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PubMed1999

Biological control of helminths.

As a potential component in future integrated parasite-control strategies, biological control by means of predacious fungi seems to be moving from a promising possibility toward becoming a reality, and the netforming nematode-destroying fungus Duddingtonia flagrans appears to be the candidate of choice. Not only has this fungus been found in, and isolated from, fresh sheep, cattle and horse faeces, but it also appears to be the only fungus that is able to consistently and significantly reduce the number of infective trichostrongyle larvae in faeces from animals fed fungal spores. Results from the last few years have shown that D. flagrans is able to trap and destroy free-living stages of the most important and common trichostrongylid larvae with very similar external life-cycles, as well as larvae of parasites with a slightly different transmission biology (Nematodirus spp., Dictyocaulus viviparus). The introduction of microfungi for biological control could be as part of a feed supplement or incorporated in feed-blocks presented to animals which are raised under relatively intensive conditions and constant surveillance. Apart from the special niche for organic farmers, such a product would be suited for horses, small ruminants (as either milking herds or housed daily for other reasons), cattle in special situations and free-roaming pigs. The most important constraint, still, for a major breakthrough in biological control in the latter is the lack of good antagonists against the long-lived and rather resistant infective stages of parasites, being transmitted as larvae inside the egg. Since the first Conference on Novel Approaches to the Control of Helminth Parasites of Livestock in Armidale, Australia, 1995, there has been a steady evolution within the area of biological control of parasitic nematodes. Today this principle is being exploited and tested out in almost all parts of the world, under various climatic conditions and production systems. Where, in the past, a large part of the work focused on cattle and to a lesser degree horse and sheep parasites, the focus of the research in many of the newly involved countries is on small ruminants, because of their importance to primarily small-scale farmers in local communities. Today research and trials are either on-going or being planned in many developing countries, as well as in countries in transition. The involvement of multinational agencies in addition to national and industrial interests is very welcome and should increase the chances and keep up the momentum for development and implementation of biological control in future animal production around the world.

Animals↗
PubMed2003

NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major.

The NF-kappaB family of transcription factors regulates the expression of a wide range of immune response genes involved in immunity to pathogens. However, the need for individual family members in regulating innate and adaptive immune responses in vivo has yet to be clearly defined. We investigated the role of NF-kappaB1 in the induction of protective IL-12-dependent Th1 cell responses following infection with the intracellular protozoan parasite Leishmania major. Whereas wild-type C57BL/6 mice controlled parasite replication, NF-kappaB1 knockout (KO) mice were susceptible to infection, developing chronic unresolving lesions associated with persistent parasites. There was a profound defect in Ag-specific CD4(+) T cell proliferation and IFN-gamma production in infected KO mice, although innate responses-including IL-12 production and control of intracellular parasite replication by macrophages-were intact. In vitro polyclonal stimulation of purified naive KO T cells revealed an intrinsic defect in CD4(+) T cell proliferation associated with reduced IL-2 receptor expression, but operating independently of APC function and IL-2 production. Critically, the frequency of proliferating KO CD4(+) T cells secreting IFN-gamma matched that of wild-type cells, suggesting that NF-kappaB1 was not required for efficient transcription of the IFN-gamma gene. Taken together, these results identify a novel role for NF-kappaB1 in CD4(+) T cell proliferation and the development of Th1 cell responses required for protective immunity against intracellular pathogens.

Animals↗
PubMed2003

The endonuclease NL1Tc encoded by the LINE L1Tc from Trypanosoma cruzi protects parasites from daunorubicin DNA damage.

In the present paper we show that the overexpression of the NL1Tc protein, encoded by the L1Tc non-LTR retrotransposon from Trypanosoma cruzi, led to a reduction of about 60% of DNA damage caused by daunorubicin treatment. This repair effect is not observed in transfected parasites overexpressing the NL1Tc mutated in the aspartic acid located in the active site of the enzyme. In addition, NL1Tc overexpression protects the parasite from the negative effect that daunorubicin has on parasite's growth rate. Thus, parasites overexpressing NL1Tc show, after treatment with 4 microM of daunorubicin, growth rate two to three times higher than the growth rate observed in treated control parasites transformed with the empty vector or overexpressing the mutated NL1Tc. Likewise, parasites overexpressing the NL1Tc protein and irradiated with a single dose of gamma-radiation (6 or 9 Gy) show higher growth rates than the parasites overexpressing the mutated NL1Tc or the control transfected parasites.

Animals↗
PubMed2004

Ruminating on complexity: macroparasites of wildlife and livestock.

Recent advances in ecology have improved our understanding of the role of parasites in the dynamics of wildlife populations. However, conditions that prevail in many wildlife systems, such as host movement, contact with livestock, and heterogeneity in the environment of the parasite outside of the host, have largely been ignored in existing models of macroparasite transmission. We need to refine these models if we are to stand a chance of developing effective parasite control strategies. New quantitative approaches enable us to address key complexities and make better use of scarce data, and these should enhance our efforts to understand and control emerging problems of interspecific parasite transmission.

Journal Article↗
PubMed1997

Modifying the formulation or delivery mechanism to increase the activity of anthelmintic compounds.

The development of resistance to current chemical classes of broad-spectrum anthelmintics poses an undeniable threat to the long-term viability of the animal health industry. Alternative treatment strategies including vaccines, biological control and breeding of parasite-resistant animals are unlikely to be widely available in the near future and even then, they will be integrated with chemotherapy. To compound the severity of the situation there appears to be no new chemical class of anthelmintics, with unique mode of action, on the horizon. The significant cost of drug research and the development costs of a drug that is to be used in food-producing animals, together with the small market share of animal health products compared to human pharmaceutical/medical and cosmetic products, provide little incentive for anthelmintic development. The chemical actives that are currently available, are all that we are likely to have for the foreseeable future. If effective parasite treatment is to continue, existing actives must be used more efficiently. Recognising the potential for the animal's physiological behaviour to assist drug action is of significant value. Reduction of feed intake before oral anthelmintic treatment slows ruminant digesta flow, prolongs and extends the availability and therefore increases efficacy, of the benzimidazole and ivermectin compounds. This is a cost effective option that can be employed which not only increases efficacy of 'older' compounds, but will be instrumental in prolonging the useful life of the 'newer' drugs. In a related approach the co-administration of metabolic inhibitors can prolong drug clearance and extend availability and increase the action of existing anthelmintics. However, given the large costs which would be associated with this development (host toxicity, residue safety) it is probable that the value of such combinations would be more appropriate for use in the treatment of non-food producing animals. The most promising approach for improved formulation lies in innovative delivery systems using chemical or physical carriers. Solubility-defining salts, oils, solid/drug matrices, liposomes and related microparticles that reduce drug absorption/metabolism and can specifically direct large quantities of active, over an extended or pre-determined period, to the site(s) of parasitic infection. The use of lipophilic actives/vehicles which deposit in and are released from body fat is of particular value in extending drug availability. The prophylactic action of extended drug residence time, when used with effective grazing/treatment management programmes, provides opportunities for sustainable antiparasitic action. Clearly, with the paucity of new chemical classes of anthelmintics, the use of 'intelligent' but still relatively inexpensive carriers/delivery systems for existing actives will form the basis of future parasite control.

Animals↗
PubMed1999

The control of the human filariases.

There is a growing momentum for the global control and elimination of the major human filariases as public health problems worldwide. The renewed optimism for undertaking this objective reflects the development of simple and potentially cost-effective strategies for mass drug delivery in onchocerciasis and the availability of new extremely effective drug combinations to treat infection, and new methods of morbidity control in lymphatic filariasis. It also reflects the development and current availability of very effective diagnostic, surveillance and control modeling tools for both parasites. Control programming will also be aided by our greater understanding of the biology of transmission, host immunity and disease pathogenesis.

Journal Article↗
PubMed2001

[Malaria vector control in Cameroon: past, present, future. Reflections].

During the fifties, large scale malaria vector control projects based upon house spraying were implemented in Southern and Northern parts of Cameroon in line of malaria eradication concept. In the South, the pilot zone of Yaounde gathered about 150,000 inhabitants, in the forest area. First operations started in 1953 but the programme became actually operational in 1956. It was divided in two parts: the western part was treated with DDT, while the eastern one was treated with dieldrin. At the same time, the whole forested area was also treated with dieldrin until 1960. Yaounde itself was not treated because it was free of anopheles and malaria. House spraying in the pilot area of Yaounde was a complete success and plasmodic index dropped below 1%. The same success was observed in most of the southern treated areas. Unfortunatly dieldrin resistance of An. gambiae hampered this programme which stopped in 1960. The northem pilot project dealt with some 250,000 inhabitants around Maroua, in a savanna area. To avoid dieldrin resistance observed in 1956, DDT was selected and house spraying started in 1959. From a strictly operational point of view, the campaign was considered as a success. But after two years, it was noticed that plasmodic index remained still around the same value of 35% and the programme stopped. It was thus stated that according to available techniques it was not possible to reach the ultimate goal of eradication even when chemoprophylaxis (chloroquin + pyrimethamin) was added. The comparison between south (= success) and north (= failure) was very interesting as it underlined the big differences between epidemiological faces, an unaccepted concept at that time. Now ecological and epidemiological diversity is the well acknowledged. It also underlined the need of diversity of strategies according to the epidemiology of the disease and the ecology of its vector Vector control was then stopped for a while. In the eighties, Primary Health Care was promoted and malaria control shifted from vector to parasite control, vector control remaining as a prevention method. But chemioresistance of Plasmodium falciparum appeared and. quickly spread, at different levels, across the country. A new emphasis was therefore given to vector control thank to the newly developed technique of insecticide impregnated mosquito nets. Two kinds of studies were undertaken: - what people were actually doing in term of mosquito control at family level, the main reason and the costs as well as current use of mosquito nets - the efficacy of pyrethroid treated mosquito nets (IMN) in different areas of southern forested area against different malaria vectors: An. gambiae, An. nili, An. moucheti. It thus clearly appeared that IMN were very successful in sharply reducing malaria transmission aAd morbidity. But its promotion is limited by the current poor use of mosquito nets in Yaoundé (1 mosquito net for 27 "beds") while in Douala, where IMN are largely used against the bite of the huge population of Culex. quinquefasciatus, the implementation of the first riational centre for impregnation of mosquito net was a great success, as long as it was headed by a motivated and skill manager Impregnated mosquito nets appear thus as a tool of great efficacy but their sustainability is still matter of concern and promotional campaigns must be developed involving private and public, political and scientific spheres as well as the general population who should be encouraged to become partners and even actors of vector and malaria control at their household level.

Animals↗
PubMed2003

Treatment and prevention of intestinal parasite-associated disease.

Since 1917, only 11 new endoparasiticides have been developed for the horse, of which five chemical classes are in common use. The selection pressure of frequent administration of deworming doses for parasite control programs has been associated with the development of resistance of small strongyle parasites to the effects of benzimidazoles and pyrantel salts. Against the background of the inevitability of the occurrence of ivermectin/moxidectin resistance, responsible use of equine anthelmintics based on the clinical pharmacology of the compounds and the biology/epidemiology of intestinal parasites is a major issue for equine clinicians. The evidence base for the recommendations for treatment and control of equine intestinal parasites is sparse, however, and few robust data exist from controlled clinical trials to validate current guidelines.

Animals↗
PubMed1990

Behavioral adaptations to pathogens and parasites: five strategies.

The ever present threat of viral, bacterial, protozoan and metazoan parasites in the environment of wild animals is viewed as responsible for the natural selection of a variety of behavioral patterns that enable animals to survive and reproduce in this type of environment. Several lines of research, some quite recent, point to five behavioral strategies that vertebrates utilize to increase their personal or inclusive fitness in the face of parasites (broadly defined to include pathogens). These are: 1) avoidance of parasites; 2) controlled exposure to parasites to potentiate the immune system; 3) behavior of sick animals including anorexia and depression to overcome systemic febrile infections; 4) helping sick animals; 5) sexual selection for mating partners with the genetic endowment for resistance to parasites. The point is made that to consider a behavioral pattern as having evolved to serve a parasite control function the parasite or causative agent should be shown to adversely impact the animal's fitness and the behavior in question must be shown to help animals, or their offspring or group mates, in combating their exposure, or reducing their vulnerability, to the parasite.

Adaptation, Psychological↗
PubMed1991

Cryptosporidiosis facilitated by murine retroviral infection with LP-BM5.

LP-BM5 murine leukemia virus infection caused alterations in splenic T cell subsets in adult C57BL/6 female mice. Prolonged infection resulted in increased immunosuppression and a concomitant decreased resistance to Cryptosporidium parvum infection. Significant Cryptosporidium colonization of the intestinal villi was seen 10 days after oral challenge in mice infected with murine retrovirus for 3 months but not in non-virally infected controls. Parasite numbers per villus of retrovirally infected mice were 20-fold higher than in controls, which showed only occasional parasites. Feces from most virally infected mice but none from controls contained oocysts. Cryptosporidium infection in mice after 4 and 5 months of retroviral infection was accompanied by severe immunosuppression and parasite levels 50-5000 times higher than in controls. A high level of infection persisted 21 days after Cryptosporidium challenge in virally infected mice, while controls cleared their transient and marginal infection. These results further characterize LP-BM5 infection as a murine model of retrovirally induced acquired immune deficiency.

Animals↗
PubMedDate not supplied

A non-invasive technique for the control of intestinal parasites in rhesus macaques (Macaca mulatta).

Control of intestinal parasites is a major concern in maintaining the health and well-being of captive primates. This study established that percutaneous application of ivermectin was as effective as subcutaneous administration for the control of nematodes in captive rhesus macaques. The method is less intrusive than the standard subcutaneous or oral delivery routes and did not adversely affect the health of any of the study subjects.

Administration, Cutaneous↗
PubMed1989

Molecular vaccines against animal parasites.

Vaccines against parasites have been significantly more difficult to develop than vaccines for other infectious agents. However much has been published within the very recent past which indicates that it is not only possible to induce protective immune responses to a broad range of parasites of veterinary importance with subunit materials but it appears that cross-isolate and cross-species immunogens may be obtainable. Advances in molecular immunology now provide technical approaches to vaccine design which directly address the question of improving the immunogenicity of parasite vaccines and the very wide potential range of prospective live vectors for recombinant vaccine antigens help to ensure the availability of practical commercial vaccine vectors for the future. From the technical-scientific aspect therefore the feasibility for developing molecular parasite vaccines for animal health is sound. On the commercial side, the need to keep discovering novel and effective parasiticidal drugs because of resistance development presents a major financial and research burden. Growing concerns on drug residues and environmental issues mitigates in favour of controlling parasitic diseases by biological methods among which vaccines would appear to be pre-eminently suitable. It is conceivable that we are now coming to the end of the era in which animal parasites are controlled very well by prophylactic chemotherapy and slowly moving into an era where vaccination will prevail. The deployment of molecular parasite vaccines in animal health can be envisaged within five years.

Animals↗
PubMed2003

Resistant mice lacking interleukin-12 become susceptible to Trypanosoma cruzi infection but fail to mount a T helper type 2 response.

Interleukin-12 (IL-12) is essential to resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-gamma (IFN-gamma) that activates macrophages to a parasiticidal effect. Investigation of mice deprived of IL-12 genes (IL-12 knockout mice) has confirmed the important role of IL-12 and IFN-gamma in controlling parasitism in T. cruzi infection. However, it has not yet been addressed whether a shift towards a T helper type 2 (Th2) pattern of cytokine response occurred in these mice that might have contributed to the aggravation of the infection caused by IL-12 deprivation. We examined the course of T. cruzi (Y strain) infection and the regulation of cytokine responses and nitric oxide production in C57BL/6 IL-12 p40-knockout mice. The mutant mice were extremely susceptible to the infection as evidenced by increased parasitaemia, tissue parasitism and mortality in comparison with the control C57BL/6 mouse strain (wild-type) that is resistant to T. cruzi. A severe depletion of parasite-antigen-specific IFN-gamma response, without an increase in IL-4 or IL-10 production, accompanied by reduced levels of nitric oxide production was observed in IL-12 knockout mice. We found no evidence of a shift towards a Th2-type cytokine response. In IL-12 knockout mice, the residual IFN-gamma production is down-regulated by IL-10 but not by IL-4 and nitric oxide production is stimulated by tumour necrosis factor-alpha. Parasite-specific immunoglobulin G1 antibody levels were similar in IL-12 knockout and wild-type mice, whereas IL-12 knockout mice had much higher levels of immunoglobulin G2b.

Acute Disease↗
PubMed2004

MHC class II expression restricted to CD8alpha+ and CD11b+ dendritic cells is sufficient for control of Leishmania major.

Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)-dependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC II-positive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)gamma-producing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-Abeta(b), expression is restricted to CD11b+ and CD8alpha+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC II-negative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNgamma. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8alpha+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection.

Animals↗
PubMed1998

Glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities in riboflavin-deficient rats infected with Plasmodium berghei malaria.

Riboflavin deficiency interferes with the growth and multiplication of malaria parasites as well as the host response to malaria. The objective of the present work was to determine the effects of riboflavin deficiency on erythrocyte glutathione peroxidase (EC 1.11.1.9; GPx) and superoxide dismutase (EC 1.15.1.1; SOD) in rats infected with Plasmodium berghei malaria. Riboflavin in its co-enzyme form, FAD, is required by glutathione reductase (EC 1.6.4.1) to regenerate GSH and GSH is an important cellular antioxidant both in its own right and also as a substrate for the enzyme GPx. Weanling rats were deprived of riboflavin for 8 weeks before intraperitoneal injection of 1 x 10(6) P. berghei parasites. Control animals were weight-matched to the respective riboflavin-deficient group. At 10 d post-infection, parasite counts were higher in the weight-matched control group than the riboflavin-deficient group (P = 0.004). GPx activity was higher in erythrocytes of rats parasitized with P. berghei than comparable non-infected rats regardless of riboflavin status (P < 0.05). As mature erythrocytes do not synthesize new protein, the higher GPx activities were probably due to the presence of the parasite protein. In erythrocytes from riboflavin-deficient rats, GPx activity tended to be lower than in those rats fed on diets adequate in riboflavin (weight-matched controls) whether parasitized or not, but the difference was not significant. Neither riboflavin deficiency nor malaria had any effect on erythrocyte SOD activity. It was concluded that riboflavin deficiency has no marked effect on erythrocyte GPx or SOD activity in the rat.

Animals↗
PubMed2006

Use of plants in novel approaches for control of gastrointestinal helminths in livestock with emphasis on small ruminants.

Helminth infections are a major cause for reduced productivity in livestock, particularly those owned by the poor worldwide. Phytomedicine has been used for eons by farmers and traditional healers to treat parasitism and improve performance of livestock, and many modern commercial medicines are derived from plants. However, scientific evidence on the anti-parasitic efficacy of most plant products is limited, regardless of their wide ethnoveterinary usage. Scientific validation of the anti-parasitic effects and possible side-effects of plant products in ruminants is necessary prior to their adoption as a novel method for parasite control. A variety of methods has been explored to validate the anthelmintic properties of such plant remedies, both in vivo and in vitro. In vitro assays are useful as pre-screens of activity and are mainly performed with the free-living rather than parasitic stages of nematodes. Concentrations of potentially active substances used in vitro do not always correspond to in vivo bioavailability. Therefore, in vitro assays should always be accompanied by in vivo studies when used to validate the anthelmintic properties of plant remedies. In vivo controlled studies have shown that plant remedies have in most instances resulted in reductions in the level of parasitism much lower than those observed with anthelmintic drugs. Whether it is necessary or not to achieve very high efficacy in order for plant remedies to have a role in the control of parasitism depends on the determination of biologically important levels of reduction of parasitism and it will be required prior to the wide-scale use of plant products for parasite control. Similarly, standardisation of validation studies in reference to the numbers of animals required for in vivo studies to measure direct anthelmintic effects of a plant needs to be established. Although in many cases the active compounds in the herbal remedies have not been fully identified, plant enzymes, such as cysteine proteinases, or secondary metabolites, such as alkaloids, glycosides and tannins have shown dose-dependent anti-parasitic properties. However, as some of the active compounds may also have anti-nutritional effects, such as reduced food intake and performance, it is essential to validate the anti-parasitic effects of plant products in relation to their potential anti-nutritional and other side effects. A concerted effort on isolation, development, and validation of the effects of these herbal remedies will have to be undertaken before their wider acceptance.

Animals↗
PubMed1987

Host effector mechanisms against parasites.

The first part of this presentation considers some of the complexities of parasitic infections and parasite-specific effector mechanisms which have hampered the development of practical methods of immunisation against parasitic diseases. In the second part, an outline is given of the effector mechanisms involved in immunity of cattle to the protozoan parasite Theileria parva. Parasites are antigenically complex organisms which often have distinct developmental stages, sometimes with different predilection sites within the host. Antigenic polymorphism between strains is a common feature of parasites and sometimes results in strain-specific immunity. Certain parasites have also evolved mechanisms of modulating surface antigens which allow them to escape host effector mechanism. Effector mechanisms which control parasitic infections may operate by preventing establishment of the parasites, by eliminating the parasites once they have established or by affecting growth or fecundity of the parasites. In addition to specific antibody and cell-mediated immune responses, inflammatory or physiological responses play an important role in the control of some parasites. Current evidence suggests that effector mechanisms against T.parva parasites operate at two levels. First, antibodies produced against the infective stage of the parasite, the sporozoite, can, by neutralising infectivity, reduce the numbers of organisms which establish in the host. Second, cytotoxic T cells directed against parasitised lymphoblasts cause destruction of parasites following their establishment in the host. Moreover, in situations where immunity is parasite strain-specific, the cytotoxic T cell responses have also been found to be strain-specific. The elucidation of these effector mechanisms has indicated potential new strategies of immunisation against T.parva.

Animals↗
PubMed2000

The CD40/CD40 ligand interaction is required for resistance to toxoplasmic encephalitis.

Since the CD40/CD40 ligand (CD40L) interaction is involved in the regulation of macrophage production of interleukin 12 (IL-12) and T-cell production of gamma interferon (IFN-gamma), effector cell functions associated with resistance to Toxoplasma gondii, the role of CD40L in immunity to this parasite was assessed. Infection of C57BL/6 mice with T. gondii results in an upregulation of CD40 expression on accessory cell populations at local sites of infection as well as in lymphoid tissues. Splenocytes from C57BL/6 mice infected with T. gondii for 5 days produced high levels of IL-12 and IFN-gamma when stimulated with toxoplasma lysate antigen, and blocking CD40L did not significantly alter the production of IFN-gamma or IL-12 by these cells. Similar results were observed with splenocytes and mononuclear cells isolated from the brains of chronically infected mice. Interestingly, although CD40L(-/-) mice infected with T. gondii produced less IL-12 than wild-type mice, they produced comparable levels of IFN-gamma but succumbed to toxoplasmic encephalitis 4 to 5 weeks after infection. The inability of CD40L(-/-) mice to control parasite replication in the brain correlated with the ability of soluble CD40L, in combination with IFN-gamma, to activate macrophages in vitro to control replication of T. gondii. Together, these results identify an important role for the CD40/CD40L interaction in resistance to T. gondii. However, this interaction may be more important in the control of parasite replication in the brain rather than the generation of protective T-cell responses during toxoplasmosis.

Animals↗