Showing papers in "Current Topics in Microbiology and Immunology in 2002"

Toll-Like Receptors and Their Ligands

Abstract: The Toll-like receptors (TLRs) are key molecules involved in the recognition of pathogens by the innate immune system. This family of germ line-encoded receptors has evolved to recognize conserved features of microbes. Currently, 10 TLR family members have been identified in mammals. The number of ligands for these receptors continues to grow, and it seems clear that multiple ligands exist for each receptor. Whether engagement of different TLRs leads to differences in gene expression and thereby differences in the immune response remains to be seen. However, recent work has demonstrated that activation of TLRs is required for initiation of only certain adaptive immune responses.

Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily.

Abstract: Toll-like receptors (TLRs) are an important point of first contact between host and microbe, and once activated generate signals which culminate in the induction of genes important for host defence. TLRs respond to different microbial products, and the signalling pathways activated are very similar to that generated by the pro-inflammatory cytokine interleukin-1 (IL-1). This is because the Type I IL-1 receptor and TLRs are highly homologous in their cytosolic portions, possessing a Toll/IL-1 receptor (TIR) domain. Signals triggered include the important transcription factor NF-кB and two MAP kinases, p38 and Jun N-terminal kinase. Receptor-proximal proteins involved include the adapter MyD88, IRAK, IRAK-2, Tollip, TRAF6 and TAK-1. These latter two proteins need to be ubiquitinated in order to be active. Differences between signals generated by TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed MyD88-adapter-like (Mal), which may regulate the expression of genes specific for the response required to eliminate infection by Gram-negative bacteria. Future studies on TLR signalling may reveal hitherto unsuspected specificities in the innate immune response to infection.

Heat shock proteins as ligands of toll-like receptors.

Abstract: Toll-like receptors (TLRs) have been described as sensors for pathogen-associated molecular patterns crucial for the initiation of an innate immune response. These mechanisms were developed long before the adaptive immune system evolved. The latest additions to the growing list of TLR ligands are heat shock proteins (HSPs). Interestingly, not only bacterial but also mammalian HSPs interact with TLRs demonstrating that the exclusive association of TLRs with microbial ligands is obsolete. Human HSP60 and Gp96 are the first examples of non-pathogen derived ligands of TLRs. More importantly, Gp96 provides the first example of how the innate and adaptive immune system can be stimulated simultaneously by the same molecule which is released under physiological conditions from necrotic cells. Understanding the mechanisms of innate immune system interaction with HSPs will make it possible to rationally modulate immune responses, either towards immunity or towards tolerance.

Japanese encephalitis virus: ecology and epidemiology.

Abstract: Japanese encephalitis (JE) virus is a mosquito-borne zoonotic flavivirus that infects a wide range of vertebrate species in an enzootic cycle primarily of large waterfowl birds and swine. Horses and humans are considered bystanders to this enzootic cycle and, once infected, dead-end hosts. JE infection in humans can manifest in a spectrum of disease from asymptomatic infection to a mildly febrile symptomatic illness to a life-threatening disease affecting the central nervous system (CNS). The latter is associated with a high morbidity and mortality as well as long-term neurologic sequelae. The pathogenesis and disease severity of JE is discussed elsewhere in this volume. JE is the most common cause of encephalitis in most of Asia and causes an estimated 35,000 cases of encephalitis annually (Igarashi 1992). By all accounts this is an underestimate of the true disease burden of this virus and evidence suggests that this virus is endemic over a far wider region today than 50 years ago, despite the use of an effective vaccine for humans and animals.

TLR4 as the Mammalian Endotoxin Sensor

Abstract: For more than a century, the ability to sense endotoxin (later known also as lipopolysaccharide; LPS) stood as the archetypal innate immune response: even before the phrase ‘innate immunity’ became popular. Yet the mechanism by which LPS initiated a signal remained unknown. The problem was solved in 1998 by positional cloning, which revealed that Toll-like receptor (TLR) 4, one of ten mammalian paralogues with homology to theDrosophila protein Toll, is the central component of the LPS receptor. During the 3 years that followed, gene knockout work supported the view that the TLRs perceive a number of indispensable molecular structures shared by diverse representatives of the microbial world. The highly specific LPS-sensing function of TLR4 is remarkable for its prevalence inMammalia, which to the present time is the only class of the phylumChordata known to have a gene encoding TLR4, and known to display exquisite sensitivity to LPS. The fact that LPS signals are elicited through a single biochemical pathway has raised important pharmacotherapeutic opportunities as well.

Pathogenesis and Clinical Features of Japanese Encephalitis and West Nile Virus Infections

Abstract: Japanese encephalitis (JE) virus is the most important cause of epidemic encephalitis worldwide with an estimated 30,000–50,000 cases annually (Solomon 2000). The geographical area affected by the virus is expanding, and despite the availability of vaccines, JE is a growing public health problem (Tsai 2000; Vaughn and Hoke 1992). The closely related West Nile (WN) virus is the most widely distributed member of the JE virus complex of flaviviruses. Until recently it was considered to be a relatively benign virus, causing epidemics of a fever—arthralgia—rash syndrome, and only occasional central nervous system (CNS) disease (Solomon and Cardosa 2000). However, its importance has grown with recent outbreaks of West Nile encephalitis (WNE) in Romania and New York (Anonymous 1999; Tsai et al. 1998). For both JE and WN viruses the number of people who present with clinical features represents only a small proportion of those infected. In addition, both diseases have a broad spectrum of clinical manifestations, ranging from a nonspecific febrile illness to a severe meningoencephalomyelitis (inflammation of the meninges, brain matter, and spinal cord). In this chapter, we will look at factors that determine who, of all those infected with JE or WN virus, develops disease. Secondly we will describe the clinical features of infection with JE and WN viruses and consider the extent to which pathophysiological and pathological studies explain these features. Finally we will consider the diagnosis and management of JE and WNE and the prospects for future therapies.

TLR2: cellular sensor for microbial and endogenous molecular patterns.

Abstract: Toll-like receptor (TLR) 2 is a member of the vertebrate protein family of TLRs that has been studied in substantial detail over the last years. The extracellular domain of the type I receptor molecule TLR2 contains 18 to 20 leucine rich repeat (LRR) and LRR like motives. The intracellular domain of TLR2 contains a Toll/IL-1 receptor/resistance protein typical TIR domain. After the first implication of TLR4 in immunity thereinafter followed by the discovery of the lipopolysaccharide signal transducer function of TLR4, TLR2 was the first of ten mammalian TLRs proven to be directly involved in recognition of pathogen associated molecular patterns (PAMPs). Among the TLR2 specific agonists are microbial products representing broad groups of species such as Gram-positive and Gram-negative bacteria, as well as mycobacteria, spirochetes, and mycoplasm. PAMP induced phagosomal localization of TLR2 and TLR2 dependent apoptosis have been shown. Complex formation with other molecules involved in pattern recognition such as CD14, MD2, TLR1, and TLR6 has been implicated for TLR2. Surprisingly even proteinaceous host material such as heat shock protein (HSP) 60 has been demonstrated to activate cells through TLR2. Thus, TLR2 may be a sensor and inductor of specific defense processes, including oxidative stress and cellular necrosis initially spurred by microbial compounds. Here we summarize the current knowledge on the structure and function of TLR2, which is far from being complete. Detailed understanding of the biology of TLR2 will probably contribute to the characterization of a number of infectious diseases and potentially help in the development of novel intervention strategies.

The ecology and epidemiology of West Nile virus in Africa, Europe and Asia.

Abstract: West Nile (WN) fever is a mosquito-borne flavivirus transmitted in natural cycles between birds and mosquitoes, particularly Culex species mosquitoes.

Genomic organization of LPS-specific loci.

Abstract: Lipopolysaccharide (LPS) genes have many of the characteristics of PAIs but also differ in significant ways. Lipopolysaccharide differs from the products of most PAI genes in that it is an essential component of the cell, and mutants totally lacking LPS are not found. However parts of the molecule such as the O antigen are not essential for growth in laboratory media, but in general are required for survival in the natural environment. For example, in many pathogens complete LPS is required for survival in the host, and in this these discretionary components do resemble the products of PAI genes. Many of the genes for these discretionary components occur in discrete clusters and these gene clusters share many properties with PAIs.

Biology and Pathogenesis of Lymphocytic Choriomeningitis Virus Infection

Abstract: The strength of the lymphocytic choriomeningitis virus (LCMV) model rests on the following five foundations. First, the virus in vivo in its natural host, the mouse, or in vitro in cultured cells is non-cytolytic. This quality allows clear separation of effects caused by the virus from those caused by the host immune system. Consequently, the host cell control of viral infection as opposed to how virus interacts with cells to distort their functions without killing them can be decoded. Second, reactions to LCMV infection can encompass a widely diverse range of immune responses (Fig. 1). Usually when immunocompetent adult mice are injected with LCMV, they generate a marked immune response to eliminate the infectious agent. Although their innate responses include the production of interferon (IFN), macrophages and natural killer (NK) cells (Muller et al. 1994; see reviews Buchmeier et al. 1980; Borrow and Oldstone 1997; see chapter by Biron et al., this volume), it is the adoptive immune response — primarily the virus-specific CD8+ CTL response — that is responsible for virus clearance.

West Nile virus in livestock and wildlife.

Abstract: WN virus is one of the most ubiquitous arboviruses occurring over a broad geographical range and in a wide diversity of vertebrate host and vector species. The virus appears to be maintained in endemic foci on the African continent and is transported annually to temperate climates to the north in Europe and to the south in South Africa. Reports of clinical disease due to natural WN virus infection in wild or domestic animals were much less common than reports of infection (virus isolation or antibody detection). Until recently, records of morbidity and mortality in wild birds were confined to a small number of cases and infections causing encephalitis, sometimes fatal, in horses were reported infrequently. In the period 1996-2001, there was an increase in outbreaks of illness due to WN virus in animals as well as humans. Within the traditional range of WN virus, encephalitis was reported in horses in Italy in 1998 and in France in 2000. The first report of disease and deaths caused by WN virus infection in domestic birds was reported in Israel in 1997-1999, involving hundreds of young geese. In 1999 WN virus reached North America and caused an outbreak of encephalitis in humans in the New York area at the same time as a number of cases of equine encephalitis and deaths in American crows and a variety of other bird species, both North American natives and exotics. Multi-state surveillance for WN virus has been in place since April 2000 and has resulted in the detection of WN virus in thousands of dead birds from an increasing number of species in North America, and also in several species of mammals. The surveillance system that has developed in North America because of the utility of testing dead birds for the rapid detection of WN virus presence has been a unique integration of public health and wildlife health agencies. It has been suggested that the recent upsurge in clinical WN virus infection in wild and domestic animals as well as in humans may be related to the emergence of one or more new strains of WN virus. Virus isolated in New York in 1999 was found to be identical to that from Israel. It was alarming for WN virus to so easily invade the United States and surprising that it became established so quickly in the temperature climate of New York. Its persistence and rapid expansion in the United States leave a number of unanswered questions. New disease characteristics and patterns have occurred and more are evolving as WN virus further invades the western hemisphere. Additional animal research is needed to answer these questions. Some of the research needs include bird migration as a mechanism of virus dispersal, vector and vertebrate host relationships, virus persistence mechanisms, laboratory diagnosis, viral pathogenesis, risk factor studies, vaccine development, and WN virus impact on wildlife (CDC 2001a). Determination of the primary reservoir host species that are involved in the epidemiology of WN virus and the suitable sentinel species for active surveillance are also important research areas.

Human infection with arenaviruses in the Americas.

Abstract: Numerous arenaviruses exist in the Americas as parasites of rodents belonging to the family Muridae, subfamily Sigmodontinae, 14 have been described (Buchmeier et al. 2001; Bowen et al. 1997). Little is known about how these viruses interact with their rodent hosts and what diseases are caused when the viruses spill over into humans. In addition, the Americas host one Old World arenavirus, Lymphocytic choriomeningitis virus, which was introduced in post-Columbian times with its host, Mus musculus.

Subversion of Host Defense Mechanisms by Adenoviruses

Abstract: Adenoviruses (Ads) cause acute and persistent infections. Alike the much more complex herpesviruses, Ads encode numerous immunomodulatory functions. About a third of the viral genome is devoted to counteract both the innate and the adaptive antiviral immune response. Immediately upon infection, E1A blocks interferon-induced gene expression and the VA-RNA inhibits interferon-induced PKR activity. At the same time, E1A reprograms the cell for DNA synthesis and induces the intrinsic cellular apoptosis program that is interrupted by E1B/19K and E1B/55K proteins, the latter inhibits p53-mediated apoptosis. Most other viral stealth functions are encoded by a separate transcription units, E3. Several E3 products prevent death receptor-mediated apoptosis. E3/14.7K seems to interfere with the cytolytic and pro-inflammatory activities of TNF while E3/10.4K and 14.5K proteins remove Fas and TRAIL receptors from the cell surface by inducing their degradation in lysosomes. These and other functions that may afect granule-mediated cell death might drastically limit lysis by NK cells and cytotoxic T cells (CTL). Moreover, Ads interfere with recognition of infected cell by CTL. The paradigmatic E3/19K protein subverts antigen presentation by MHC class I molecules by inhibiting their transport to the cell surface. In concert, these viral countermeasures ensure prolonged survival in the infected host and, as a consequence, facilitate transmission. Elucidating the molecular mechanisms of Ad-mediated immune evasion has stimulated corresponding research on other viruses. This knowledge will also be instrumental for designing better vectors for gene therapy and vaccination, and may lead to a more rational treatment of life-threatening Ad infections, e.g. in transplantation patients.

Bacillus anthracis genetics and virulence gene regulation.

Abstract: The Bacillus anthracis genome consists of an approximately 5.3-Mb chromosome and two plasmids, pXO1 (182 kb) and pXO2 (96 kb). Genetic analysis has focused primarily on the structural genes for the anthrax toxin proteins, pagA, lef, and cya, the biosynthetic genes for capsule synthesis, capB, capC, and capA, and a gene associated with depolymerization of capsule, dep. The three toxin genes are located at distinct loci on pXO1, while the cap and dep genes are arranged in an apparent operon on pXO2. Additional genes that may play a role in B. anthracis virulence include the germination operon gerX and the general stress transcription factor sigB. Host-related signals affecting transcription of the toxin and capsule genes include temperature (37°C) and bicarbonate/CO2. The B. anthracis plasmids carry two regulatory genes that share little sequence similarity with regulators in other bacteria. The pXO1-encoded gene atxA positively controls expression of the toxin and capsule genes, and has been implicated in control of other genes of unknown function. atxA mutants are avirulent in mice, and mice infected with atxA-null strains show a decreased immunological response to the toxin proteins. The pXO2-encoded regulator, acpA, shares sequence similarity with atxA. Yet acpA function appears to be restricted to positive control of capsule gene expression. The chromosomal gene abrB, a homologue of a well-characterized B. subtilis transition state regulator, controls growth phase-specific transcription of the toxin genes. Genetic manipulation of B. anthracis can be achieved by using natural means of DNA transfer and by electroporation of recombinant DNAs into B. anthracis. Genetic exchange can occur between B. anthracis strains and between B. anthracis and closely-related species. Although pXO1 and pXO2 are not self-transmissible, these plasmids and others can be transferred by conjugative plasmids originating in B. thuringiensis. Generalized transducing phage that permit inter-species transfer of chromosomal and plasmid DNA have also been described.

The Role of Birds in the Ecology of West Nile Virus in Europe and Africa

Abstract: The aim of this chapter is twofold; firstly, to review the literature published since the comprehensive review of Hayes in 1989, and second, to summarize some of the data accumulated during the recent West Nile (WN) virus epizootic in Israel during 1997–2001 including an evaluation of bird migration in the region.

Evolution of the TIR, tolls and TLRs: functional inferences from computational biology.

Abstract: The mammalian toll-like receptors (TLRs) are products of an evolutionary process that began prior to the separation of plants and animals. The most conserved protein motif within the TLRs is the TIR, which denotes Toll, the Interleukin-l receptor, and plant disease Resistance genes. To trace the ancestry of the TLRs, it is desirable to draw upon the sequences of TIR domains from TLRs of diverse vertebrate species, including species with known dates of divergence (i.e., representatives of Mammalia and Aves) in order to establish a relationship between time and genetic divergence. It appears that a gene ancestral to modern TLRs 1 and 6 duplicated approximately 130 million years ago, only shortly before the speciation event that led to humans and mice. Though it is not represented in mice, TLR10 split from the TLR[l/6] precursor about 300 million years ago. The origins of other TLRs are more ancient, dating to the origins of vertebrate life, and some present-day vertebrate species appear to have many more TLRs than others. Moreover, the patterns of TLR expression are quite variable at the level of tissues, even among closely related species. A given TLR in species that are related by descent from a common ancestor may acquire different duties within each descendant line, so that some microbial inducers are avidly recognized in one species but not in others; likewise the intensity and the anatomic location of an innate immune response may vary considerably. In this review, we discuss the computational methods used to analyze divergence of the TIR, and the conclusions that may be safely drawn.

MyD88 as a Bottle Neck in Toll/IL-1 Signaling

Abstract: Myeloid differentiation factor 88 (MyD88) is an adaptor molecule composed of an N-terminal death domain and a C-terminal Toll/interleukin (IL)-1R homology domain. Ligand binding to Toll-like receptor (TLR)/IL-1R family members results in the association of MyD88 to the cytoplasmic tail of receptors; this then initiates the signaling cascade that leads to the activation of nuclear factor-кB and mitogen-activated protein kinases. Analysis of MyD88-deficient mice revealed its essential role in TLR/IL-1R signaling as well as in both the innate and the adaptive immune response.

Introduction: anthrax history, disease and ecology.

Abstract: The familiarity with the ancient disease anthrax from the second millennium b. c. through the second millennium a.d. is reviewed, providing the backdrop to the modern understanding of this disease as covered in the remainder of the volume.By means of an overview of the aetiology, ecology, epidemiology, clinical manifestations, pathology and bacteriology of the naturally acquired disease, this opening chapter also lays down the groundwork for the subsequent state-of-the-art chapters.

Japanese encephalitis as an emerging virus: the emergence and spread of Japanese encephalitis virus in Australasia.

Abstract: Japanese encephalitis (JE) virus has a great propensity to spread, expanding its range through much of southeastern Asia in the past four decades (Umenai et al. 1985; Burke and Leake 1988; Vaughn and Hoke 1992; Monath and Heinz 1996). In the 1990s, JE spread into southern Pakistan (Igarashi et al. 1994) and to Haryana State (Prasad et al. 1993) and Kerala State (Dhanda et al. 1997) in northwestern and southwestern India, respectively. In the east, JE has invaded the eastern Indonesian archipelago, New Guinea, and the Torres Strait of northern Australia (Hanna et al. 1996b; Mackenzie et al. 1997a). The eastward spread of JE from the Oriental to the Australasian zoogeographic region and the threat this poses to the Pacific is the focus of this chapter. It is also interesting to note that there are also certain parallels in the emergence of JE in the Australasian region with the recent emergence of West Nile (WN) virus in North America, and particularly the emergence of the two viruses in novel zoogeographic regions.

Arenaviruses: Genomic RNAs, transcription, and replication

Abstract: The arenavirus genome comprises two single-stranded RNA molecules of negative polarity, designated L and S, that contain essentially nonoverlapping sequence information (for extensively referenced reviews see Buchmeier et al. 1980; Lehmann-Grube 1984; Howard 1986; Salvato 1993a; Southern 1996). There is some variability in the lengths of the genomic RNA segments for individual arenaviruses (L approximately 7,200 bases, S approximately 3,400 bases), but the general organization of the L and S genomic RNA species appears to be well conserved across the virus family. An extensive compilation of arenavirus genomic RNA sequence is now available, and this information has been used to derive phylogenetic relationships amongst the known arenaviruses (Bowen et al. 1997; Albarino et al. 1998). Sequence alignments have also facilitated the development of a generalized scheme to amplify arenavirus genomic RNAs by RT-PCR (Lozano et al. 1997) This innovative diagnostic resource, together with a specific RT-PCR assay for LCMV (Park et al. 1997), should have a significant positive impact on the rapid recognition and characterization of new arenavirus infections.

The Ecology and Epidemiology of Kunjin Virus

Abstract: Kunjin (KUN) virus has long been considered an arbovirus of minor medical and veterinary significance in Australia, with human infections associated with a mild febrile illness and rare reports of encephalitis in both horses and man. However its close relationship to a more virulent Australian arbovirus, Murray Valley encephalitis (MVE) virus, in terms of epidemiology, ecology and cross-reactivity in traditional serological diagnostic assays has necessitated that the activity of both viruses be carefully monitored in surveillance of mosquito-borne viruses in Australia. For a thorough discussion on the history, ecology and epidemiology of MVE and KUN viruses the reader is referred to an extensive review by Marshall (1988).Of more recent relevance, are the outbreaks of a fatal viral encephalitis in Europe, Russia, North America and the Middle East caused by strains of West Nile (WN) virus shown to be genetically closely related to KUN virus (Tsai et al. 1998; Briese et al. 1999; Jia et al. 1999; Lanciotti et al. 1999; Platonov et al. 2001; Hindiyeh et al. 2001). These events have stimulated additional interest in WN virus and its relationship to KUN virus with respect to taxonomy, and clinical and ecological comparisons. The purpose of this report is to review briefly the ecology and epidemiology of KUN virus, and to discuss methods of surveillance, diagnosis and control, with pertinent comparisons to WN and MVE viruses. Brief reference will also be made to the recent changes in the phylogeny and taxonomy of KUN in relation to WN virus; however, this aspect is covered in depth by Scherret et al., in this volume.

The Emergence of West Nile Virus in North America: Ecology, Epidemiology, and Surveillance

Abstract: The discovery of the flavivirus, West Nile (WN) virus, in the summer of 1999 in the USA dramatically altered the landscape of arthropod-borne virus (arbovirus) disease ecology and epidemiology in the western hemisphere Arboviruses capable of causing human encephalitis exist throughout much of North America, but large epidemics or epizootics have not occurred since the last major outbreak of St Louis encephalitis (SLE) in the 1970s (Bruetman et al 1976; Levy et al 1978; Maetz et al 1978; Paulson and Brinker 1978; Powell and Blakey 1976, 1977; Powell and Kappus 1978; Zweighaft et al 1979) Because of the sporadic nature of arboviral diseases, it has been difficult to mobilize political and public support for funding needed to maintain effective arboviral surveillance and control programs The loss of this infrastructure has made much of the USA potentially vulnerable to new mosquito-borne disease outbreaks The complex and multi-factorial biology of arboviral diseases makes re-establishing the expertise needed to prevent and control human disease outbreaks very difficult Therefore, regions of the USA that for years have been spared from these diseases, now must evaluate their need for establishing or rebuilding programs for mosquito-borne disease prevention and control, given the introduction and rapid spread of WN virus in the northeastern USA WN virus also poses a threat to wildlife and domestic animals, with high fatality rates among a wide variety of avian species and equines Therefore, wildlife and veterinary health officials need to work in concert with their human health counterparts in responding to WN virus

Mammalian reservoirs of arenaviruses.

Abstract: Arenaviruses are negative-stranded RNA viruses that have been isolated from several species of mammals in various parts of the world. With two exceptions, these viruses have all been isolated from rodents of the family Muridae — sensu Musser and Carleton (1993). Tacaribe virus was originally isolated from fruit-eating bats of the genus Artibeus, while Sabia virus has no known wild reservoir. Arenavirus infections in their rodent reservoirs are characterized by persistent shedding of infectious virus in the urine (Johnson 1970).

Potential vectors of West Nile virus in North America.

Abstract: The recent outbreak of illness due to infection with West Nile (WN) virus in the New York City metropolitan area (CDC 1999a,b; Lanciotti et al. 1999) represents the first documented introduction of WN virus into the New World. This virus is enzootic in Africa, Asia (east to the Indian highlands), and southern/central Europe. In addition, Kunjin virus, a virus closely related to WN virus (Lanciotti et al. 1999), is found in much of northern Australia.

Junin Virus Vaccines

Abstract: Argentine hemorrhagic fever (AHF) was recognized as a new clinical entity from the richest farming region of Argentina in the 1950s (Arribalzaga 1955) The etiologic agent of this disease, Junin virus (JUN), was isolated in 1958 (Parodi et al 1958; Piroski et al 1959) JUN belongs to the Arenaviridae family, which includes other rodent-borne pathogens which are important causes of hemorrhagic fever in Africa, (Lassa) and South America (Machupo, Guanarito, and Sabia viruses) The Arenaviridae comprises at least 20 recognized members Arenaviruses are enveloped RNA viruses, and are divided into two groups, with low level antigenic relatedness: the Old World group, and New World group or Tacaribe complex Two antigenic subgroups were defined within the New World arenaviruses JUN is contained into the first group, together with Amapari, Latino, Machupo and Tacaribe viruses Phylogenetic analysis have shown that Old World and New World arenaviruses occupied two distinct clades, and that New World arenaviruses comprise three evolutionary lineages, named A, B, and C JUN is contained in lineage B, together with the other three agents causing South American hemorrhagic fevers (Enria et al 1999a)

Lymphocytic choriomeningitis virus and immunology.

Abstract: I. Neonatal tolerance, absence of immunity after intra-uterine or neonatal infection (TRAUB 1936, 1938). The comprehensive view and interpretation was made by BURNET (1949). 2. Immunity can cause disease (RowE 1954; HOTCHIN 1962). 3. Different LCMV isolates and mutants exhibit distinct tropism and distinct immunopathological diseases (HOTCHIN 1962; JACOBSON 1980; AHMED et al. 1984). 4. Immunity controls virus only partially, since virus survives at low levels (infection-immunity) (RowE 1954; VOLKERT and LUNDSTEDT 1968; CIUREA et al. 1999), but adoptive cytotherapy of virus-carriers (OLDSTONE et al. 1986) is possible by CD8 + T cells and/or CD4 + T cells plus neutralizing antibodyproducing B cells (VOLKERT 1963; PLANZ et al. 1997). 5. Immune complexes in neonatal virus-carriers question B cell tolerance (OLDSTONE and DIXON 1967). 6. Cytotoxic T cells (CTLs) against virus-infected cells act comparably to alloreactive CTLs (OLDSTONE and DIXON 1970; MARKER and VOLKERT 1973). 7. CTLs cause lethal pathology in the form of T cell-mediated choriomeningitis (COLE et al. 1972). 8. T cells (MIMS and BLANDEN 1972), (in particular CTLs, DOHERTY et al. 1976; ZINKERNAGEL and WELSH 1976) also mediate anti-viral protection against LCMV, as had first been shown for ectromelia virus by R.V. Blanden. 9. MHC disease association of choriomeningitis (OLDSTONE et al. 1973; ZINKERNAGEL et al. 1985) and of aggressive hepatitis (LEIST et al. 1989). 10. CTLs recognize a combination of MHC plus viral antigen (MHC restriction) (ZINKERNAGEL and DOHERTY 1974). Heterozygous MHC expands T cell repertoire and response (hybrid vigor) (DOHERTY and ZINKERNAGEL 1975). MHC class I regulates cytotoxic T cell immune response (DOHERTY et al. 1978; ZINKERNAGEL et al. 1978).

Japanese encephalitis vaccines: current vaccines and future prospects.

Abstract: Eighty million children are born annually in countries where Japanese encephalitis (JE) is endemic and epidemic (Table 1). Exposure to JE virus occurs in childhood, and antibody prevalence is 80%–100% in adults. One in 300 persons infected by JE virus becomes ill (Halstead and Grosz 1962). Approximately 35,000 cases of JE are reported annually, but the true incidence is higher due to inadequate surveillance and reporting. The incidence of disease is estimated to range from 1 to 10 cases per 100,000 population in endemic areas, but during epidemics attack rates may exceed 600 per 100,000 (Igarashi 1992; Burke and Leake 1988; Tsai et al. 1999). The incidence of JE appears to be similar to that of Hemophilus influenzae B (Hib) meningitis and to poliomyelitis during the prevaccine era (Tsai 2000).

Structure and function of anthrax toxin.

Abstract: Anthrax toxin is a binary A-B toxin comprised of protective antigen (PA) and two enzymatic moieties, edema factor (EF) and lethal factor (LF). In the presence of a host cell-surface receptor, PA can mediate the delivery of EF and LF from the extracellular milieu into the host cell cytosol to effect toxicity.In this delivery, PA undergoes multiple structural changes — from a monomer to a heptameric prepore to a membrane-spanning heptameric pore. The catalytic factors also undergo dramatic structural changes as they unfold to allow for their translocation across the endosomal membrane and refold to preserve their catalytic activity within the cytosol. In addition to these gross structural changes, the intoxication mechanism depends on the ability of PA to form specific interactions with the host cell receptor, EF, and LF. This chapter presents a review of experiments probing these structural interactions and rearrangements in the hopes of gaining a molecular understanding of toxin action.

Replication and gene function in Kunjin virus

Abstract: Kunjin virus has for many years provided a useful model system for study of replication of Flaviviruses. A very close antigenic relationship between KUN virus strain MRM61C and West Nile (WN) virus strain Sarafend, both within the Japanese encephalitis (JE) virus antigenic group, was established previously by plaque neutralization tests (Westaway 1965), and by haemagglutination-inhibition tests in which IgM antibodies were required for specific diagnosis (Westaway 1968). KUN virus is distributed widely throughout Australia (see chapter by Hall et al., this volume) but in contrast to WN virus, it is very rarely isolated from man or associated with severe disease, and the genetic variation among many KUN virus isolates in Australia was estimated to be only about 1% (Mackenzie et al. 1994). The original sequence comparisons between KUN virus and WN virus (Wengler or Nigeria strain) indicated 79% nucleotide homology with 93% homology for deduced amino acid sequences (Cola et al. 1988). These data were adequate for separate Flavivirus species identity either according to the criterion specifying no more than 84% nucleotide sequence identity (Kuno et al. 1998) or by phylogenetic analysis of the amino acid sequences of NS5, the most conserved product (see Westaway and Blox 1997). However, the recent nucleotide sequence analysis of the WN virus New York (WN-NY99) strains involved in the 1999 epidemic of encephalitis in New York City established a very close phylogenetic relationship with KUN virus, especially in the highly conserved NS3 (99% amino acid identity) and NS5 genes (98.8% identity) (Jia et al. 1999; Lanciotti et al. 1999).

Toll-like receptor-5 and the innate immune response to bacterial flagellin.

Abstract: The innate immune system identifies the presence of infection by detecting structures that are unique to microbes and that are not expressed in the host. The bacterial flagellum (Latin, a whip) confers motility on a wide range of bacterial species. Vertebrates, plants, and invertebrates all have evolved flagellar recognition systems that are activated by flagellin, the major component of the bacterial flagellar filament. In mammals, flagellin is recognized by Toll-like receptor-5 and activates defense responses both systemically and at epithelial surfaces. Here, we review the role for Toll-like receptor-5 in mediating the mammalian innate immune response to flagellin, and how this provides for defense against infections caused by many different species of flagellated bacteria.