Parasiticidal Effects Research Articles

Parasiticidal effect of δ‐aminolevulinic acid‐based photodynamic therapy for cutaneous leishmaniasis is indirect and mediated through the killing of the host cells

Several clinical reports have shown promising, but not optimal, results from photodynamic therapy with delta-aminolevulinic acid-derived protoporphyrin IX, termed ALA-PDT, as a treatment for cutaneous leishmaniasis (CL). Therefore, understanding the basis of the phototoxic response of Leishmania parasites to ALA-PDT may be critical for optimization. We report here both in vitro and in vivo mechanistic studies of ALA-PDT against CL. Following in vitro co-incubation of Leishmania major with 0.1 microM ALA, the PpIX concentration remained at the basal level, whereas after co-incubation with 0.1 microM exogenous PpIX, the PpIX level was 100-fold higher. No differences in ALA-derived PpIX levels were detected between Leishmania-infected and non-infected J774.2 cells, and PDT did not demonstrate any parasiticidal effects on amastigotes. In contrast, in vivo topical ALA-PDT, performed on a murine CL model, resulted in significant reductions of the parasite loads and vigorous tissue destruction. After ALA-PDT, a dramatically decreased percentage of macrophages and increased levels of interleukin-6 were observed in the infected skin. The clinical outcome observed with ALA-PDT is likely the result of unspecific tissue destruction accompanied by depopulation of macrophages rather than direct killing of parasites.

Inhibitors of Nonhousekeeping Functions of the Apicoplast Defy Delayed Death in Plasmodium falciparum

Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical "delayed death" phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.

Parasiticidal effects of peroxynitrite on ovine liver flukes in vitro.

Peroxynitrite (ONOO-) is a cytotoxic anion, produced by interaction between nitric oxide and superoxide in vivo in some inflammatory cells. This study investigated its effects on Fasciola hepatica and Dicrocoelium dendriticum isolated from ovine livers and kept in bile at room temperature. Peroxynitrite was synthesized using a quenched flow reactor and assayed spectrophotometrically. It was applied at different concentrations (10(-3.5) to 10(-2.3 M)) to the flukes kept in bile. The viability of the peroxynitrite-treated flukes was compared with a control group (n=5-7 per group). Control F. hepatica and D. dendriticum lived for 226+/-11and 208+/-14min, respectively. Life times were decreased by peroxynitrite at all concentrations used (P<0.001). At the highest concentration of peroxynitrite, F. hepatica and D. dendriticum lived only for 6.1+/-0.4 and 4.1+/-4.1+/-0.2min, respectively. Correlation between peroxynitrite concentration and parasite viability was significant in the case of F. hepatica (r= -0.842; P= 0.0035). A single application of peroxynitrite can decrease the life span of ovine liver flukes. A failure in the activation of hepatic macrophages in infected animals may lead to a decreased production of free radicals and, thus, peroxynitrite. Such a failure is likely to deprive the body of a defence tool against multicellular parasites.

Influence of antibodies in mother's milk on antigenic variation of Giardia lamblia in the murine mother-offspring model of infection.

In the present study, neonatal ZU.ICR mice and their mothers were infected with trophozoites of Giardia lamblia clone GS/M-83-H7 expressing the variant surface protein (VSP) H7. The infection experiments included a detailed analysis of the specificities of anti-Giardia immunoglobulin A (IgA) antibodies in mother's milk and a determination of the effects of the milk antibodies on both the growth of the parasite during in vitro cultivation and colonization of the parasite within the intestine of suckling offspring. These investigations revealed that transiently emerging milk IgA antibodies against a variant-specific 314-amino-acid N-terminal region of VSP H7 exhibit a strong parasiticidal effect on VSP H7-type trophozoites both in vitro and in vivo. These findings indicated that parasiticidal effects of local IgA antibodies against the N-terminal part of VSP H7 select for new variant types within the intestinal parasite population of suckling mice. The selective influence of such antibodies promotes in vivo antigenic variation of G. lamblia clone GS/M-83-H7 and modulates the early course of parasite infection in these animals.

Toxoplasma gondii: Parasiticidal Effects of Bovine Lactoferricin against Parasites

Toxoplasma gondii: Parasiticidal Effects of Bovine Lactoferricin against Parasites

Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection.

Parasitic infection is frequently accompanied by a downregulation in host cell-mediated immunity. Recent studies suggest that this modulation of helper T cells and effector cell function can at least in part be attributed to the action of a set of inhibitory cytokines produced by T lymphocytes as well as by a number of other cell types. The best characterized of these inhibitory lymphokines are IL-4, IL-10 and TGF-beta. Interestingly, both IL-4 and IL-10 are produced by the Th2 but not the Th1 subset of CD4+ helper cells. The former subset dominates in many situations of chronic or exacerbated parasitic infection and is thought to suppress Th1 function as a consequence of the cross-regulatory activity of these two cytokines. The latter hypothesis is supported by recent experiments demonstrating that mAb-mediated neutralization of IL-10 reverses suppressed IFN-gamma responses and/or disease susceptibility in mice with parasitic infections. In vivo neutralization of TGF-beta has also been reported to increase host resistance to parasite challenge. In addition to suppressing T-cell differentiation, function or proliferation, IL-4, IL-10 and TGF-beta each inhibit the ability of IFN-gamma to activate macrophages for killing of both intracellular and extracellular parasites. Moreover, the three cytokines are able to synergize with each other in downregulating these parasiticidal effects. Interestingly, each of the cytokines inhibits the production of reactive nitrogen oxides, an effector mechanism previously demonstrated to play a major role in parasite killing by activated macrophages. In the case of IL-10, this suppression of nitrogen oxide production appears to result from an inhibition of TNF-alpha synthesis leading to defective macrophage stimulation. While distant from parasites in their biology and phylogeny, some retroviruses also appear to induce an over-production in downregulatory cytokines which is closely associated with the onset of immunodeficiency. Thus, in an animal model involving infection of mice with LP-BM5 MuLV and in human HIV infection, Th2 (IL-10 and/or IL-4) cytokine synthesis is increased while Th1 (IFN-gamma and/or IL-2) cytokine production is suppressed. These observations suggest that cytokine-mediated cross-regulation may play a role in the pathogenesis of acquired immune deficiency disease, contributing both to the progression of retroviral infection and the increase in susceptibility to opportunistic infections and malignancy. Observations of similar cytokine cross-regulatory activities in organisms as diverse as helminths, protozoa and retroviruses predict that comparable mechanisms may operate in a wide variety of infectious diseases.

Eosinophils: a review.

The eosinophil was discovered by Jones in 1846 (Dessein and David, 1982) but its proclivity to stain with aniline dyes was first described by Paul Ehrlich in 1879 (Hirsch and Hirsch, 1980). Recognized and named for this quality, eosinophils possess an abundance of highly basic proteins within their granules which confer their affinity for acidic dyes (Gleich and Loegering, 1984). Eosinophils are traditionally viewed as killer-effector cells in parasitic infestations and as modulators of Type I hypersensitivity reactions (Butterworth and David, 1981; Kay, 1985). The eosinophils' reserve of cationic proteins and enzymes which imparts their profound parasiticidal effects (Butterworth and David, 1981) contrasts with this leukocyte's purported regulatory function in inflammation (Kay, 1985; Fechter et al., 1986). The opposing functions possessed by this leukocyte exemplify the enigma of the eosinophil. Recent evidence suggests that although the eosinophil does posses some regulatory capabilities, its presence is, in fact, a harbinger of tissue destruction (Gleich and Adolphoson, 1986, Wardlaw and Kay, 1987; Spry, 1988). Nor does the presence of the eosinophil automatically infer IgE mediated hypersensitivity, as evidenced by studies examining the interaction of the eosinophil with the cellular arm of the immune system (Basten and Beeson, 1970; Ruscetti et al., 1976; Beeson and Bass, 1977; Raghavachar et al., 1987; Ohnishi et al., 1988). The purpose of this review is to provide a brief overview of the structure and biology of the mammalian eosinophil and to emphasize the fact that eosinophils fulfil a paradoxical role as effectors of tissue damage and as benign modulators of inflammation.

Flow cytometric analysis ofEimeria tenella sporozoite populations exposed to salinomycin sodium in vitro: A comparative study using light and electron microscopy and an in vitro sporozoite invasion-inhibition test

Eimeria tenella sporozoites exposed to 100, 70, 60 and 50 micrograms salinomycin sodium (SAL)/ml medium 199 at 41 degrees C and then stained with propidium iodide/fluorescein diacetate were analysed by means of flow cytometry (FCM). After 20 min exposure, they showed dose-dependent alterations in their size and shape, i.e. ballooning of most cells, and enhanced intracellular esterase activity as compared with untreated controls. After longer exposure periods (40 and 70 min), inflated cells gradually changed into shrivelled or crumpled, nonviable ones, thereby showing a gradual decrease in esterase activity and a gradual loss of membrane integrity (RFA+). As compared with untreated controls, sporozoites treated with 10 micrograms SAL/ml showed negligible RFA+ values (0.4%-2%), whereas those exposed to 1 and 0.1 microgram SAL ml and to the solvent dimethylsulfoxide (DMSO, 1%) did not, even after 70 min exposure. Slight to severe structural changes manifesting as an extremely wavy surface (1 microgram SAL/ml), vacuolization of the cytoplasm, distension or destruction of the mitochondrion and rupture of cell membranes (10 micrograms SAL/ml) were seen not only at higher SAL concentrations but also (rarely) at lower ones. The ability of sporozoites to invade primary chick-kidney cells was significantly inhibited by 70, 60 and 50 micrograms SAL/ml. In general, there were close relationships between findings obtained using FCM, electron microscopy and an invasion-inhibition test. The results indicate that FCM is a reliable and sensitive technique for characterizing the parasiticidal effects on and the possible mode of action of drugs in free coccidian sporozoites.

The in vitro action of antisera on the adults of Clonorchis sinensis

The action of immune sera on adult Clonorchis sinensis was studied in vitro in the “circumadult” test. Precipitates of various kinds were consistently demonstrated when the living parasites were incubated with heated or unheated immune sera from experimentally infected rabbits and guinea-pigs, and from rabbits and guinea-pigs artificially immunized with whole fluke extracts or adult metabolic products. Sera from 18 of 20 clonorchiasis patients and from 3 of 20 patients without Clonorchis eggs in the stools were also positive. There was no reaction when the living flukes were incubated with normal sera or with sera against Clonorchis eggs or other parasites, or when dead flukes were incubated with immune serum. When the positive sera were absorbed with metabolic products before incubation, the precipitates were greatly diminished or entirely abolished. Precipitates were located at the oral sucker, the genital pore and the cuticle, and also lay free and suspended in the serum. The parasites began to disintegrate after 24 hours' incubation, and died. In comparisons of normal with immune rabbit sera, and of human clonorchiasis antisera with sera from patients without Clonorchis eggs in the stools, it was found that the immune rabbit sera and the human clonorchiasis antisera possess parasiticidal effects in vitro. The differences between these two groups are statistically highly significant. The reaction develops remarkably early after infection, but is probably based on an immunological mechanism elicited in infection by absorption of metabolic products secreted by the flukes. The chief sites of these secretions are the oral sucker and genital pore, and to a less degree the cuticle.

The effect of X irradiation on immunity of the mouse to Trypanosoma duttoni.

on immunity have been most recently reviewed by Taliaferro and Taliaferro.' In general, the results of these and subsequent investigations indicated that X irradiation in large doses inhibits antibody formation and increases susceptibility to infection. In the present investigation the course of infection by Trypanosome duttoni, a nonpathogenic hemoflagellate of the mouse, was followed in irradiated mice. This parasite offers several advantages in the study of immunity. Among these are : (1) The parasite is large enough for morphological study. (2) The parasite is limited to the blood stream; therefore, changes in the parasitic population may be observed daily without sacrificing the host. (3) The extent of reproductive activity of the parasite may be followed by daily examination of blood smears for division forms. The last gives a measure of the rate of reproduction irrespective of the number of organisms killed. Measurement of the basic rate of parasite reproduction in conjunction with change in numbers of the surviving population permits a sharp distinction between reproductioninhibiting and parasiticidal effects.

Reproduction-inhibiting and parasiticidal effects of Plasmodium gallinaceum and Plasmodium lophurae during initial infection and homologous superinfection in chickens.

Journal Article Reproduction-Inhibiting and Parasiticidal Effects on Plasmodium Gallinaceum and Plasmodium Lophurae During Initial Infection and Homologous Superinfection in Chickens Get access William H. Taliaferro, William H. Taliaferro From the Department of Bacteriology and Parasitology, The University of Chicago, Chicago 37, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar Lucy Graves Taliaferro Lucy Graves Taliaferro From the Department of Bacteriology and Parasitology, The University of Chicago, Chicago 37, Illinois Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 86, Issue 3, May 1950, Pages 275–294, https://doi.org/10.1093/infdis/86.3.275 Published: 01 May 1950 Article history Received: 31 January 1950 Published: 01 May 1950