This series ofreviews focuses on recent developments in understandingbacterialpathogenesisthathavebeengained by studying the genetic control of the susceptibility to particular diseases. The topics of the reviews include a description ofbacterial genes that effect virulence and a studyofthe genetic susceptibilityofhumans to group A streptococci and to leprosy. The most versatile model system for studies of disease susceptibility is the inbred mouse. Although seven of the chapters deal with the geneticsoftheresistanceofmice to infection, allofthem point out general principles and, wherever possible, parallelswithappropriatehumandiseases. Genetic studies of the mechanisms of resistance and pathogenesishaveanadvantageoverotherapproaches. By utilizing animals ofappropriate genotypes, it is possible tostudytheinvivoconsequencesofvariationsinparticular hostdefensesinintactanimals.Someofthemoderngenetic approachesusedinmousegeneticsarealsodescribed. Allofthechaptersdealingwithmousegeneticsdescribe studieswithrecombinantinbredmice.Achapterhasbeen included thatdescribesapproaches for the useofmice in genetic studies of disease resistance. This chapter also describesrecombinantinbred miceandameans bywhich theycanbeusedtoexaminethelinkageofgenesaffecting diseaseresistance. Thebulkofthevolumefocusesonthegeneticregulation by three different murine loci: Ips, xid, and fty. fty was the first name given to a locusthatgoverns resistance to infections with leishmania, bacille Calmette-Guerin and salmonella. Different reviews describe the relationshipof thefty locusto thediseasescaused bytwoofthese three pathogens. Thesetwo reviewsalsoincludeadiscussionof other geneticfactors that affect the susceptibilityofmice toeachpathogen.TworeviewsaredevotedtotheX-linked immunodeficiency (xid) locus. One describes the pre sent state of immunological knowledge about the immunological deficits that have been shown to be VI Preface associatedwiththedefectivexidallele.Theotherdescribes theeffectoftheseimmunodeficienciesonthesusceptibility of mice to infection with Streptococcus pneumoniae. Anotherchapter describes the effectsofthe Ips locus on the immune system and the concomitant effects these changeshaveontheresistancetobacterialinfection.There is also a chapter describing genetic studies that examine the relationship between the genetic control of certain macrophage properties and the susceptibility to Listeria infection."

This volume on enzootic bovine leukosis (EBL) and bovine leukemia virus (BLV) is the second in our series "Developments in Veterinary Virology." Each book in this series is devoted to a major virus disease of agricultural significance. The chapters in each volume are planned to supply information on a range of subjects from pathogenesis of the causative virus to vaccination, eradication, and rules regarding disease control. The present volume on enzootic bovine leukosis and bovine leukemia virus updates the reader on the disease and its causative agent and includes the nucleotide sequence of the BLV genome as well as data on its integration into the DNA of the tumor cell. Insights into diagnosis, veterinary legislation, and the economic aspects of EBL are also provided. Intense research conducted on EBL and BLV during the course of a decade is presented in a most concise and in-depth manner, so as to provide the reader with a comprehensive overview of this economically important disease of cattle. I wish to thank the editors, A. Burny and M. Mammerickx, as well as all the authors, for making this excellent book available at a stage when the knowledge on bovine leukemia virus will also contribute to our understanding of the virus causing human AIDS.

Any branch of biology depends for its progress on the development of new concepts and to a lesser, but sometimes crucial, extent on the elimination of erroneous notions. Understanding the roles of bacteria required first the observation that such minute creatures existed, and subsequently the exper imental demonstrations that their presence was necessary for the occurrence of particular phenomena. In this first volume, the authors review the development of scientific understanding of the role of microbes as agents of diverse natural processes. Notably absent is a separate review of the history of microbes as agents of disease, a his tory available in many other publications. Regrettably absent is a review of the his tory of microbes as agents of inorganic transformations, a serious omission that resulted from the illness of the prospective author late in the preparation of this volume. The topic will of course be treated in later volumes, although not predominantly in a historical manner. Otherwise, the emphasis in this volume is on the history of understanding interrelationships between modes of bacterial existence and the inanimate environment. These relationships were established long be fore multicellular, differentiated or ganisms appeared as potential microbial habitats, and their recognition and elucidation contributed greatly to the widened appreciation of bacterial di versity and the importance of these simpler creatures to the physiochemical conditions of the biosphere."

The incidence of lung cancer has reached epidemic proportions throughout the civilized world. One indication of the dimensions of this problem is that in the United States lung cancer has become the leading cause of cancer death in women as well as men. In 1912 there was a "nearly complete consensus of opinion that primary malignant neoplasms of the lung (were one) of the rarest forms of disease," according to Adler. By 1937, however, it had become clear that the incidence of lung cancer was increasing significantly; this increase has been progressive ever since. It is now well known that some lung cancers give rise to a variety of hormones which, at times, produce clinical manifestations. The association of hormone production with a "nonendocrine" tumor raises many questions, the answers to which may shed some light on the etiology of this prevalent form of cancer. This fascinating prob lem has stimulated a wide variety of studies in both the clinical and the basic sciences. A number of the more recent studies in this field were discussed at the International Symposium on Peptide Hor mones and Lung Cancer held in Marburg, West Germany, on June 18-20, 1984. This volume contains the papers that were pre sented on this occasion."

For decades retroviruses have been riding the crest of a wave of experimental research directed toward the identification of an infectious agent of human neoplastic diseases. In the early 1970s, several scientists successfully demonstrated the presence of retroviruses in numerous animal species and proved their etiological role in some related diseases. Corresponding findings in humans were somewhat discouraging. Although financial support for this line. of research declined, a few dedicated retrovirologists survived and continued to collect more biological information and technological expertise that opened a new approach to the search for a human retrovirus. The rewards came with the discovery that the genes responsible for neoplastic transformation (oncogenes) are of cellular origin and can be shuttled about by retroviruses, and with the identification of a new family of Human T-cell Lymphotrophic retroViruses (HTLV) from patients with diseases ranging from leukemia to the acquired immunodeficiency syndrome (AIDS). An understanding of the role and significance of retroviruses in human pathology requires basic knowledge of the major animal systems studied. With this perspective in mind, we present here a survey that includes general overviews, minireviews on each animal system studied with selected experimental reports and, finally, a stimulating review of the field of human retrovirology by many of the pioneer scientists who created it. We are especially grateful to Profs. C. A. Romanzi and G. C. Schito for promoting the organization of the Symposium. On behalf of the Sym posium Committee, we thank E. Soeri, L. Casarino, G. P. Gesu, M."

Although adenoviruses have been established for quite some time as one of the most pliable tools to study the molecular biology of mammalian cells, rapid progress continues to be made with this virus system. The adenoviral genome introduced into the nucleus of cells as a Trojan Horse, as it were, is now facili- tating investigators to uncover details of cellular mechanisms. In this volume twelve chapters have been collected that summarize important current research on different mechanisms in adenovirus- infected and -transformed cells. It has become increasingly apparent that some of these mechanisms do not only pertain to highly specialized strategies of the viral genome and its expres- sion or replication, but may simultaneously shed light on events indigenous to the cell. "Adenovirus DNA: The Viral Genome and its Expression" high- lights the first publication of the entire annotated sequence of 35. 937 nucleotide pairs of adenovirus type 2 DNA by the Cold Spring Harbor and Uppsala groups (chapter 1). Goran Akusjarvi, Ulf Pettersson (Uppsala University) and Rich Roberts (Cold Spring Harbor) present a survey on the structure and function of the adenovirus-2 genome (chapter 2). A considerable amount of in- formation has been collected on the biochemical mechanisms in- vol ved in adenov irus DNA repl ication in human cells. Al though highly specialized in the way of initiating DNA replication, adenov irus DNA repl ication represents probably one of the best studied systems in work on eukaryotic DNA replication.

It goes almost without saying that there has been a marked increase in the incidence of sexually transmitted diseases throughout the world in the past two to three decades. Indeed, despite the progress that has been made in methods of diagnosis and treatment, the sexually transmitted diseases as a whole are the most common communicable diseases and as such constitute an important health problem. The increase in incidence may be accounted for by changes in sexual behaviour, the introduction of contraceptives and the increasing mobility of the population. In addition, during the same time period, the number of infectious agents recognized as being sexually transmitted has increased considerably. These include Chlamydia trachomatis, herpes simplex virus, cytomegalovirus and hepatitis B virus. Indeed, some are as dependent on sexual transmission as the agents which cause the traditional venereal diseases and collectively they cause morbidity which has out-stripped that caused by gonorrhoea and syphilis. It could almost be said that to know the sexually transmitted diseases is to know micro biology. However, the approach taken in this book has not been to consider individual infectious agents and evaluate what they do and do not cause but to consider clinical conditions and what might be responsible for them. To cover the complete spectrum of the sexually transmitted diseases in a comprehensive way now takes a text book of massive proportion."

Rabies-as in former times-is still today a major killer affecting man and animals especially in many tropical and sub-tropical countries of Asia, Africa and South America. Some 50,000 people and literally millions of animals suffer and die of this disease each year. This dramatic death toll and the enormous economic losses which ensue are nowadays un tolerable and no longer justified. Worldwide strategy for Rabies control has been established and the World Health Organization recently formulated an elimination programme for dog Rabies. Methods for wildlife Rabies control are also under way. For the realisation of control campaigns, careful epid emiological analysis is necessary. This involves: - antigenical characterisation of Rabies Virus Strains using monoclonal antibodies, - observation of foci, - follow-up of the front wave of the disease, - specific ecology of target populations and Rabies carrier species. The financial point of view of such campaigns has of course to be ascertained. It is for the first time ever that representatives and specialists of different biological disciplines from nearly 70 countries have had the opportunity in Tunis to discuss these important issues and to evaluate, on the basis of their own experimental results and personal epidemiological observations, the possibility of ultimate elimination of Rabies in tropical and sub-tropical countries and also to contribute their share for a better understanding of the natural history of this disease."

Years ago when we were asked to write a book on the present-day knowledge of the molecular biology of poliovirus, we did not expect that such an apparently simple task could involve so much time and effort. Our writing was hampered by the fact that both of us are full time "workers," so that this monograph is mainly a spare time expedience. The main attention of this book focuses on a detailed review of the molecular biology of poliovirus and especially on the advances of the last decade; medical and environmental aspects are only briefly mentioned. Observations from older studies are considered in view of more recent information. Some of the older ob servations provided fundamental insights and paved the way for present day research; too often such data has been neglected or independently rediscovered. Today, poliovirus research has again attracted considerable interest. High points gained within the last few years were the elucidation of the complete nucleotide sequences of the RNAs of the three poliovinls serotypes and the corresponding vaccine strains, the demonstration of genome evolution during transmission of poliovirus in an epidemic, further characterization of the antigenic sites on the virus particle and of the antigenic drift, characterization of alternate conforma tional states of the virion capsid, the development of monoclonal antibodies against some of the virus proteins, observations on the role of the plasma membrane, cytoskeleton, and cytoplasmic membranes as mediators in the virus induced redirection of the synthetic machinery of the host cell, and characteriza"

Proceedings of the 18th Joint Conference on Cholera

The nucleotide sequence of the gene from which messenger RNA mole cules are transcribed is in a form that can be translated by cellular ribosomes into the amino acid sequence of a particular polypeptide, the product of the gene. The discovery of messenger RNA more than twenty years ago led to a series of studies on its organization and function in cells in the presence of infecting viruses. This volume is devoted to current studies in the field of cellular and viral messenger RNA. The studies presented provide an insight into molecular and genetic aspects of messenger RNA. Special attention was paid by the authors to the molecular organization of mRNA species, to the processing of mRNA molecules, and to the different strategies employed by DNA and RNA viruses in the synthesis of their mRNA. The ability of a virus to take over the protein-synthesizing mechanisms of an infected cell depends on its ability to produce mRNA molecules which can affect the host mRNA or utilize cellular components more efficiently. The differences between, and similarities of, the strategies of mRNA synthesis devised by various DNA and RNA viruses are described herein. This book should be of interest to all students of cellular and viral genes and scientists in the field. It is suitable as a textbook for workshops and courses on mRNA. I wish to thank the authors for their fine contributions and for their interest."

The present volume contains the Proceedings of an EMBO Workshop organized in June 1983 by the Institute of Virology, Veterinary Faculty, State University of Utrecht, The Netherlands. Some 70 scientists from 11 countries followed the invitation to present and discuss their recent data on the structure, replication, genetics and pathogenesis of coronaviruses. It was the second international meeting on these viruses; the Workshop, which was held in Zeist near Utrecht followed the example of the Wuerzburg symposium of October 1980. At that time it became clear that coronaviruses are unique in many respects. Once a group of viruses that were defined merely on the basis of their characteristic peplomer morphology, Coronaviridae family members are known today - to be constructed from essentially three polypeptides - to use a "nested set" of 5-6 subgenomic mRNAs in the expression of their large, positive and single stranded RNA genome, - to generate these subgenomic RNAs through specific fusion of non contiguous sequences, - to mature by budding from intracellular membranes, - to cause persistent infection with neurological involvement and sometimes immunopathological conditons. These and many other findings have been established only very recently. The articles collected in this book reveal and/or further detail these findings. Since these Proceedings contain the combined scientific presentations of representatives from virtually all laboratories engaged in the field, they provide a fairly comprehensive review of the state of the art in corona virology."

Since the discovery of Australia antigen and its association with type B hepatitis, molecular characterization of the components making up hepatitis B virus (RBV) have been pursued with worldwide interest. Over the past two decades, such characterization has led to the development of sensitive assays to screen and exclude contaminated units from blood banks and has recently resulted in the licensing of several RBV vaccines. That more than 200 million people worldwide are chronically infected with RBV, and that they are at a high risk for the development of chronic hepatitis and hepatocellular carcinoma, still represent formidable problems in our understanding of host-virus relationships on the molecular level. In the absence of a suitable tissue culture system, and with a very limited host range of infection, characterization of RBV on the molecular level has made remarkable progress recently with the advent of genome cloning, sequencing and expression of individual virus genes by recombinant DNA technology. The presence of hepatitis B-like viruses in an expanding number of animal hosts, and the possibility of virus replication in cells other than hepatocytes, provide great promise that future work will elucidate the molecular mechanisms operative in the various outcomes of RBV infection.

The development of recombinant DNA technology has made a marked impact on molecular virology. The cleavage of viral DNA genomes with restriction enzymes and the cloning of such DNA fragments in bacterial p1asmids has led to the amplification of selected viral DNA fragments for sequencing and gene expression. RNA virus genomes which can be transcribed to their cDNA form were also cloned in bacterial p1asmids, facilitating the study of RNA virus genes. With the elucidation in recent years of the promoter sequence of various viral genes and the expression of these genes in bacteria or yeast, the understanding of many viral gene functions has made great progress. Cloning and expression of viral genes in mammalian cells was made possible by the construction of shuttle plasmid vectors which carry the origins of DNA replication from bacteria and/or mammalian viruses. The expression of viral genes in bacteria, yeast and eukaryotic cells gives reason to hope that it will be possible to produce viral antigens in large quantities for use as human or animal vaccines. The present volume attempts to capture for the reader some of the high lights of recombinant DNA research in the field of animal and plant viruses."

Research on antiviral drugs and their mode of action in infected cells. in animals and in man. has led to a better understanding of the molecular pro cesses involved in virus replication. Screeninq of large numbers of natural and semisynthetic compounds resulted in the characterization of certain sub stances that had a limited efficiency as antiviral druqs. A few chemically synthesized compounds were also found to be effective as antiviral agents in the chemotherapy of human virus diseases. A major difficulty in the develop ment of effective antiviral agents has been the lack of selectivity. and toxicity for uninfected cells. of drugs that effectively inhibited virus replication in vitro. Further understanding of the molecular processes of virus replication in infected cells has resulted in the development of new antivirals directed at virus-coded enzymes or proteins. Recent studies on antivirals that are activated by the herpes simplex virus type l-coded thy midine kinase from a prod rug to an antiviral drug have opened new directions in the development of effective antiviral drugs. The present book deals with a number of antiviral drugs effective against herpes simplex viruses and provides some insight into the molecular aspects of virus replication. It also throws light on the new approaches to the development of antiviral drugs. The molecular basis of the antiviral activity of new and known drugs and their possible use in chemotherapy of viral disease are presented in this book."

Venezuelan equine encephalitis (VEE) virus was first isolated in 1938 by Kubes and Rios (1) from the brain of a horse which died during an epizootic of a previously unrecognized disease in Venezuela. VEE-related viruses were subsequently isolated during t~e period of 1943-1963 in Venezuela, Colombia, Peru, Trinidad, Brazil, Surinam, Argentina, Panama, Mexico, and the United States (2) * Shope et ~. (3) fi rst defi ned the vi ru ses in the VEE comp 1 ex t-y showing serological relationships between classical VEE, ~lucambo, and Pixuna viruses. Young and Johnson (2) serologically characterized a variety of VEE isolates and proposed that the complex t>e divided into four subtypes (I, II, III, and IV). Viruses in subtype I were divided into five variants designated IA through IE. During 1069-1~71 a VEE epizootic-epidemic occurred in South America, Central America, and the United States involving a subtype lAB virus which caused high mortality among equines and human d i sea se (4). Venezuelan equine encephalitis viruses are alpha-togaviruses w~ic~ contain a positive strand rit>onucleic acid genome enclosed in an icosa~edral nucleocapsid. The virion has an envelope which contains blO glycoproteins: E2 of 5F,000 daltons (gp56) and E1 of ~O,OOO daltons (gp50) (5,6). Viral neutralization (N) and hemagglutiration (HA) sites have been placed on E2 by the use of monospecific rabtdt antisera and monoclonal antibodies specific for purified viral structural proteins (7-10). Only anti-E2 antisera neutralized virus infectivity or blocked virus hemagglutination.

Biosynthesis of cellular and viral DNA and RNA has been a major topic in molecular biology and biochemistry. The studies by Arthur Kornberg and his colleagues on the in-vitro synthesis of DNA have opened new avenues to understanding the processes controlling the duplication of the genetic information encoded in the DNA and RNA of bacterial and mammalian cells. Viral nucleic acids are replicated in infected cells (bacterial, plant, and animal) by virus coded enzymes with or without the involvement of proteins and enzymes coded by the host cells. The ability of the virus to replicate its genome within a relatively short period in the infected cell makes it an excellent biological tool for studying the molecular events in nucleic acid replication. Indeed, the identification of a number of virus-coded proteins that participate in the biosynthesis of X174 and SV40 DNA has led to the construction of in-vitro systems for the study of nucleic acid biosynthesis. Similarly, studies on the replication of other phage, animal and plant viruses have provided an insight into the nucleic acid sequences from which DNA synthesis is initiated, as well as the proteins and enzymes that regulate the catalyse biosynthetic processes. Investi gation of the molecular processes involved in the replication of cellular and mitochondrial genomes has gained momentum from the rapid developments in the analyses of viral nucleic acid biosynthesis."

When discussing the drug, the bug, and the host in the past, emphasis was laid mainly upon the interaction between antibiotics and bacteria or the reaction of the host to the invading organism. Today, however, standardized immunologic parameters are available for evaluating cellular and humoral responses and an increasing number of publications deal with the host reaction to the antibiotics administered. Some re searchers and clinicians felt that the time had come to bring together investigators studying the influence of antibiotics on the host-parasite relationship. The first section of this book therefore covers the influence of chemotherapy on the host defense system. Here antibody production and cellular immunity, the influence of antibiotics on the function of phagocytic cells, and immunostimulation combined with antibiotics in the treatment of infection are presented. The second section deals with the influence of antibiotics on the produc tion of extracellular and cellular virulence factors by bacteria, the adherence of bacteria being of utmost importance here. In addition, phagocytosis and serum bactericidal activity are discussed. In Prof. Opferkuch and Prof. Hahn I found two colleagues keen and knowledgeable enough to organize the First International Meeting on the Influence of Antibiotics on the Host-Parasite-Relationship. These proceedings of the meeting constitute a survey of the latest develop ments in this field, and should be of interest to clinical and researchers. Bielefeld, September 1982 Hans-Udo Eickenberg Berlin Helmut Hahn Bochum Wolfgang Opferkuch Contents Introduction H. -U."

This book was written during a period when the technologies of genetic engineering were being applied to the study of animal viruses and when the organization and function of individual virus genes were being elucidated. This book, which uses human and animal viruses as models, aims to under stand the developments in molecular virology during the last 20 years. Al though molecular virology could also be taught by means of bacteriophages or plant viruses, the advantage of using animal viruses is in their ability to cause human and animal diseases as well as to transform cells, a primary problem in medicine. For the sake of clarity and convenience, not all the individual contributors to the various aspects of molecular virology were cited in the text. Instead, the reader is referred to review articles or key papers that list the numerous excel lent publications that have contributed to clarification of the various molecular processes. Thus the end-of-chapter bibliographies will guide the reader to the publications in which the original contributing authors are quoted. References given under the heading Recommended Reading are intended to assist those interested in pursuing a given subject further. I hope that this book will fulfill the purpose for which it is designed, and I urge readers to contact me if errors are found or updating is required."

R. VANFURTH Infection is an inseparable part of communal life, and infections are more common and more severe in hospital communi ties because the sick are more easily infected than the healthy. However, even though progress in the medical sciences has meant that many more patients suftering from relatively severe diseases can be helped at present, the use of more sophisticated and complex treatment leads to impairment of the defence mechanisms in more patients than was the case ten to twenty years ago, and these patients are also more prone to develop an infection. Two questions are particularly relevant in this context. 1) Under what conditions do hospital infections occur? Defects of host defence mechanisms are of great importance in this respect. Such defects can be due to the disease or to the treatment given to the patient. 2) Which of the host defence mechanisms can be affected by a stay in the hospital? Among the factors involved in the host defence against infections (Table I), a number are especially important in this respect. For instance, venepuncture, indwelling catheters, and surgery all cause a breach in the surface structures. Anaesthesia causes temporary impairment of mechanical factors. Vascularization may be defective -- especial ly in the aged and patients with diabetes mellitus -- and this may complicate the healing of wounds in the skin and mucous membranes after surgery."

Since the beginning of this century there has been a growing interest in the study of the epidemiology and population dynamics of infectious disease agents. Mathematical and statistical methods have played an important role in the development of this field and a large, and sophisticated, literature exists which is concerned with the theory of epidemiological processes in popu lations and the dynamics of epidemie and endemie disease phenomena. Much ofthis literature is, however, rather formal and abstract in character, and the field has tended to become rather detached from its empirical base. Relatively little of the literature, for example, deals with the practical issues which are of major concern to public health workers. Encouragingly, in recent years there are signs of an increased awareness amongst theoreticians of the need to confront predictions with observed epidemiological trends, and to pay elose attention to the biological details of the interaction between host and disease agent. This trend has in part been stimulated by the early work of Ross and Macdonald, on the transmission dynamics of tropical parasitic infections, but a further impetus has been the recent advances made by ecologists in blending theory and observation in the study of plant and animal populations.

Venomous Animals have been a threat to man at all times, in the warm and wilder regions more than in the temperate areas. People in especially dangerous regions know about these risks and live accordingly. However, with modern tourism and nearly unlimited travel oppor tunities more and more people without experience and knowledge about venomous animals come into contact with them; this book is intended to provide these people with an introduction to the subject. Venomous animals, their habits, their whole ecology and their venoms have been the object or research since the beginning of this century; truly intensive work, how ever, first started about thirty years ago. Medical treat ment therefore has been changed by new insights in the mechanism of action and the constituents of the various venoms. In this regard this book is also directed to physi cians, biologists and chemists to give them an introduc tion in this important and interesting field. New aspects of treatment of envenomations are reported. This book cannot replace bigger textbooks and monographs - they are cited in the references - but it gives an overview and an entry into this field. The original German edition was written at the request of colleagues and students of medicine, biology and chemistry as well as frequent travellers in tropical countries. It was sold out within eight months, thus showing that it really filled a gap."