The challenge of intracellular pathogens.
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Animals↗
Biomedical subjects
A A Mahmoud
Publications and source records attributed to A A Mahmoud.
Glycocalyx of bodies versus tails of Schistosoma mansoni cercariae. Lectin-binding, size, charge, and electron microscopic characterization.
Infection with Schistosoma mansoni is initiated by penetration of the intact skin of the mammalian host with the head but not the tail of the parasite cercariae. The surface of cercariae is covered by a 1-2-micron thick carbohydrate-rich glycocalyx (gx). Furthermore, the transformation of cercariae to schistosomula (the next parasitic stage in the mammalian host) is associated with loss of gx from the bodies. To understand the role of gx in the host-parasite relationship, we have characterized the gx of both bodies and tails of S. mansoni cercariae. A fluorescent fucose-specific lectin-stained bodies and not tails of the organism. Moreover, when an enriched preparation of gx obtained by extraction with 40% aqueous phenol and exclusion from Sepharose CL-6B was subjected to affinity chromatography on insolubilized Lotus lectin, which binds fucose-containing glycans, only body gx was retained. Body gx is smaller and less negatively charged than tail gx. Electron microscopy showed that gx from bodies and tails is composed of 25-40-nm particles and fibrillar material. Carbohydrate composition of gx of bodies and tails indicate that fucose and glucose are major components, respectively. beta-Elimination experiments indicate that the linkage sugar is N-acetylgalactosamine in both cases. Upon treatment with alkaline borohydride, nearly 90% of gx of both bodies and tails was recovered as two glycan chains: I and II (Mr approximately 10,500 and 5,600, respectively). Glycan I was in both cases more negatively charged than glycan II. Fucose is the predominant sugar in glycan I of the bodies while glycan I of tails is mainly composed of glucose. The gx was resistant to several proteases. This resistance and the abundance of carbohydrate in gx may be of biological importance for survival of cercariae. The substantial differences observed between the gx of bodies and tails may provide the basis for understanding the mechanism of selective release of body gx during transformation.
Animals↗
Ultrastructural localization of a protective 68,000 molecular weight antigen in Schistosoma mansoni.
Vaccination with SMW 68, an Mr 68,000 glycoprotein of Schistosoma mansoni, induces significant protection in mice against challenge schistosome infection. This resistance occurs without the use of adjuvants and without sensitizing animals to granuloma formation. Likewise, passive transfer of monoclonal antibody (MAb) 31-3B6 against SMW 68 confers partial protection against challenge infection. As a first step in understanding how the immune response to this molecule leads to resistance, SMW 68 was localized in three developmental stages of the parasite by immunoelectron microscopy using MAb 31-3B6 and polyclonal antisera raised against purified SMW 68. In cercariae and schistosomula, MAb 31-3B6 bound electron-dense granules within the head gland and similar granules in the preacetabular glands. In adult worms, SMW 68 or related antigens were found to be widely distributed in tissues. Binding of specific antisera was most pronounced in the gut and tegument of male worms, but less so in subtegumental muscles. We conclude that SMW 68 is presented to the immune system in various ways during parasite development. The protective protein or epitope is excreted, and presented on the surface and in the cytoplasm at various stages of the life cycle. The relationship of the location of this protein to its role in protective immunity is discussed.
Animals↗
Direct inhibitory action of EGTA-Ca complex on reverse-mode Na/Ca exchange in Myxicola giant axons.
Giant axons from the marine annelid Myxicola infundibulum were internally dialyzed with solutions containing 22Na ions as tracers of Na efflux. In experiments performed in Li-substituted seawater, Na efflux that is dependent on external Ca ion concentration, [Ca2+]o, was measured using dialysis to maintain [Na+]i at 100 mM, which enhances the [Ca2+]o-dependent Na efflux component, (i.e., reverse-mode Na/Ca exchange). When dialysis fluid contained EGTA (1 mM) to buffer the internal Ca concentration, [Ca2+]i, to desired levels, Na efflux lost its normal sensitivity to external calcium. The inhibition was not simply due to the Ca-chelating action of EGTA to produce insufficient [Ca2+]i to activate Na/Ca exchange. The addition of EGTA inhibited Cao-dependent Na efflux even when a large enough excess of [Ca2+]i was present to saturate the EGTA and still produce elevated values of [Ca2+]i. Control experiments showed that these high values of [Ca2+]i resulted in normal Na/Ca exchange in the absence of EGTA. It is concluded that the presence of EGTA itself interferes with the manifestation of reverse-mode Na/Ca exchange in Myxicola giant axons.
Animals↗
Effect of Leishmania major on human polymorphonuclear leucocyte function in vitro.
The effect of various antigens of Leishmania major promastigotes on the function of human polymorphonuclear leucocytes (PMNLs) was examined. Different concentrations of L. major antigens were incubated with isolated PMNLs for various periods and the respiratory burst was assessed by Luminol-dependent chemiluminescence. All the Leishmania antigens employed inhibited the PMNL respiratory burst by 35-64%. PMNL viability was not affected either by the concentrations or type of the parasite antigen. Oxygen free radical scavengers enhanced the action of the antigens on the PMNL respiratory burst.
Allopurinol↗
Association of reduced antibody response to "SMW68" (an affinity purified schistosomal antigen) with hepatosplenomegaly in Egyptian schoolchildren infected with Schistosoma mansoni.
Studies of the pathogenesis of schistosomal infections have revealed that the occurrence of disease is so strongly related to host responses to parasite products, that schistosomiasis can be considered as an immunological disease. Further, numerous genetic and environmental factors may modify the host resistance or susceptibility to disease. To test whether hepatosplenic patients manifest different immune capabilities, and the effects of intensity of infection on immune responses; we evaluated anti-SMW68 and anti-crude antigens (SWAP & SEA) antibody levels in 100 children aged 9-15, having light and moderate S. mansoni infection (80-360 eggs/gm of stool). In this group, anti-SMW67 antibody levels (determined by ELISA) were significantly higher in those with lower levels of infection (P less than 0.001). Furthermore, the hepatosplenic patients showed a lower anti-SMW68 antibody levels than those with intestinal schistosomiasis. (P less than 0.05). We conclude that the worm burden and so the resultant morbidity may be influenced by the immune capabilities of the host. Whether enhanced antibody response to SMW68 represents acquired protective humoral immunity remains to be determined.
Adolescent↗
Parasitic protozoa and helminths: biological and immunological challenges.
Parasitic protozoans and helminths pose considerable medical as well as scientific challenges. Investigations of the complex and very different life cycles of these organisms, their adaptation to the obligate parasitic mode of life, and their ability to face the hostile host environment have resulted in many exciting discoveries. Invasion of host erythrocytes by plasmodial sporozoites and intact skin by schistosomal cercariae are outlined as examples of the elaborate mechanisms of parasitism. Isolation and characterization of single protective antigens or subunit vaccines from these two organisms are examined as models for vaccine development. Finally, developments in exploring gene regulation in protozoans and free and parasitic nematodes are briefly outlined.
Animals↗
Drugs five years later: praziquantel.
PURPOSE: To identify advances in knowledge of the pharmacokinetics, mechanism of action, clinical use, and side effects of the antihelminthic drug praziquantel in the 5 years since its introduction in the United States. DATA IDENTIFICATION: Studies reported from 1983 to July 1988 were identified by computer searches of MEDLINE and TOXLINE, and review of textbooks and review articles. STUDY SELECTION: Of 57 articles originally identified, 39 were selected by two readers. DATA EXTRACTION: Study quality and significance were independently assessed by each reader. RESULTS OF DATA ANALYSIS: The pharmacokinetics and clinical efficacy of praziquantel have been well documented. Yet, despite extensive in vivo and in vitro laboratory studies, the drug's mechanism of action in killing parasites is unknown. Although the efficacy of praziquantel was first established for treating schistosomiasis, in the last 5 years its clinical use has been expanded to the treatment of intestinal, tissue, and lung flukes, and intestinal and tissue cestode infections, including neurocysticercosis. The introduction of praziquantel was a significant advance in antihelminthic therapy, in that it was effective therapy for several parasites that had been previously considered untreatable. Availability of a safe, effective broad-spectrum oral antihelminthic agent consolidated the central role of chemotherapy in population-based control of many trematode and cestode parasites. Randomized trials have shown, however, that older, cheaper agents may be more cost-effective in controlling Schistosoma mansoni and Schistosoma haematobium in some endemic areas. CONCLUSIONS: Although praziquantel is the treatment of choice for most human trematode and cestode infections, cost factors have limited its use in developing countries.
Animals↗
Dynamics of hepatic connective tissue matrix constituents during murine Schistosoma mansoni infection.
Hepatic fibrosis is the major clinical sequela of infection with the helminth Schistosoma mansoni. However, little is known regarding its dynamics and regulation in schistosomiasis. The present study presents the dynamics of deposition and resorption of two major extracellular matrix components of fibrosis, glycosaminoglycans and collagens, during the course of experimental S. mansoni infection. Early in infection (6 weeks), glycosaminoglycan biosynthesis was markedly elevated, as was collagen biosynthesis. This led to significant accumulations of these two molecules at a glycosaminoglycan/collagen ratio similar to that observed in livers of uninfected mice (uronic acid/hydroxyproline ratio of 1.10 at 6 weeks compared to normal value of 1.25). During maximal hepatic fibrosis (12 to 18 weeks), both collagen and glycosaminoglycan biosynthesis continued to increase but the extracellular matrix shifted to a lower glycosaminoglycan/collagen ratio of 0.42, suggesting enhanced glycosaminoglycan breakdown. In addition, during this acute stage of infection, Type I collagen was the predominant isotype synthesized, whereas total collagenolytic activity degrading Type I collagen was maximal. During chronic infection, a decrease in the content of both hepatic glycosaminoglycans and collagens were noted, with a glycosaminoglycan/collagen ratio of 0.63. Decreased glycosaminoglycan content paralleled diminished biosynthetic rates. On the other hand, an over 50% reduction in collagen content (from 18 to 24 weeks) appeared not to result from diminished biosynthesis but from a switch in the predominant collagen isotype synthesized (from Type I to Type III), matched by an enhanced constitutive collagenolytic activity directed toward this type of collagen.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Entamoeba histolytica depresses chemiluminescence in stimulated human polymorphonuclear leukocytes.
Effect of Entamoeba histolytica proteinase/toxin (Ehp/t) on the luminol-dependent chemiluminescence (CL) in stimulated human polymorphonuclear leukocytes (PMN) was studied. The role of superoxide (SO) and hydroxyl (OH) anions in the Ehp/t-associated enhancement/inhibition of CL was also studied using specific scavengers and a biological response modifier, muramyldipeptide (MDP). Ehp/t was isolated from axenic trophozoites of the HM-1:IMSS strain of virulent strain of E. histolytica. Proteinase activity was assayed on a synthetic substrate, Z-arg-arg-AFC and cytotoxicity was tested on HeLa cell monolayers. PMN isolated from blood were incubated with Ehp/t prior to stimulation by phorbol myristateacetate (PMA, 2 micrograms/ml), serum-treated zymosan (2.5 mg/ml) and glucan (2 mg/ml). CL was monitored in an LKB (Wallac) Luminometer. Ehp/t was found to depress up to 90% of CL induced by PMA, glucan and zymosan. Such a depression was Ehp/t concentration-dependent. A 150 micrograms/ml concentration of Ehp/t, obtained from a 0.015-1.5 mg/ml concentration range tested at different incubation times and temperatures, was used in most of our experiments. Incubation time and temperature optima were 15 min and 37 degrees C, respectively. Ehp/t partially inhibited the CL associated with SO and OH. MDP, in the presence of Ehp/t, enhanced CL response in human PMN to about 67% with reference to normal CL without inhibitor. PMN were confirmed to play a vital role in amebic tissue invasion mechanisms.
Acetylmuramyl-Alanyl-Isoglutamine↗
Intensity of Schistosoma mansoni infection in a human population is inversely correlated with antibody response to SmW68, a protective parasite antigen.
Vaccination with SmW68, a Schistosoma mansoni surface antigen, significantly protects mice against challenge infection. To investigate the vaccine potential of SmW68 in clinical schistosomiasis, human antibody response to SmW68 was studied as a function of intensity of infection in a chronically infected Egyptian population. In 85 serum samples obtained randomly from families in El Gazairy (population 1,310), antibody to SmW68 (determined by ELISA) was found to increase significantly with age, reaching a plateau at 15-19 y, 1-5 y after peak prevalence and intensity of infection. Among infected individuals (n = 54), antibody response showed a significant inverse correlation (r = -.28, P less than .04) with intensity of infection. In isotype analysis, a higher IgM but not IgG response was significantly associated with low parasite burden. These studies demonstrate that significant antibody response to SmW68 could occur in chronically infected humans. Whether parasite burdens suppress circulating levels of antibody to SmW68 or whether enhanced antibody response to SmW68 represents acquired protective humoral immunity remains to be determined.
Adolescent↗
Strategies for vaccine development: schistosomiasis.
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Animals↗
Induction of resistance to Schistosoma mansoni infection in mice by purified parasite paramyosin.
Freeze-thaw (FT)-disrupted schistosomula or their membrane extract induced significant resistance in mice to Schistosoma mansoni infection (34 and 25%, respectively) without the use of adjuvant. Antigens identified in schistosome extracts by sera from immunized animals were then evaluated for protective potential. Immunization with schistosomal antigens of 97 and 68-70 kD resulted in significant protection that was equivalent to that obtained by FT schistosomula. Since the 97-kD antigen was suggested to be parasite paramyosin, we used a biochemical technique to purify this muscle protein. Purified schistosome paramyosin ran as a single band on 10% SDS-PAGE and was recognized both by sera from mice immunized with FT schistosomula and a polyclonal antiserum raised against the 97-kD parasite protein. Preincubation of schistosome paramyosin with sera from mice immunized with FT schistosomula resulted in the removal of reactivity with the 97-kD protein in crude worm extracts. Paramyosin was identified by Western blotting to be in the tegument of schistosomula. The purified schistosome paramyosin resulted in significant protection in three separate experiments (24, 46, and 53%) without the use of adjuvant. Addition of BCG to paramyosin resulted in enhanced protection.
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Dose-finding study for praziquantel therapy of Schistosoma haematobium in Coast Province, Kenya.
To assess the efficacy of low dose praziquantel regimens in comparison with standard 40 mg/kg dosing in the treatment of urinary schistosomiasis, a random allocation dose-finding trial was performed in children and adults from a Schistosoma haematobium endemic region in Coast Province, Kenya. Following an initial screening, 280 individuals with greater than or equal to 50 eggs/10 ml urine were randomly assigned to receive either 10, 20, 30, or 40 mg/kg of the drug in a single oral dose. Two to three months later, cure rates of 26%, 68%, 78%, and 84% were found for the 10, 20, 30, and 40 mg/kg doses, respectively. The results of 10 mg/kg oral dosing were significantly worse than for all other doses in terms of cure rate and of post-treatment prevalence of morbidity. The 40 mg/kg dosing resulted in a significantly higher cure rate than the 20 mg/kg doses; nevertheless, there was no significant difference between 20 mg/kg and 40 mg/kg doses in terms of mean post-treatment intensity of infection or post-treatment prevalence of hematuria or proteinuria. For large-scale control programs, oral 20 mg/kg praziquantel therapy for urinary schistosomiasis may prove as effective as the standard oral 40 mg/kg dosing for control of infection-associated morbidity and reduction of parasite transmission.
Adolescent↗
Effects of borehole wells on water utilization in Schistosoma haematobium endemic communities in Coast Province, Kenya.
To determine the impact of the introduction of borehole wells on water use patterns and the consequent risk of transmission of Schistosoma haematobium in 3 endemic villages in Kenya, we performed a survey (a 1:6 sample of affected households) to identify sources of water and types of water utilization before and after well introduction. Water usage was also determined in 2 unaffected neighboring villages not given borehole wells, but having continuous access to piped water from communal taps. Prior to borehole well construction, significantly more high-risk water use occurred in the borehole villages vs. comparison villages in terms of water gathered for cooking, drinking, dish washing, and bathing; residents of both types of villages preferred high-risk sources (marshes and ponds) for clothes washing. Following well introduction, there were significant declines in the use of high-risk water for drinking, cooking, and dish washing, but not for bathing or clothes washing. A higher proportion of individuals from the 3 borehole villages reported some type of continued contact with high-risk water sources. Despite well introduction and a 3 year chemotherapy program among school-aged children, a 21-28% incidence of infection persisted among children in the villages, suggesting minimal impact on transmission. Regular monitoring for S. haematobium infected snail sites showed no decline in the number or proportion of infected snails. Borehole well introduction can significantly alter some forms of water usage, but social and water quality factors may limit the ability of communal wells to reduce S. haematobium transmission.
Adult↗
Effect of targeted mass treatment on intensity of infection and morbidity in schistosomiasis mansoni: seven-year follow-up of a community in Machakos, Kenya.
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Adolescent↗
Effect of Leishmania major on luminol-dependent chemiluminescence of human whole blood phagocytosis.
The aim of this study is to examine the effect of L. major on human whole blood phagocytosis. The phagocytosis was activated by phorbol myristate acetate (PMA) or opsonized zymosan. Various types of Leishmania antigens were tested on luminol-dependent chemiluminescence. In PMA-activated whole blood phagocytosis group, promastigotes and infected medium significantly (P less than 0.001) depressed the maximum peak of chemiluminescence to 5.77 +/- 1.6 and 5.65 +/- 0.45 mV respectively, compared to 9.85 +/- 22 in control group. In a similar fashion a significant reduction of the area under the curve was noted. On the other hand, opsonized zymosan-activated phagocytosis was significantly (P less than 0.025) inhibited in the promastigote treated group only. The maximum peak response was 4.68 +/- 1.5 and 10.8 +/- 0.46 mV in promastigote and control groups, respectively. The above data indicated; a) an inhibition of whole blood phagocytosis induced by Leishmania and b) a marked reduction of the oxygen-reactive metabolites radicals generated by whole blood phagocyte cells and measured by luminol-dependent chemiluminescence suggesting the important role of oxygen free radicals in the pathogenesis of leishmaniasis.
Animals↗