importantly, tuberculosis also became the focus of attention for many investigations during the 19th and even the 20th centuries. Major advances were made in the areas of isolation and identification of M. tuberculosis and related microorganisms. The discovery, by Robert Koch, that tuberculosis was caused by an infectious agent revolutionized our thinking about dis­ eases. Koch's postulates were developed with tuberculosis in mind and became a focal point for many advances in microbiology and medicine. Studies with mycobacteria as a central focus have also led to revolu­ tionary new concepts about immunology in general. Koch himself showed that those exposed to M. tuberculosis develop a skin hypersen­ sitivity or allergy to the microorganism's antigens, an observation which was the starting point for many important developments. Indeed, imme­ diate-type hypersensitivity and atopic or IgE-mediated allergy were de­ fined in relation to the delayed-type cutaneous hypersensitivity evi­ denced with the tubercle bacillus.

It is now widely acknowledged that at the beginning of this century Claude von Pirquet first pointed out that a viral disease, i. e. , measles, resulted in an anergy or depression of preexisting immune response, namely, delayed continuous hypersensitivity to PPD derived from Mycobacterium tuberculosis. Thereafter ob­ servations that viral infections may result in immunosuppression have been recorded by many clinicians and infectious disease investigators for six or seven decades. Nevertheless, despite sporadic reports that infectious diseases caused by viruses may result in either transient or prolonged immunodepression, investigation of this phenomenon languished until the mid-1960s, when it was pointed out that a number of experimental retroviral infections of mice with tumor viruses may result in marked immunosuppression. However, it was not until the recognition of the new epidemic of acquired immunodeficiency syn­ drome (AIDS) caused by the human immunodeficiency virus and related vi­ ruses that acquired immunodeficiencies associated with virus infection became general knowledge among biomedical investigators as well as the lay public. A number of reviews published during the past decade or so pointed out that numerous viruses may affect humoral and cellular immune responses. Furthermore, expanding knowledge about the nature and mechanisms of both humoral and cellular immunity and pathogenesis of viral infections has pro­ vided clinical and experimental models for investigating in depth how and why viruses of man and animals profoundly affect immune responses.

There has been a tremendous increase in interest in the neuropathogenicity of viruses during the past decade as we have come to recognize that the human immunodeficiency virus, which causes the acquired immunodeficiency syndrome (AIDS), can infect glial cells and cause neurological disease. Yet this increase has not been limited to AIDS but has extended to viruses that infect either or both the central and peripheral nervous systems. The changes examined here include both neurological and psychological diseases or syndromes. Moreover, the chapters in this volume review the interaction of the host immune system with the viruses examined and how such interactions may increase or decrease the neuropatho­ genicity of the viruses. Questions regarding viral neuropathogenesis include: (I) What is the mode of transmission of virus to the nervous system? (2) What types of cells are infected, and do they contain receptors for the virus? (3) What is the extent of damage that results from viral infection? (4) What are the immunologic mecha­ nisms by which damage is mediated or limited? Many of these questions remain unanswered, but this volume delves into efforts to provide some answers.

It is now just 40 years since coxsackieviruses were first isolated by Dalldorf and Sickles in the "eponymous" town of Coxsackie, New York. Yet the overall contribution of coxsackieviruses to clinically evident dis­ ease of humans is still largely an open problem. Following their discov­ ery, coxsackieviruses were under intense clinical and laboratory scrutiny for a long time. Because of their relationship to polioviruses, the under­ standing of their structure, biochemistry, biology, and epidemiology ad­ vanced rapidly as a result of the formidable efforts that eventually led to the defeat of poliomyelitis. The ability of these viruses to infect mice permitted dissection of their pathogenicity in an experimental host and elucidation of conditions that influence its expression. Coxsackieviruses have been progressively associated with an increasing array of widely diverse human diseases. However, only some of the suggested causal correlations have been substantiated with satisfactory certainty. For others, conclusive evidence has so far resisted investigation. Most impor­ tant, among the latter are chronic maladies, such as dilated car­ diomyopathy and juvenile diabetes, that demand consideration. In recent times, there has been a partial eclipse of the subject of coxsackieviruses in the medical literature. In addition to the difficulties encountered in pinpointing their pathogenic potential, possible reasons include the general decline of interest in enteroviruses, which ensued after the conquest of poliomyelitis, and the continuous appearance in the limelight of new, more esoteric, and therefore more "appealing" viruses.