Genital Papillomavirus Infections provides a state of the art survey on the clinical aspects, diagnosis, treatment, and prevention of genital papillomavirus infections, written by experts in the respective fields. Two introductory sections on epidemiology and molecular biology are followed by chapters on new techniques for the detection of genital papillomaviruses and their presence in genital carcinomas. Contributions on the clinical aspects cover infections of the cervix, male and female external genitalia, urethra, and oral cavity. A discussion of the immunobiology of papillomaviruses ends in an evaluation of the prospects for vaccination, and the application of podophyllotoxin, cryosurgery, laser therapy, and interferon treatment are described in detail. This book is unique in placing a strong emphasis on clinical aspects of genital papillomavirus infections. Mainly addressed to clinicians, it provides practical guidelines on methods for their diagnosis and treatment.

In the rapidly evolving field of Helicobacter infection new data on pathogenetic and pathophysiological mechanism have appeared. New methods which will be more sensitive and specific in the diagnosis of the infection are being developed and in this proceedings the first attempt using PCR technology is published. From the clinical point of view, a challenging aspect that needs clarification, is the observation which suggests an appearance of a correlation between the presence of the bacteria and abdominal pain and other symptoms in children whereas in old age no such correlation is evident. The relationship of H. pylori and gastric cancer is studied with histopathological data and epidemiological approaches. On the treatment side schemes using short courses and new antibiotic combinations are being investigated and preliminary data are reported.

This volume, Biology of Poxviruses, marks our debut as editors of this well known series. We plan to continue the tradition of providing a forum for exten sive, critical reviews of individual virus groups, as exemplified by the present volume. But the pace of discovery is accelerating so rapidly that we feel the need to offer an additional format: volumes that contain collections of shorter, topical reviews on a group of related subjects. Such collections might cut across con ventional boundaries between virus groups, dealing, as an example, with a partic ular aspect of virus-cell interaction. Admittedly, this new format stretches the term "monograph" beyond the accepted definition, but we believe that we should pay that price to maintain the usefulness of the series as a medium of scientific communication. Whenever possible, we will enlist the aid of deputy editors to bring such col lections to fruition. As in the past, the editors and the publisher will welcome suggestions for topics and contributions."

Natural resistance is now coming to be recognized as a potentially important phenomenon in host defense against infection and ma lignancy. Genetically controlled resistance mechanisms are usUally effective early in infection and before conventional immune responses are generated. Comparisons of experimental systems where natural resistance plays a prominent role demon strate the complexities of the host defense mechanisms involved, as evidenced in the present volume. Nevertheless, some com mon components of genetic resistance are discernible and largely comprise natural killer cells, macrophages, and interferon These and additional factors would seem to constitute a first line of de fense in host resistance against both viruses and tumors. It is evi dent that considerable variation in the relative importance of di stinct mechanisms may be found among various resistance sy stems and that, most likely, additional effector functions will be discovered. Resistance to tumors and most viruses is under polygenic control, has a complex mode of inheritance, and depends on appro priately complex effector mechanisms. Instances, however, whe re a single gene locus determines resistance or susceptibility to a virus, as in the case of resistance to flaviviruses or influenza viru ses, would seem to offer good prospects for elucidating the basic factors involved. Resistance to influenza virus would indeed seem to represent a comparatively simple situation: resistance is expressed at the host cell level, and interferon is its main media tor. The present volume provides insight into current concepts of such resistance mechanisms."

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."

The substantial and impressive changes in microbial ecology can scarcely be chronicled in a meaningful fashion, and a review series such as Advances in Microbial Ecology can thus not do justice to the numerous studies that have been published in recent years. On the other hand, the mere existence of this series bears testimony to the many and diverse activities. The growing concern with microbial communities and processes in natural ecosystems is not restricted to scientists in one region and is not limited to particular groups of organisms or to individual theoretical or applied problems. The recent and successful international symposium on microbial ecology held in New Zealand-sponsored in part by the International Commission on Microbial Ecology, as is the Advances-and the general microbiology and ecology conferences and congresses have included reports from investigators from all corners of the globe and have explored both new and traditional areas, agricultural and public health problems, individual species and complex communities, and heterotrophs and autotrophs as well as ecosystem models relying on mathematical concepts and environmental processes needing sophisticated chemistry for their definition. The reviews in the present volume thus can offer only a minute sampling of the multitude of topics being actively explored at the present time. Two of the reviews focus attention on biogeochemical cycles regulated by microorganisms, in particular the way these organisms contribute to or control the levels and identities of chemical substances in the atmosphere. The chapter by Y. Dommergues, L. W. Belser, and E. L.

In June 1986 a symposium was held in Giessen on Modern Trends in Virology. It was initiated by the Deutsche Forschungsgemeinschaft, which had supported virus research for the past 18 years in the Sonderforschungsbereich 47 at the University of Giessen. The purpose of the meeting was to serve as a forum for the members of the Sonderforschungsbereich to discuss scientific topics of mutual interest with about 200 virologists that had come from various parts of Europe, the United States, and Japan. It was not by chance that the symposium took place shortly after the 60th birthday of Rudolf Rott, who had founded the Sonderforschungsbereich in 1968 and has been its speaker ever since. Without his vision and his never resting energy Giessen would not have gained the position in the field of virology that it has today. This Festschrift, which contains the contributions presented at the plenary sessions of the symposium, is therefore dedicated to Rudolf Rott. HEINZ BAuER HANS-DIETER KLENK CHRISTOPH SCHOLTISSEK Table of Contents A Genetic Approach to Determining Glycoprotein Topology: The Influenza B Virus NB Glycoprotein has an Extracellular NHz-Terminal Domain Containing two N-linked Carbohydrate Chains R. A. LAMB and M. A. WILLIAMS . . . . . . . . . . . . . . . . . . . . . . . . . 1 Paramyxovirus Metabolisms Associated with the Cytoskeletal Framework Y. NAGAI, T. ToYODA, and M. HAMAGUCHI . . . . . . . . . . . . . . . . . . . 15 Correlation of High Evolutionary Rate of Influenza A Viruses in Man with High Mutation Rate Measured in Tissue Culture: A Hypothesis P. PALESE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The larvae of Anisakis, whose adult form lives on sea mammals such as whales, seals, and dolphins, are parasitic upon many species of salt-water fish. When the final host animals eat paratenic hosts, the larvae grow to adulthood in the hosts' stomach. However, when hu mans eat these infested fish, the larvae die instead, causing a disease called anisakiasis. In 1960, in the Netherlands, van Thiel et al. found a worm in the intestinal wall of a patient who had eaten raw herring and had suffered symptoms of acute abdomen. The impact of this report was tremendous among Japanese parasitologists because of the Japanese habit of eating raw fish. In 1964, the Special Research Group from the Ministry of Education was established to investigate the disease, stimulating progress in the study of anisakiasis. Three types of worm, Anisakis simplex larva (previously known as Anisakis larva type I), Anisakis physeteris larva (Anisakis larva type II), and Pseudoterranova decipiens larva type A, are believed to cause anisakiasis. As many as 165 kinds of fish and squid in the seas near Japan are hosts to Anisakis simplex, and 9 species are hosts to Pseudoterranova decipiens larvae. Contra caecum has experimentally been observed to invade the gastrointestinal tract, but no infection by this larva has been reported in humans. A case of infection by Pseudoterranova decipiens type B has been described. In Japan, the name Terranova decipiens (Shiraki 1974) has been adopted instead of Phocanema decipiens (Mozgovoi 1953)."

Prokaryotic Toxins - Antitoxins gives the first overview of an exciting and rapidly expanding research field. Toxin - antitoxin (TA) genes were discovered on plasmids 30 years ago. Since then it has become evident that TA genes are highly abundant in bacterial and archaeal chromosomes. TA genes code for an antitoxin that combine with and neutralize a cognate toxin. When activated, the toxins inhibit protein synthesis and cell growth and thereby induce dormancy and multidrug tolerance (persistence). Remarkably, in some species, the TA gene families have undergone dramatic expansions. For example, the highly persistent major human pathogen Mycobacterium tuberculosis has "100 TA loci. The large expansion of TA genes by some organisms is a biological mystery. However, recent observations indicate that TA genes contribute cumulatively to the persistence of bacteria. This medically important phenomenon may thus for the first time become experimentally tractable at the molecular level.

During the late 1970's the application of hybridoma technology led to an explosion in the discovery and characterization of proteins expressed at the surface of hematopoietic cells. The understanding of T lymphocyte biology benefited enormously from this advance and from newly developed techniques for obtaining clonal T cells. Application of these methodologies resulted in the identification of the clonally restricted T cell antigen receptors (TCRs) and of a number of other molecules expressed more broadly on T cells. Among these, the CD4 and CD8 glycoproteins stood out because they were differentially expressed on distinct functional subsets of T lymphocytes. Moreover, blocking studies with monoclonal antibodies sug gested a functional role for CD4 and CD8 in T cell responses to antigen. Shortly thereafter, it was shown that T helper cells were the primary targets for the human immunodeficiency virus (HIV) and that CD4 serves as the viral receptor on these cells. These findings fueled an intense interest in CD4 during the last decade, in the hope that understanding the molecular nature of the HIV-CD4 interaction could hold the key to controlling AIDS.

Attention to viral infections and pathology previously focussed on diseases of economically important fish. In recent years, however, much new information on molecular virology and oncogenicity derives from viruses occurring in amphibians. New insights into the field of zoonosis were gained by studies of lower vertebrates serving as intermediate hosts in multiple human infections. Certain viruses, e.g. the influenza virus or calicivirus, seem capable of bridging species lines and even the land - sea interface. Global developments in aquaculture are indicated in influenza pandemics. These proceedings present research findings on viruses of fish, amphibians and reptiles, including defence mechanisms, zoonoses, evolutionary considerations and diagnostic approaches.

With the advent of genetic engineering methods and improved biochemical tech niques, much has been learned about the replication of influenza viruses, their structure and their epidemiology. It appears that the time is ripe to review these efforts and to provide a molecular perspective of influenza virology. It is hoped that this book will stimulate our thinking, help us in designing new experiments, and possibly show avenues leading to the control of the diseases associated with influenza viruses. Peter Palese, New York, N. Y. August 1983 David W. Kingsbury, Memphis, Tenn. Contents List of Contributors. . . . . . . . . . . . . . . . . XV 1. The Evolution of Influenza Viral Genetics - A Perspective. By E. D. Kilbourne. . . . . . . . . . . . . . . . 1 I. Introduction. . . . . . . . . . . . . . . . . 1 II. The Development of Modern Influenza Viral Genetics 2 A. Early Evidence of Genetic Variation in the Laboratory 2 B. Application of Formal Genetic Techniques to Studies of Influenza Virus . . . . . . . 3 C. Genetic Markers. . . . . . . . . 3 D. Development of Plaquing Systems. . . 4 E. The Use of Conditional Lethal Mutants 5 F. New Approaches in Influenza Virus Genetics. 6 1. The Biochemical Identification of Viral Gene Products in the Unambiguous Definition of Viral Inheritance . . . 6 2. Mapping of the Influenza Virus Genome by Correlative Physico-Chemical and Biological Techniques. . . . . . 7 3. The Application of Molecular Biological Techniques to the Study of Viral Genetic Variation. . . . . . . . . 8 4. Oligonucleotide Mapping of Viral RNA's . . . . . . . 8 5. Contribution of Protein and RNA Sequencing to Influenza Viral Genetics-Intragenic Mapping . . . . . . . 8 III. Viral Genetics and the Understanding of Viral Virulence and Pathogenicity . . . . . . . . . . . . . . . . . . ."

Stress, high blood pressure, smoking, pollution, fast foods, overweight, excessive travelling, surgery, less movement are common features in our modern life. These features are risky for blood clotting disorders. According to WHO, over 29% of the total mortalities worldwide are due to thrombosis. By the year, 2020 cardiovascular diseases (CVDs) may cause an estimated 25 million deaths per year, thus antithrombotic therapy is of great interest.

The available thrombolytic agents such as urokinase are highly expensive, antigenic, quite unspecific, pyretogenic and hemorrhagenic. Therefore, the production of fibrinolysing enzymes, which rapidly dissolute thrombi within the vascular tree, without the detriments by microorganisms, as described in this book, is the desirable aim of today s research. "

The International Congress on Rapid Methods and Automation in Microbiology and Immunology, held in 1990 (RAMI-90) in Helsinki Espoo, Finland, attracted considerable interest from the international scientific community. This reflects both the rapid progress and numerous new challenges in the field covered by RAMI-90. New biotechnical approaches, such as the polymerase chain reaction, recombinant gene products and synthetic peptides are gaining wide acceptance. New important pathogens have emerged, such as hepatitis C, Helicobacter pylori, Borrelia burgdorferi, herpes virus 6 and Chlamydia pneumoniae. "Super streptococci" are recognized again as well as the agent responsible for bovine spongiform enceph alopathy. The current diagnostic methods are clearly unsatisfactory for many of these and other microbes. Moreover, there is an increas ing need for more accurate microbial control of our environment, and of the food and water we consume. What is needed are rapid, sensitive and reliable procedures which, on the one hand, should be suitable for automation and, on the other hand, presented in a cost-effective version suitable for field use. We view these needs as a clear and loud challenge for future RAMI congresses. This volume provides an up-to-date presentation of the highlights of RAMI-90 and prospects for the future. For the preparation of this volume we wish to thank Dr. Maija Leinonen for her invaluable con sultation and Ms. Virpi Tiilikainen for secretarial assistance. ANTTI V AHERI RICHARD C. TILTON ALBERT BALOWS Contents Nucleic Acid Detection Controlled Synthetic Oligonucleotide Networks for the Detection of Pathogenic Organisms M. S. Urdea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ."

Although immunologists know rather a lot about the manif estation of immunological memory, an understanding of the mechanism of memory at cellular and biochemical levels eludes us. Indeed, as we shall see, it is not even clear which of the several models used to explain the working of memory approximates to the truth. It is in order to report on approaches to this problem and on recent experimental advances in the field of memory cells that this volume has been put together. In the past 4-5 years cell surface molecules that may enable us to define memory Band T cells have been identified. It may now be possible to ask how memory cells are generated and to define what signals are required during or after antigenic encounter for a cell to enter the memory cell pool rather than to terminally differentiate into an effector cell. The transition from virgin cell to memory cell is clearly accompanied by several biochemical changes. For B cells, isotype switching and somatic mutations (leading to affinity maturation) are well-defined phenomena, although the molecular mechanisms remain mys terious. Both have received attention in many excellent reviews of late and so are not considered in detail in this book. Neither switching nor somatic mutation is a feature of peripheral T-cell maturation; biochemical differences between virgin and mem ory T cells may only relate to differing activation requirements and possibly changes in the expression of accessory molecules.

Postreplicative methylation of bacterial DNA has long been known to be the molecular basis of" modification," which protects DNA against destruction by restriction endonucleases. More recently, another function of DNA methylation was found in Escherichia coli, where methy- lation is involved during DNA replication in the recogni- tion of old and newly synthesized strands. The intensive search for new restriction enzymes during the 1970s yielded an enormous arsenal of such enzymes and re- vealed the ubiquitous distribution of restriction/modifi- cation systems in the bacterial kingdom without provid- ing much information on the corresponding modifica- tion methyltransferases. However, it is obvious that DNA methyltransferases represent an ideal class of en- zymes to those interested in protein/DNA interactions; these enzymes are at least as interesting as the restriction enzymes, with which they share the capacity to recognize and interact with specific sequences of DNA. In recent years the interest in DNA methylation has been greatly stimulated by two discoveries: the correla- tion between gene expression and hypomethylation in eukaryotes and the convertability of DNA into its Z form through cytosine methylation. In fact, studies on DNA methylation are now being intensively performed in many laboratories. A description of the state of the art of DNA methylation has been the topic of two con- gresses: The Cologne Spring Meeting in 1981 organized by WALTER DOERFLER and an EMBO Workshop at Nethybridge in 1982 organized by ROGER ADAMS.

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.

Tropical diseases such as leishmaniasis, malaria. trypanosomiasis, toxoplasmosis and amebiasis continue to plague the world, resulting in considerable morbidity and mortality, especially in the third world countries. These diseases are caused by a group of protozoa which have, over the years, undergone evolutionary adaptation to live often intracellularly in a parasitic way of life. So well-adapted have they become that they recognize the right hosts or cells to parasitize, yet at the same time they escape recognition and destruction by the host immune system. The mechanisms of such recognition and the escape of recognition are governed largely by host-parasite surface membrane interactions at the cellular and molecular level. Unique molecules produced by unusual pathways of these parasites have also been discovered and found to play important roles in their survival in the host. Understanding these mechanisms and pathways is essential not only to formulate a rational strategy for chemo- and immuno-prophylaxis and -therapy but also to unravel the mystery of biological evolution in symbiosis and parasitism. In the advent of our knowledge on the molecular biology and biochemistry of parasite membrane and other molecules, it is opportune to examine and discuss their possible roles in host-parasite recognition and interaction in a comparative approach. To highlight the recent advances of this area in various host-parasite systems, a NATO advanced Research Workshop was held from September 27 to October 1, 1986 at Hotel Villa del Mare, Acquafredda di Maratea, Italy.

It is surprising, and even disappointing, that there have been very few meetings and published volumes resulting from these meetings that focus attention upon all of the groups of DNA tumor viruses. Historically, separate meetings were held each year for the adenovirus-SV40-polyoma researchers, the herpes viruses, hepatitis B virus and the papillomaviruses. It was as if these four virus groups were four fields of study developing independently with a literature and culture of their own. When a virologist crossed the field from the adenovirus group to the herpesvirus or papillomaviruses, he or she was lost to their former group because of the structure of separate meetings and remote literature. This, of course, has resulted from historical accident and is being rectified by the rapid progress made in our understanding of how these viruses contribute to the causation of cancer in animals and humans. It was pre cisely because of these factors that it was time to hold a meeting and publish its proceedings on the subject of transforming proteins of DNA tumor viruses. For the first time, DNA tumor viruses were defined as all of the virus groups that can contribute to cancer in animals with the exception, unfortunately, of the . poxviruses. The purpose of the meeting was to bring together scientists who rarely attend meetings together but actually work on the same problems with different viruses.

Intracellular pathogens are responsible for a number of important diseases worldwide, including tuberculosis, plague and bacillary dysentery. This volume focusses on those intracellular pathogens that have been studied most extensively at the molecular, genetic, and cellular level. The reviews attempt to integrate the information derived from these diverse approaches into a cohesive picture. In recent years the entry steps have been described at the molecular and genetic level, and the important signal transduction events are being elucidated. It is now becoming clear that there are both similarities and differences both in terms of the steps involved and of the genetic basis of bacterial invasiveness. These reviews of the "state of the art" provide a foundation from which to proceed.

The Bloomsbury Series in Clinical Science is growing and changing. Its Editorial Board and contributors were all originally selected from, or had links with, the University College and Middlesex School of Medicine. Now, as the Series develops, board members and con tributors alike identify with the wider reaches of Bloomsbury and Islington. The aims of the Series remain, however, to highlight, to review and to record significant areas of research and development in the field of clinical science. All contributors are experts in their particular field and monographs may be the work of a single author or several, guided by individual editors. Diseases in the Homosexual Male is the third monograph in the Series. Edited by Michael Adler, Professor of Genito-Urinary Medicine at the University College and Middlesex School of Medicine, it presents contributions from a number of distinguished workers with special expertise. AIDS has perhaps highlighted the problem but this monograph illustrates the wider profile and gives wit ness to the multidisciplinary nature of clinical science."

Many bacteria, such as certain Neisseria and Haemophilus or Escherichia coli, are able to withstand the bactericidal activity of complement and phagocytes. This bacterial self protection is brought about by encapsulation. Bacterial capsules thus enable the pathogenic bacteria to survive in the host by counter action or evasion of the nonspecific host defense in the early pre immune phase of an infection. It is only in the late immune phase of the infection, when specific anticapsular antibodies are formed and enforce the host's defense system, that this protective action is overcome. Encapsulated bacteria are then killed and eliminated. Interestingly, some capsules can not or only inefficiently be handled by the immune system. The ensuing lack of antibody formation results in a prolonged susceptibility of the host to the pathogenic bacteria exhibiting such capsules. It was found that bacterial capsules consist of acidic poly saccharides. From this it followed that the role of the capsules in the interaction of encapsulated bacteria with the host may be due to the chemistry of the capsular polysaccharides. This led to intensive studies of capsular polysaccharides in many laboratories. Our increasing knowledge of the structural features of capsular polysaccharides prompted not only immuno chemical studies analyzing the interactions of these poly saccharide antigens and characterizing the epitopes, but also investigations into their biosynthesis. These studies were complemented and supported by genetic analyses. Today many interdisciplinary investigations of capsular polysaccharides are in progress.

In spite of a long history of intense investigation the transmissible spongiform encephalopathies remain a poorly understood family of neurodegenerative diseases. This group of diseases has been described in a wide variety of animal species and includes kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler syndrome in humans, and scrapie, bovine spongiform encephalopathy, and related syndromes in ruminants and rodents. In all cases spongiform degeneration and astrocytosis are seen in specimens of brain and a filterable transmissible agent is present in the brain and some other tissues of affected individuals. However, the precise nature of this agent remains unknown. Agent infectivity, which can so far only be assayed by serial transmission to new individuals, be remarkably resistant to inactivation has been shown to by heat, chemicals, and irradiation. These properties create significant biohazard possibilities during exposure to infected tissues. Transmission between humans was originally reco gnized in the unique epidemiology of kuru in New Guinea tribesmen, and concern about transmission from animals to humans has re-emerged as a result of the current epidemic of bovine spongiform encephalopathy in dairy cattle in Great Britain. Although interspecies transmission has often been achieved experimentally, its efficiency is highly variable. There fore, the possibility of spread of bovine spongiform encephalopathy from cattle to humans or various animal populations cannot be accurately predicted at this time. This volume presents a comprehensive update of know ledge concerning the transmissible spongiform encephalo pathies."

Shigellosis is present all over the world. Anyone traveling in developing countries knows that the control of this invasive disease of the intestine is a priority task for physicians and public health authorities. Victims are essentially young children, and complications such as the hemolytic uremic syndrome make shigellosis a systemic disease rather than simply an infection of the colonic mucosa. However, "Westerners" should not consider shigeJlosis as an unlikely threat of the tropics. The disease arises in industrialized countries as soon as breaches in sanitation appear. A few months ago, at least 500 people developed shigellosis in northern France in an outbreak of Shigella sonnei infection due to accidental contamination of an urban water delivery system. The pathogenesis of shigellosis is an extraordinary topic of research because study of the invasion of the colonic mucosa addresses fundamental questions on. the molecular and cellular mechanisms by which a bacterial pathogen can pene trate non phagocytic cells, survive, multiply, spread in the intra cellular compartment, and eventually kill host cells. Further development of the infection within subepithelial tissues as well as the mechanisms that contribute to the eradication of this process have barely been studied."