Showing papers in "Current Topics in Microbiology and Immunology in 1992"

Use of adeno-associated virus as a general transduction vector for mammalian cells.

Abstract: Adeno-associated virus (AAV) is a human virus that can be propagated either as an integrated provirus or by lytic infection (Atchison et al. 1965; Hoggan et al. 1966, 1972). The ability to form a latent infection appears to be an integral part of the AAV life cycle. Except under special circumstances (Yacobson et al. 1987; Schlehofer et al. 1986; Yalkinoglu et al. 1988), AAV requires the presence of a helper virus to initiate a productive viral infection (Fig. 1). Members of either the herpes or adenovirus families can provide the necessary helper functions (Atchison et al. 1965; Melnick et al. 1965; Hoggan et al. 1966; Buller et al. 1981; McPherson et al. 1985) and vaccinia virus can provide at least partial helper function (Schlehofer et al. 1986). In the absence of a helper virus AAV produces no progeny virus, but instead integrates into a host chromosome (Hoggan et al. 1972; Berns et al. 1975; Handa et al. 1977; Cheung et al. 1980). With rare exceptions, AAV proviruses appear to be stable. However, if a cell line that is carrying an AAV provirus (Fig. 1) is subsequently superinfected with a helper virus, the AAV genome is excised and proceeds through a normal productive infection (Hoggan et al. 1972; Cheung et al. 1980). This ability to establish a latent infection which can later be rescued appears to be a mechanism for ensuring the survival of AAV in the absence of a helper virus. The unusual life cycle of AAV has led a number of parvovirus laboratories to explore the possibility of using AAV as a general mammalian transduction vector.

RNA virus populations as quasispecies.

Abstract: This chapter discusses the high mutation frequencies and rapid evolution potential of RNA viruses. The concepts discussed are applicable to all “ordinary” RNA viruses (riboviruses), viroids and satellite RNAs; to retroviruses; and to viruses (such as the hepadnaviruses) with DNA genomes which replicate via RNA transcripts. Because DNA virus polymerases can have proofreading (Kornberg 1974), their mutation frequencies can be much lower than those of RNA viruses. For example, the mutation rate of bacteriophage T4 approximates 10−8 per base pair per replication (Drake 1969). However, some DNA viruses may avoid high-fidelity replication mechanisms (Drake et al. 1969; Hall et al. 1984) to gain the evolutionary advantages of high mutation frequencies (Smith and Inglis 1987).

Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis.

Abstract: Dysentery was well known and clearly described in many ancient texts and histories. The first step towards the description of the genus Shigella, however, was the identification of Entamoeba histolytica by Losch in 1875 and the separation of amebic from all other forms of dysentery (Losch, 1875). With this discovery, attention could be focused on the etiology of epidemic dysentery, and a partial description of the prototype Shigella sp., Shigella dysenteriae type 1, was published by Chantemesse and Widal in 1888. The definitive description of this organism was provided by Kiyoshi Shiga following an extensive dysentery epidemic in Japan in 1896 (Shiga 1898). It did not take long to determine that there was a potent toxic activity in this organism, and in 1900 Flexner reported that either living or killed cultures of Shiga’s bacillus injected into the peritoneal cavity of animals caused fever and diarrhea. Flexner concluded that shigellosis was due to a “toxic agent rather than to an infection per se”; however, the Observed effects were Probably due to endotoxin. The presence of a lethal toxin in extracts of heat-killed bacteria was shown independently by Neisser and Shiga (1903) and by Conradi (1903). Conradi (1903) also described the limb paralysis following parenteral inoculation of Shigella extracts in rabbits, characteristic of the so-called Shiga neurotoxin.

Emergence and Transmission of Influenza A Viruses Resistant to Amantadine and Rimantadine

Abstract: Many clinical studies have documented the efficacy of amantadine and rimantadine for prophylaxis and treatment of influenza A virus infections (Douglas 1990; Tominack and Hayden 1987). Antiviral activity has been demonstrated in various animal models of influenza (Hayden 1986) and during clinical use in humans (Douglas 1990). Amantadine- and rimantadine-resistant mutants have been recovered during studies in mice (Oxford et al. 1970, Oxford and Potter 1972), birds (Webster et al. 1985; Beard et al. 1987; Bean et al. 1989), and recently in children and adults treated with these drugs (Hall et al. 1987; Thompson et al. 1987; Belshe et al. 1988; Hayden et al. 1989). The impact of drug resistance on the clinical usefulness of these drugs is thus of obvious concern. Factors which may influence the clinical importance of drug-resistant viruses include their frequency and rapidity of emergence, genetic stability, transmissibility, pathogenicity, and ability to compete epidemiologically with wild-type viruses (Bean et al. 1989). The following sections review the limited information available from animal and human studies that address these characteristics and the correlation of these factors with particular resistance mutations.

Genetic Diversity and Evolution of Retroviruses

Abstract: Retroviruses are one of the most widespread and probably the most biologically diverse group of infectious agents of vertebrates. Virtually all mammals—as well as some birds, reptiles, and fish—have yielded infectious retroviruses when examined sufficiently closely. Within a species, the viruses isolated can display considerable diversity of biological properties. For example, within the group of closely related murine leukemia viruses are found agents which differ in receptors used for infection; in mode of transmission for genetic (as endogenous germline proviruses) to horizontal and vertical (via milk or infection in utero); in pathogenicity from benign to highly virulent; and in disease spectrum from a variety of malignancies of varying latency to immunodeficiencies, anemias, neurological diseases, and others.

The biology of CSF-1 and its receptor.

Abstract: The constant renewal of blood cells in vertebrate species depends on the proliferation and differentiation of hematopoietic stem cells in the bone marrow (Harrison et al. 1988). These cells in turn give rise to progenitor cells which are committed to more restricted pathways of differentiation. The survival, proliferation, and differentiation of these progenitor cells are regulated by the colony stimulating factors (CSFs), so named because of their ability to promote the in vitro proliferation and differentiation of single progenitor cells into macroscopic colonies with discernible differentiated cell types (Pluznik and Sachs 1965; Bradley and Metcalf 1966; Ichikawa et al. 1966). This group of hematopoietic growth factors includes interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin-5 (IL-5), and colony stimulating factor-1 (CSF-1) (reviewed in STANLEY and JUBINSKY 1984; METCALF 1986).

Expression of heterologous sequences in adenoviral vectors.

Abstract: Adenoviruses (Ad) have served as outstanding agents in contributing to an understanding of transformation and regulation of gene expression in cultured cells (reviewed in Tooze 1981; Doerfler 1983, 1984; Ginsberg 1984). Three decades after their original isolation (Rowe et al. 1953) 41 serotypes of Ad which cause infections in over a dozen species have been identified. Initial classification was based on immunological criteria and on turmorigenicity in immunocompetent rodents, which ranges from highly oncogenic (e.g., Ad 12) to generally nononcogenic (e.g., Ad2 and Ad5). More recently DNA homology has also been included as a criterion. Because they provided the first example of a human virus capable of inducing tumors in experimental animals and because Ad is capable of transformation in vitro, there was obvious, immediate interest in them. Subsequent revelation that the Ad heavily employs much of the cellular machinery during its life cycle made the adenovirus family an excellent probe for dissecting macromolecular biosynthesis and expanded this interest. Adaptation of Ad as a vector for various applications was thus a natural consequence of the considerable wealth of information accrued about this virus. Establishing cell lines by transformation with Ad recombinants that contain heterologous genes was one obvious application. Another was its development as a vector for producing high level expression of heterologous genes, stimulated by the extremely efficient lytic expression of this virus.

Antigen markers of macrophage differentiation in murine tissues.

Abstract: Cell-restricted membrane antigens have made it possible to map the distribution of mature macrophages in many murine tissues. Monoclonal antibodies (mAbs) have been used to define the appearance of macrophages dusing foetal and postnatal development, to establish the anatomic relationships between macrophages and other cells in the normal and diseased adult, and to investigate cellular modulation and heterogeneity within different microenvironments. Current studies have illustrated the complex differentiation pathway of mononuclear phagocytes in vivo and have raised questions concerning the mechanisms that determine monocyte entry, migration and fate within tissues. Macrophages constitute a major, widely dispersed system of cells that regulate homeostasis in the normal host and respond to tissue injury by contributing essential functions during inflammation and repair. In this review we consider several membrane marker antigens which have proved useful in studying the life history and biologic properties of macrophages, and relate immunochemical studies on antigen expression to lineage analysis and macrophage differentiation in vivo. We restrict our discussion to the mouse, in which it is possible to manipulate the system in its entirety. Where known, properties of macrophages in other species are broadly similar.

Macrophage-derived growth factors.

Abstract: In the early decades of the twentieth century biologists sought to grow cells in culture. Clotted blood was found to contain molecules that accomplished this purpose (Carrel 1912), but only later did biochemists seek to purify these molecules. By the middle of the century, biochemists and biologists sought to explain neonatal eye opening in mice in molecular terms (Cohen 1987; Levi-Montalcini 1987). Each of these goals ultimately led to the isolation of single species of molecules called growth factors by using in vitro or in vivo bioassays for growth and a biochemical algorithm for isolation. Epidermal growth factor (EGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), interleukin-1 (IL-1), and macrophage colony-stimulating factor (M-CSF, or CSF-1) were isolated and directly sequenced or molecularly cloned (based on partial sequences) by these means in the 1970s and early 1980s. The production of transformed foci of cells by introduction of fragments of cloned transcripts or genes from tumors also produced a subclass of oncogenes that turned out to be growth factors [c-sis, or PDGF-B chain, and Kaposi’s sarcoma-fibroblast growth factor (kFGF, or FGF-4)]. Most recently, the formation of tumors in vivo after random integration of a highly active viral promoter upstream of cellular genes has produced the int-1 and int-2 (also known as FGF-3) growth factors. Finally, after the founding member of a growth factor family is identified with a bioassay, low-stringency cDNA library screens and polymerase chain reaction can be used to complete the family (JAKOWLEW et al. 1988; HEBERT et al. 1990). All growth factors are operationally isolated and defined by their ability to cause growth, but may also act as nonmitogenic inflammatory factors.

The role of T cell immunity in control of herpes simplex virus.

Abstract: Since their characterization in the mid-1960s, thymus-derived, or T lymphocytes have been shown to participate in virtually every process of mammalian immunity. This participation can take the form of response modification, mediated by secreted physiologically active cytokines, or direct effector activity, as exemplified by cell-mediated cytolysis and the inhibition of viral replication by interferon-γ (IFN-γ).

Foot-and-mouth disease virus populations are quasispecies.

Abstract: The term “quasispecies” describes complex distributions of replicating molecules subject to mutation and competitive selection (Eigen 1971; Eigen and Schuster 1979; Eigen and Biebricher 1988). The original theoretical concept of Eigen and colleagues concerned populations of infinite numbers of individual molecules and ideal, steady-state equilibrium conditions (recent review on the theoretical concept in Eigen et al. 1989). It is clear that in spite of their large population size, RNA viruses deviate from such idealized behaviour. However, several key features of RNA viruses such as nucleotide sequence heterogeneity, generally high mutation rates, and potential for very rapid evolution are best understood in the framework of the quasispecies concept (see the chapter by Holland et al.). Viral isolates, either in their natural niche or disturbed by adaptation to growing in cell culture, consist of a multitude of viable and defective mutants termed the “mutant spectrum” of the population. During replication, each genomic distribution is dominated by one (or several) “master sequence (s),” that generally coincides with the average or consensus sequence of the population. With the levels of genetic heterogeneity for foot- and-mouth disease virus (FMDV) documented in the following paragraphs, the master sequence often represents as little as 1% or less of the population of molecules, and it may have a brief life span. Here we review the evidence for the quasispecies structure of FMDV and its biological implications, notably the antigenic diversity of this widespread pathogen.

Clostridium botulinum C3 ADP-ribosyltransferase

Abstract: During the last few years various clostridial ADP-ribosylating exoenzymes have been described. These exoenzymes can be divided into two groups. One group is represented by clostridial cytotoxins which are characterized by their ability to ADP-ribosylate actin. Furthermore, all these toxins are binary in structure and consist of a binding component and an unlinked ADP-ribosyltransferase. Members of this family of clostridial ADP-ribosylating toxins are Clostridium botulinum C2 toxin, Clostridium perfringens toxin, and Clostridium spiroforme toxin. These toxins are described in detail by Aktories et al., in this volume. The other group of clostridial ADP-ribosylating exoenzymes is represented by C. botulinum ADP-ribosyltransferase C3 and by the novel ADP-ribosylating Clostridium limosum exoenzyme.

Effects of the membrane attack complex of complement on nucleated cells.

Abstract: In the last quarter of the nineteenth century several workers described the heatlabile lytic action of serum on bacteria and erythrocytes, and it was these observations which led to the discovery of the complement system (Nuttal 1888; Bordet 1898; Ehrlich and Morgenroth 1899). These lytic activities were subsequently shown to be mediated by the final stage in the complement system, the membrane attack complex (MAC). Given this history it is therefore perhaps not surprising that, until very recently, the MAC was considered by the majority of immunologists to be a lytic entity, the sole role of which was kill target cells. The concept that the MAC might cause more subtle (and often more pathologically relevant) changes in target cells has only recently gained widespread acceptance. The concept is of particular relevance when the targets are nucleated and metabolically active, although important nonlethal changes may also be induced in non-nucleated cells (see Chap. 7).

Evolutionary Processes in Influenza Viruses: Divergence, Rapid Evolution, and Stasis

Abstract: Interspecies transmissions combined with isolation of host species contribute to the evolutionary divergence of viruses because of the separation of host-specific virus gene pools. Barriers to frequent interspecies transmissions maintain the separation of progeny and parent virus gene pools and allow independent evolution of host-specific strains. These barriers may be in the form of infrequent likelihood of transmission because of different ecologies of host species, a lack of infectivity of the virus in new hosts, or interference from established viruses mediated by host immunity. Partitioning of avian influenza virus gene pools can result from geographic separation of waterfowl populations by separation of flyways and breeding and overwintering grounds. This mechanism has been suggested for the divergence of H4 hemagglutinin lineages in avian viruses (Donis et al. 1989). The subdivision of host populations provides a great deal of heterogeneity to virus populations and enhances the maintainence of a large number of virus subtypes.

Membrane Cofactor Protein

Abstract: Membrane cofactor protein (MCP, CD46) is a widely distributed regulatory protein that inhibits complement activation on host cells. Except for erythrocytes, it has been found on every cell examined (Liszewski et al. 1991 ). Cole et al. (1985) originally identified MCP as a third class, in addition to CR1 and CR2, of electrophoretically distinct, C3 binding, membrane proteins of human peripheral blood leukocytes. Initially termed gp45–70, to reflect its electrophoretic mobility on SDS-PAGE, the common name was changed to MCP when its cofactor activity was recognized (Seya et al. 1986). MCP was hypothesized and subsequently found to belong to a family of structurally, functionally, and genetically related proteins collectively termed the regulators of complement activation (RCA) (DeCordoba et al. 1984, 1985; Holers et al. 1985; Hourcade et al. 1989). Recently, MCP was given its leukocyte differentiation number (CD46) and a monoclonal antibody (E4.3) was designated as the standard typing reagent (Hadam 1990; Purcell et al. 1989a). This chapter will review our current understanding of the structure and function of MCP, emphasizing recent contributions made possible by molecular analyses (Post et al. 1991).

Genetic recombination in RNA viruses.

Abstract: Recombination in RNA viruses involves the exchange of genetic information between two nonsegmented RNA genomes, as distinct from the reassortment of RNA seen in viruses containing segmented genomes. The mechanism of RNA recombination appears to be similar to the generation of defective interfering (DI) RNA, since they both involve polymerase jumping during RNA synthesis. However, unlike the production of DI RNA, which is a relatively common phenomenon among RNA viruses, RNA recombination has so far only been demonstrated in a few RNA viruses. Homologous RNA recombination, which is defined as the exchange of two comparable RNA regions at precise locations, was first detected in poliovirus by Hirst (1962) and Ledinko (1963) in the early 1960s. Soon after, another member of the pircornavirus family, foot-and-mouth disease virus (FMDV), an aphthovirus, also was shown to undergo recombination (Pringle 1965). Subsequently, a series of temperature-sensitive (ts) mutants was used to determine recombination frequencies and do obtain a linear genetic recombination map (Cooper 1968, 1977). The definitive evidence for the occurrence of RNA recombination eventually came from the biochemical analysis of protein and RNA structure of the recombinant viruses (King et al. 1982). The second virus family to be shown to undergo RNA recombination is coronavirus (Lai et al. 1985). And more recently, several plant viruses, including brome mosaic virus and cowpea chlorotic mottle virus, also have been shown to undergo RNA recombination in rare situations (Bujarski and Kaesberg 1986; Allison et al. 1990). Thus, RNA recombination is being recognized increasingly as a general biological phenomenon among RNA viruses and probably plays an important role in viral biology and virus evolution. This chapter will deal mainly with homologous RNA recombination and will not discuss DI RNA, which is one form of nonhomologous RNA recombination.

Mononuclear phagocytes as targets, tissue reservoirs, and immunoregulatory cells in human immunodeficiency virus disease.

Abstract: We have presented evidence in this review for the following: 1. Macrophages are likely the first cell infected by HIV. Studies document recovery of HIV into macrophages in the early stages of infection in which virus isolation in T cells is unsuccessful and detectable levels of antibodies against HIV are absent. 2. Macrophages are major tissue reservoirs for HIV during all stages of infection. Unlike the lytic infection of T cells, many HIV-infected macrophages show little or no virus-induced cytopathic effects. HIV-infected macrophages persist in tissue for extended periods of time (months) with large numbers of infectious particles contained within intracytoplasmic vacuoles. 3. Macrophages are a vector for the spread of infection to different tissues within the patient and between individuals. Several studies suggest a "Trojan horse" role for HIV-infected macrophages in dissemination of infectious particles. The predominant cell in most bodily fluids (alveolar fluid, colostrum, semen, vaginal secretions) is the macrophage. In semen, for example, the numbers of macrophages exceed those of lymphocytes by more than 20-fold (Wolf and Anderson 1988). 4. Macrophages are major regulatory cells that control the pace and intensity of disease progression in HIV infection. Macrophage secretory products are implicated in the pathogenesis of CNS disease and in control of viral latency in HIV-infected T cells. This litany of events in which macrophages participate in HIV infection in man parallels similar observations in such animal lentivirus infections as visna-maedi or caprine arthritis-encephalitis viruses. HIV interacts with monocytes differently than with T cells. Understanding this interaction may more clearly define both the pathogenesis of HIV disease and strategies for therapeutic intervention.

Genetic diversity and slow rates of evolution in New World alphaviruses.

Abstract: Alphavirus is a genus of arthropod-borne viruses (arboviruses) in the family Togaviridae. These viruses have a single-strand messenger or plus-sense RNA genome of ca. 11 700 bases. 42S genomic RNA is found in virions and infected cells; a subgenomic 26S RNA species, identical to the 3’-third of the 42S genomic messenger RNA (mRNA), is present only in infected cells and codes only for the structural proteins (Strauss and Strauss 1986; Schlesinger and Schlesinger 1990).

ADP-ribosylation of signal-transducing guanine nucleotide-binding proteins by pertussis toxin.

Abstract: The gram-negative bacterium Bordetella pertussis, the causative agent of whooping cough, produces a number of virulence factors, among which pertussis toxin is undoubtedly of major importance (Weiss and Hewlett 1986). Pertussis toxin elicits a myriad of biological effects in patients suffering from whooping cough or infected laboratory animals and has thus received several names, including histamine-sensitizing factor, lymphocytosis-promoting factor, islet-activating protein (IAP), or simply pertussigen.

Mutations and A/I hypermutations in measles virus persistent infections.

Abstract: The molecular biology of measles virus (MV) and of other nonsegmented negative strand RNA viruses is currently subject to intense scrutiny for several reasons. First, acute MV infection is among the primary causes of infant death in third world countries (Bloom 1989). Second, on rare occasions, MV persistence induces lethal syndromes of the central nervous system known as subacute sclerosing panencephalitis (SSPE) and measles inclusion body encephalitis (MIBE) (reviewed in Ter Meulen et al. 1983). Third, unexpected phenomena such as biased hypermutation and RNA editing recently have been described for these viruses (reviewed in Billeter and Cattaneo 1991; Cattaneo 1990).

Diphtheria toxin and Pseudomonas aeruginosa exotoxin A: active-site structure and enzymic mechanism.

Abstract: Diphtheria toxin (DT), secreted by lysogenic strains of Corynebacterium diphtheriae carrying the phage-encoded DT gene, was the first ADP-ribosylating toxin for which the molecular mechanism of action was elucidated (Collier 1975; Pappenheimer 1977), and for many years DT has served as an important model system for studying the pathogenesis of bacterial exotoxins (Collier 1982; Jacobson and Jacobson 1989; Moss and Vaughan 1990). DT and the closely related exotoxin A from Pseudomonas aeruginosa(ETA) both catalyze the ADP-ribosylation of a post-translationally modified histidine (diphthamide) on elongation factor 2 (EF-2) (Honjo et al. 1968, 1969; Gill et al. 1969; Iglewski and Kabat 1975; Iglewski et al. 1977). EF-2 is a GTP-binding protein involved in protein biosynthesis by eukaryotic cells. ADP-ribosylated EF-2 is no longer able to mediate polypeptide chain elongation, and consequently, toxin-treated cells lose the ability to synthesize protein and ultimately die. Although toxins have not yet been described in detail, recent studies have yielded relevant information. This chapter will focus on some of the more recent studies and what the findings tell us about the structure of the active site and’the nature of the reaction catalyzed by these toxins.

Paroxysmal Nocturnal Hemoglobinuria

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of the hematopoietic stem cell (Hartmann and Arnold 1977) resulting in the production of blood cells which are defective in that they lack or are markedly deficient in glycan-phosphatidylinositol (GPI)-linked surface proteins (Rosse 1990a). To date, 11 such proteins have been found to be missing or deficient on the abnormal cells (Auditore et al. 1960; Kunstling and Rosse 1969; Beck and Valentine 1951; Burroughs et al. 1988; Nicholson-Weller et al. 1983a; Pangburn et al. 1983; Holguin et al. 1989a; Hansch et al. 1987; Selvaraj et al. 1987,1988; Simmons et al. 1989; van der Schoot et al. 1989) (see Table 1). Other GPI-linked proteins that have not been identified are probably also missing.

Molecular and cellular biology of Shigella flexneri invasiveness: from cell assay systems to shigellosis.

Abstract: Also known as bacillary dysentery, shigellosis, an invasive disease of the human colon, is present worldwide. It is of particular concern in tropical regions, especially in overcrowded areas of the developing world, where Shigella flexneri causes the endemic form of the disease and Shigella dyseriteriae 1 devastating epidemics. Children are the most common victims of this disease which is principally transmitted by the fecal-oral route in areas having inadequate hygiene and sanitation.

The role of immune mechanisms in control of herpes simplex virus infection of the peripheral nervous system.

Abstract: Underlying the recurrent cutaneous lesions caused by herpes simplex virus (HSV) is a sophisticated virus-host relationship involving primary sensory neurons. These cells may become productively infected, but sometimes virus replication is interrupted for long periods, producing a reservoir of latent herpes in the nervous system from which infection can periodically reactivate. How the balance is tipped in favor of either productive or latent infection and how productive infection of neurons is rapidly controlled (which, in general, it is) are prominent contemporary questions for herpes virologists. In this chapter, we critically review the clinical and experimental evidence suggesting that the host’s adaptive immune response makes a vital contribution to the control of established HSV replication in the nervous system, and we dwell on the controversial issue of the fate of productively infected neurons.

Human immunodeficiency virus type 1 quasispecies in vivo and ex vivo

Abstract: This chapter will cover the extensive data now available for human immunodeficiency virus type 1 (HIV-1) and attempt to point out the particular aspects associated with HIV-1 quasispecies. It should not come as any surprise to realise that much work remains to be done. Nonetheless there are many features of HIV-1 which render it unique. A discussion of HIV-1 genetic variation and quasispecies in order to be meaningful must bear in mind the biology of the virus. Accordingly a brief outline is included so as to make subsequent discussion more fruitful.

Macrophages in the Uterus and Placenta

Abstract: Macrophages are abundant in the mesenchymal and connective tissue stroma of the cycling and pregnant uterus, and constitute a significant proportion of the villous or labyrinthine mesenchymal cells in the human and murid placenta In other contexts, the activities of these multifunctional cells are strongly influenced by regulatory molecules such as steroid hormones, polypeptide growth factors, and bioactive lipids All of these are present at particularly high concentrations in the pregnant uterus and placenta Thus, uterine and placental macrophages stimulated by endogenous factors could contribute to the complex cellular and molecular interactions that result in successful pregnancy

Lipopolysaccharide receptors and signal transduction pathways in mononuclear phagocytes.

Abstract: It is generally accepted that bacterial products are among the most potent stimuli leading to the activation of monocytes and macrophages. Of all the bacterial products which have been investigated during the past 50 years, the endotoxic lipopolysaccharides (LPS), derived from gram-negative microorganisms, have become recognized as the microbial activator of choice for many studies. This has, in part, been due to the fact that relatively low concentrations of LPS are required to effect macrophage stimulation. In addition, however, LPS may be obtained in highly purified form and active principle of LPS responsible for biologic activity has been identified and chemically characterized.

Decay accelerating factor (CD55).

Abstract: Complement is a mediator system comprised of 12 activation proteins and at least 11 inhibitors. The activation proteins interact sequentially to generate cleavage fragments and condensation products with specific and potent biologic activity. Activated complement proteins can function as anaphylatoxins, adherence factors, chemotaxins, opsonins, and a transmembrane pore, which can be lytic (reviewed in Fries and Frank 1987). Regulated complement activation is essential for the survival of the host, while unregulated complement activation contributes to inflammation and is detrimental to the host. Complement is regulated by the specificity of its activation, by the lability of its activation products, and by the potent inhibitors found in the fluid phase and within the membranes of host cells. The structure, function, and expression of one important membrane regulator of complement, namely, the decay accelerating factor (DAF), will be reviewed here.

Urokinase-catalyzed plasminogen activation at the monocyte/macrophage cell surface: a localized and regulated proteolytic system.

Abstract: In the adult organism, monocytes and macrophages are among the few cell types that can migrate within and between body compartments. To do so, they must have the capacity to clear for themselves a path through the macromolecular barriers of basement membranes and other extracellular matrices. This requires the controlled and localized degradation of matrix proteins by extracellular proteases. Mononuclear phagocytes can produce a number of such enzymes, including collagenolytic, elastinolytic, and gelatinolytic hydrolases (Takemura and Werb 1984). Because they can, directly or indirectly, catalyze the degradation of most components of extracellular matrices, plasminogen activators (PAs) are thought to play a key role in the proteolytic events that accompany the migration of a wide variety of cell types, during ontogeny as well as in pathologic circumstances. Monocytes and macrophages can produce PAs, and the regulation of their PA-dependent proteolytic activity has been a focus of attention in recent years. The findings of a number of investigators converge to suggest that the expression of PA activity is a tightly controlled phenotypic property of human and murine mononuclear phagocytes, and that multiple mechanisms act concurrently to achieve the exquisitely focused and regulated generation of plasmin precisely where and when it is needed to allow cell migration in the context of inflammatory reactions.

The baculovirus-infected insect cell as a eukaryotic gene expression system.

Abstract: Baculovirus-infected insect cell cultures are established as an easily manipulated eukaryotic system for highly efficient expression of gene products. The system takes advantage of several unique attributes of this virus group, including highly active late gene promoters, the capacity for insertion of large fragments of foreign DNA, replication competence of the resulting recombinants, and the relative ease of handling both the insect cell cultures and the viruses.