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Biomedical subjects

A F Slater

Publications and source records attributed to A F Slater.

At least 37 records · Page 2Linked to original sources
PubMed1995

Antioxidant inhibition of thymocyte apoptosis by dihydrolipoic acid.

Recent findings suggest that intracellular oxidants are involved in the induction of apoptosis, and that this type of cell death can be inhibited by various thiol-containing antioxidants such as N-acetyl cysteine. To study the effects of a physiologically important thiol reductant, rat thymocytes were preincubated with either lipoic acid, dihydrolipoic acid, or lipoamide and then exposed to methylprednisolone or etoposide, two stimuli known to induce apoptosis in these cells. Dihydrolipoic acid and lipoamide both exerted an inhibitory effect on apoptosis induced by the two stimuli, while lipoic acid was inactive. Inhibition of apoptosis was evident as (a) reduced formation of condensed, pyknotic nuclei; (b) a prevention of cell shrinkage; and (c) decreased chromatin degradation. Furthermore, the depletion of reduced glutathione that occurs as thymocytes undergo apoptosis was also prevented in the presence of DHLA. Investigation of the pattern of chromatin fragmentation revealed that DNA in the antioxidant-loaded thymocytes remained above 50 kb pairs in size, indicating that inhibition by DHLA was operative at an early step in the apoptotic pathway. These results suggest that intracellular oxidation is an obligate, early component of thymocyte apoptosis.

Animals↗
PubMed1995

Malaria-specific metabolite hemozoin mediates the release of several potent endogenous pyrogens (TNF, MIP-1 alpha, and MIP-1 beta) in vitro, and altered thermoregulation in vivo.

A characteristic feature of malaria infection is the occurrence of periodic bouts of fever. Experimental and clinical studies have strongly implicated inflammatory cytokines, like tumour necrosis factor (TNF), in the induction of these intermittent fevers [Clark et al., Infect Immunol 32:1058-1066, 1981; Clark et al., Am J Pathol 129:192-199, 1987; Karunaweera et al., Proc Natl Acad Sci USA 89:3200-3203, 1992], but the malaria-specific metabolite(s) which induce the production of such endogenous pyrogens have not yet been fully characterized. It is well known that during the course of malaria infection, a unique schizont component, alternatively referred to as "malaria pigment" or hemozoin, is released along with merozoites as the host erythrocyte bursts [Urquhart, Clin Infect Dis 19:117-131, 1994]. We have recently determined that the core structure of hemozoin comprises a novel insoluble polymer of heme units linked by iron-carboxylate bonds [Slater et al., Proc Natl Acad Sci USA 88:325-329, 1991; Slater et al., Nature 355:167-169, 1992]. We now report that purified native, as well as chemically synthesized, hemozoin crystals potently induce the release of several pyrogenic cytokines, including TNF, MIP-1 alpha, and MIP-1 beta, from murine macrophages and human peripheral blood monocytes in vitro. Also, intravenous administration of chemically synthesized preparations of hemozoin to anaesthetized rats results in a marked drop in body temperature. A similar drop in body temperature is observed following the intravenous injection of other well-characterized pyrogenic cytokines (e.g., TNF) which are known to induce a fever response in awake animals, and is thought to reflect the inability of rats to appropriately regulate their body temperature while anaesthetized. As a consequence of its ability to induce pyrogenic cytokines in vitro, and thermal dysregulation in vivo, we propose that this unique parasite metabolite is an important pyrogen released by malaria parasites at schizogomy, which acts by eliciting the production of a group of potent endogenous pyrogens, which include MIP-1 alpha and MIP-1 beta, as well as TNF, in macrophages.

Animals↗
PubMed1995

Chloroquine resistance is not associated with drug metabolism in Plasmodium falciparum.

Chloroquine-sensitive and -resistant clones of Plasmodium falciparum were incubated in vitro with [3H]chloroquine for 16 hr, and the resulting culture supernatants and cell pellets were analyzed by high-performance liquid chromatography for evidence of chloroquine metabolism. After separation by normal- or reverse-phase chromatography, there was no evidence of drug metabolism by the chloroquine-resistant P. falciparum. However, a single, unidentified, radiolabeled metabolite, which did not coelute with desethylchloroquine, was produced by 1 of the chloroquine-sensitive clones. Thus, chloroquine resistance does not appear to be due to drug metabolism by the resistant parasites.

Animals↗
PubMed1993

Reinfection with hookworm after chemotherapy in Papua New Guinea.

Reinfection with hookworm (Necator americanus) following chemotherapy was studied over 2 years in a rural village in Madang Province, Papua New Guinea. The prevalence of hookworm infection had returned to pre-treatment levels after 2 years, and the geometric mean hookworm burden had returned to 58% of the pre-treatment value. The rate of acquisition of adult worms was independent of host age, and was estimated as a geometric mean of 2.9-3.3 worms/host/year (arithmetic mean 7.9-8.9 worms/host/year). There was significant predisposition to hookworm infection; the strength of this predisposition did not vary significantly between age or sex classes.

Age Factors↗
PubMed1992

Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites.

The incidence of human malaria has increased during the past 20 years; 270 million people are now estimated to be infected with the parasite. An important contribution to this increase has been the appearance of malaria organisms resistant to quinoline-containing antimalarials such as chloroquine and quinine. These drugs accumulate in the acid food vacuoles of the intraerythrocytic-stage malaria parasite, although the mechanism of their specific toxicity in this organelle is uncertain. The primary function of the food vacuole is the proteolysis of ingested red cell haemoglobin to provide the growing parasite with essential amino acids. Haemoglobin breakdown in the food vacuole releases haem, which if soluble can damage biological membranes and inhibit a variety of enzymes. Rather than degrading or excreting the haem, the parasite has evolved a novel pathway for its detoxification by incorporating it into an insoluble crystalline material called haemozoin or malaria pigment. These crystals form in the food vacuole of the parasite concomitant with haemoglobin degradation, where they remain until the infected red cell bursts. The structure of haemozoin comprises a polymer of haems linked between the central ferric ion of one haem and a carboxylate side-group oxygen of another. This structure does not form spontaneously from either free haem or haemoglobin under physiological conditions, and the biochemistry of its formation is unclear. Here we report the identification and characterization of a haem polymerase enzyme activity from extracts of Plasmodium falciparum trophozoites, and show that this enzyme is inhibited by quinoline-containing drugs such as chloroquine and quinine. This provides a possible explanation for the highly stage-specific antimalarial properties of these drugs.

Animals↗
PubMed1992

Malaria pigment.

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Animals↗
PubMed1992

The pathway of hemoglobin degradation in malaria parasites.

Hemoglobin degradation in malaria parasites appears to be a vital and massive undertaking during intraerythrocytic development. An ordered pathway exists that efficiently catabolizes hemoglobin to yield amino acids that the parasite uses as a nutrient source, and that co-ordinates the resultant heme into a remarkable crystalline structure called hemozoin. Daniel Goldberg and Andrew Slater explain that the enzymes involved are specific and present prime targets for chemotherapeutic intervention.

Journal Article↗
PubMed1991

Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease.

Hemoglobin is an important nutrient source for intraerythrocytic malaria organisms. Its catabolism occurs in an acidic digestive vacuole. Our previous studies suggested that an aspartic protease plays a key role in the degradative process. We have now isolated this enzyme and defined its role in the hemoglobinolytic pathway. Laser desorption mass spectrometry was used to analyze the proteolytic action of the purified protease. The enzyme has a remarkably stringent specificity towards native hemoglobin, making a single cleavage between alpha 33Phe and 34Leu. This scission is in the hemoglobin hinge region, unraveling the molecule and exposing other sites for proteolysis. The protease is inhibited by pepstatin and has NH2-terminal homology to mammalian aspartic proteases. Isolated digestive vacuoles make a pepstatin-inhibitable cleavage identical to that of the purified enzyme. The pivotal role of this aspartic hemoglobinase in initiating hemoglobin degradation in the malaria parasite digestive vacuoles is demonstrated.

Amino Acid Sequence↗
PubMed1991

An iron-carboxylate bond links the heme units of malaria pigment.

The intraerythrocytic malaria parasite uses hemoglobin as a major nutrient source. Digestion of hemoglobin releases heme, which the parasite converts into an insoluble microcrystalline material called hemozoin or malaria pigment. We have purified hemozoin from the human malaria organism Plasmodium falciparum and have used infrared spectroscopy, x-ray absorption spectroscopy, and chemical synthesis to determine its structure. The molecule consists of an unusual polymer of hemes linked between the central ferric ion of one heme and a carboxylate side-group oxygen of another. The hemes are sequestered via this linkage into an insoluble product, providing a unique way for the malaria parasite to avoid the toxicity associated with soluble heme.

Animals↗
PubMed1990

Epidemiology and immunology of Necator americanus infection in a community in Papua New Guinea: humoral responses to excretory-secretory and cuticular collagen antigens.

Baseline data from an immuno-epidemiological study of hookworm infection in a rural village in Madang Province, Papua New Guinea are reported. Necator americanus was found to be the commonest helminth infection, with a prevalence of near 100% and intensity of 40 worms per host in adults. Enterobius vermicularis, Ascaris lumbricoides and Trichuris trichiura were also present, at prevalences of 53, 10 and 3% respectively; Ancylostoma duodenale was absent. The frequency distribution of N. americanus was highly over-dispersed, and was well described by a negative binomial distribution with aggregation parameter, k, of 0.370. Intensity of infection was significantly related to host age, but did not differ between the sexes. Haemoglobin levels and haematocrit values were indicative of anaemia in the community, but were unrelated to hookworm infection. Levels of antibodies (IgG, IgA and IgM combined) against adult Necator cuticular collagen and excretory-secretory (ES) products were determined. Serum concentrations of the two types of antibody were significantly correlated with each other. Significant positive correlations were found between anti-ES antibody levels and hookworm egg production, and between anti-collagen antibody levels and host age. It is suggested that the level of anti-collagen antibodies may reflect cumulative exposure to infection, whereas levels of anti-ES antibodies may be more dependent on current worm burden. No evidence was found to suggest that either antibody response is important in regulating parasite population growth. Similarly, the presence of a positive correlation between eosinophil concentration and infection intensity in adults indicates that eosinophilia reflects, rather than determines, the host's worm burden.

Adolescent↗
PubMed1990

Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle.

The malaria parasite Plasmodium falciparum uses host erythrocyte hemoglobin as a major nutrient source. We report the purification of P. falciparum digestive vacuoles and characterization of the degradative process therein. Vacuoles were isolated by a combination of differential centrifugation and density gradient separation. The pure vacuoles were capable of degrading hemoglobin to small fragments with a pH optimum of 5-5.5. Proteolysis in the vacuoles appears to be an ordered process, requiring an aspartic protease to clip intact hemoglobin before other proteolytic activities can function efficiently. The vacuoles do not contain other hydrolases commonly found in lysosomes and therefore appear to be unique proteolytic organelles designed specifically to degrade hemoglobin.

Animals↗
PubMed1988

The influence of dietary protein on the experimental epidemiology of Heligmosomoides polygyrus (Nematoda) in the laboratory mouse.

The influence of dietary protein on the epidemiology of an intestinal helminth infection was investigated with an experimental system that allowed transmission of the nematode Heligmosomoides polygyrus to occur naturally between laboratory mice. Mortality of mice was greatly increased in infected populations that were fed ad libitum on synthetic diets containing 2% compared with 16% protein. Larger numbers of larval and adult H. polygyrus were found to infect mice in the low-protein cage compared with the high-protein cage. No evidence for density dependence in the fecundity of female worms was detected; on average the daily egg output per female worm was greater for parasites infecting mice in the low-protein cage. The rate at which naïve mice acquired infection was also higher in the low-protein cage. Pinworm (Aspiculuris tetraptera) became established in each cage, and average worm burdens were again greater in the low-protein cage. The acquisition of resistance to reinfection was not found to be an important factor influencing the survival of parasites infecting mice in either cage. The epidemiology of H. polygyrus and A. tetraptera was therefore characterized by low average worm burdens and high host survival in a well-nourished population of mice, and by a high intensity of infection and severe parasite-induced host mortality in a malnourished colony of mice. This reflects differences in the survival and fecundity of adult parasites between mice in the two cages, and suggests that malnourished mice are predisposed to acquire large numbers of several species of intestinal worm.

Animals↗
PubMed1988

The influence of protein deficiency on immunity to Heligmosomoides polygyrus (Nematoda) in mice.

The influence of dietary protein on the efficiency with which mice could be immunized against infection with the nematode Heligomosomoides polygyrus was investigated. Immunization with irradiated larvae did not protect outbred mice fed synthetic diets containing 2% or 4% protein against a challenge infection, while animals fed a diet containing 8% protein were significantly resistant. In further experiments with high-responder NIH mice, protein malnutrition was again found to cause a significant depression in immunity. Immunization primed all mice for an intense production of antibody against larval worms in a challenge infection, and although a slightly higher titre of antibody was detected in the plasma of mice fed a 16% compared with a 2% protein diet it seemed unlikely that this was sufficient to account for the reduced resistance of the malnourished mice. The development of eosinophilia in the blood of immunized mice was significantly delayed in malnourished animals following challenge, and it is suggested that a reduction in the number of granulocytes attacking larval worms contributed to the low level of resistance observed in these animals. Protein malnutrition thus markedly suppresses the effectiveness of immunization of mice against an intestinal nematode, and it is suggested that this result may be of general significance with regard to the potential for widespread immunization of people against infections of this type.

Analysis of Variance↗
PubMed1987

The population dynamics of acquired immunity to helminth infection: experimental and natural transmission.

Recently we described a mathematical model of the role of acquired immunity in host-helminth interactions. The model gives a good quantitative description of the results of experiments involving the nematode Heligmosomoides polygyrus in laboratory mice. Here we apply the model to the results of two further laboratory studies of the same parasite-host interaction: (i) the repeated experimental infection of a genetically heterogeneous host population, and (ii) the natural transmission of the parasite within mouse populations under different dietary conditions. Numerical simulation again reveals good quantitative agreement between the model predictions and laboratory data. Finally, the model is extended to give a preliminary description of the dynamics of helminth-host interactions of medical and ecological significance in the real world.

Animals↗
PubMed1987

Helminth fecundity: density dependence or statistical illusion?

Density-dependent constraints on fecundity or survival are critical for the regulation and stability o f all populations. Helminth parasites are no exception to this rule. In medical helminthology, it has been widely assumed that the most effective density-dependent constraints act upon parasite fecundity and are the result of intra-specific parasite competition or acquired immunity to infection. In this article, Anne Keymer and Andrew Slater advocate a more detailed examination of the evidence on which this assumption rests.

Journal Article↗
PubMed1986

Heligmosomoides polygyrus (Nematoda): the influence of dietary protein on the dynamics of repeated infection.

The influence of the protein component in the diet of the host on the population dynamics of gastrointestinal helminth infection was studied by using a mouse-H. polygyrus experimental model. Mice fed a 2% (by mass) protein diet ad libitum maintained body weight during the experiment, but gained weight steadily when fed a diet containing 8% (by mass) protein. When repeatedly infected with 5, 10, 20 or 40 larvae every 2 weeks, the mice fed the 2% (by mass) protein diet accumulated adult worms in direct proportion to exposure to the infective stages. Under similar infection régimes, mice fed an 8% (by mass) protein diet acquired a partly effective immunity to reinfection by the nematode. Acquired immunity was principally manifest as a reduction in the survival of adult worms, although a slight increase in the mortality rate and/or the development time of the tissue-dwelling larval phase was observed. Worm fecundity per head was significantly depressed in hosts fed the 8% protein diet. In conclusion, in these experiments it is demonstrated that the nutritional status of the host can influence the population dynamics of helminth infection.

Animal Nutritional Physiological Phenomena↗
PubMed1986

The population dynamics of acquired immunity to helminth infection.

Based on experimental evidence we develop and exploit a mathematical model to describe the role of acquired immunity in host-helminth interactions. We show that the model gives a quantitative description of the population dynamics in a laboratory situation involving a host immunological response. We make practical predictions based on these results.

Animals↗