Immunizing against toxic malarial antigens.
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Journal Article↗
Biomedical subjects
I A Clark
Publications and source records attributed to I A Clark.
Interleukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis.
Adverse reactions following treatment of onchocerciasis and bancroftian filariasis are common and frequently severe. They are generally caused not by direct drug toxicity but by host inflammatory responses to dying microfilariae. To define the responsible mechanism, serial blood levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were studied in 15 microfilaria-positive patients (10 with bancroftian filariasis, 5 with onchocerciasis) and 4 microfilaria-negative persons after diethylcarbamazine treatment. Elevations in IL-6 correlated with the occurrence and severity of clinical symptoms after treatment; for the onchocerciasis patients IL-6 levels directly reflected pretreatment intensity of infection. Serum TNF levels also rose but did not correlate directly with infection intensity or reaction severity. Microfilaria-negative controls remained asymptomatic with no significant rise in either cytokine. These findings suggest an etiologic role for systemically elevated cytokines in the inflammatory reactions developing after treatment of filarial infections in humans.
Adult↗
Possible role of nitric oxide in malarial immunosuppression.
We have tested the hypothesis that nitric oxide may be responsible for the immunosuppression reported during malaria infections. We first showed that reactive nitrogen intermediates, which indicate nitric oxide generation, were increased in the plasma of Plasmodium vinckei-infected mice. We next found that Concanavalin A-induced proliferation of spleen cells from these mice was reduced compared with that observed in uninfected animals. The addition of NG-methyl-L-arginine (L-NMMA) for the duration of the cultures restored the malarial proliferative response to normal. We then tested the effect of oral L-NMMA on the proliferative response of P. chabaudi-infected mice to a human red blood cell lysate. The secondary response to this antigen, measured as spleen cell proliferation in vitro ten days after immunization and when there was no discernible parasitaemia, remained normal in L-NMMA-treated P. chabaudi mice, but was decreased in the untreated infected mice. These results suggest a role for nitric oxide in malarial immunosuppression.
Animals↗
Tumor necrosis factor and interleukin-1 synergy in the context of malaria pathology.
Reports linking human malarial illness and pathology with serum tumor necrosis factor (TNF) levels are now common, although the association is not always precise. Possible reasons for this discrepancy include the reported variation in levels of interleukin-1 (IL-1), a cytokine known to synergize with TNF. We have examined the extent of synergy between recombinant human TNF and either recombinant human IL-1 alpha or recombinant human IL-1 beta in producing hypoglycemia and increasing plasma levels of nitric oxide in malaria (Plasmodium vinckei)-infected CBA mice. Very low concentrations of either IL-1 alpha or IL-1 beta, with negligible effects on their own, greatly enhanced the effectiveness of TNF in bringing about these changes. In particular, synergy in generating nitric oxide, a mediator argued to induce cerebral malaria, was profound. Thus, variation in generation of IL-1 during infection provides one explanation for the poor correlation sometimes encountered between serum TNF levels and clinical condition.
Analysis of Variance↗
The pathophysiology of canine babesiosis: new approaches to an old puzzle.
The haemoprotozoan parasite, Babesia canis, is the cause of an economically important and potentially life-threatening disease of dogs in South Africa, the pathophysiology of which is incompletely understood. Available literature is reviewed, with emphasis on the pathophysiology of the anaemia and complications of babesiosis. The remainder of the review explores the possibility that pathophysiological mechanisms currently being investigated in human malaria and bovine babesiosis (in which, as in canine babesiosis, an intra-erythrocytic parasite causes multi-systemic pathology) might also be active in B. canis infections. The entity referred to as the multiple organ dysfunction syndrome is discussed as a proposed mechanism within which apparently unrelated aspects of babesiosis form a predictable pattern. The molecular mediators of multiple organ dysfunction, including cytokines, nitric oxide and free oxygen radicals, are generated by host tissues, and are now under active study to help elucidate the pathophysiology of malaria. The similarities between the manifestations of different diseases in different host species can be explained by the concept that the disease process is largely mediated by these molecules, generated by the host in response to the parasite, rather than arising directly from the parasite itself. The current direction of malaria research provides a basis for future research into the pathophysiology of canine babesiosis.
Anemia↗
Nitric oxide and cerebral malaria.
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Amino Acid Oxidoreductases↗
TNF in cerebral malaria.
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Antibodies, Monoclonal↗
Possible central role of nitric oxide in conditions clinically similar to cerebral malaria.
The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the blood brain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.
Amino Acid Oxidoreductases↗
In vivo induction of nitrite and nitrate by tumor necrosis factor, lymphotoxin, and interleukin-1: possible roles in malaria.
Tumor necrosis factor and related cytokines are thought to be implicated in cell-mediated immunity and pathophysiology in malaria, but their mechanism of action has not been ascertained. Tumor necrosis factor has been reported to generate nitric oxide in vitro, so we have measured levels of this molecule and its products in the plasma of mice after they have received an injection of tumor necrosis factor, lymphotoxin, interleukin-1, gamma interferon, or interleukin-6, all of which have been reported to be increased in malaria. Total reactive nitrogen intermediate levels in plasma were assayed spectrophotometrically after exposing plasma to a copper-cadmium-zinc catalyst to convert nitrate to nitrite and then to Griess reagent. Tumor necrosis factor, lymphotoxin, and interleukin-1 all induced reactive nitrogen intermediates in vivo, with interleukin-1 showing the most activity. Tumor necrosis factor was then examined more closely. It induced more reactive nitrogen intermediates in malaria-infected mice than in normal mice, and appreciably more was in the form of nitrate than was in the form of nitrite. NG-methyl-L-arginine inhibited the in vivo generation of reactive nitrogen intermediates by tumor necrosis factor in a dose-dependent manner, implying that these molecules were arginine derived. These results are consistent with the possibility that tumor necrosis factor, lymphotoxin, and interleukin-1 may contribute to host pathology and parasite suppression through generation of nitric oxide.
Animals↗
Roles of TNF in malaria and other parasitic infections.
Comprehension of the involvement of cytokines in the host response against invading parasites, to the detriment of the parasite and (in larger doses) to the host, is expanding rapidly. Most of these studies, largely for historic reasons and availability, have been done with TNF rather than the other mediators. As is emerging in other fields, study of interleukin-1 alone, and synergistically with TNF and IFN-gamma, warrants further exploration in parasitic diseases. There may well be a similar story for TNF-beta, waiting to unfold. It is appropriate here to show deference to earlier malariologists, back to the nineteenth century, whose observations and reasoning were evidently accurate when they attributed malarial illness and pathology (including cerebral malaria) to a malarial toxin (reviewed by Clark and Tomlinson, 1949). The only additional insight required of present-day workers has been to see the malaria parasite not as a source of a direct toxin, but of molecules, harmless in themselves, that can act as a trigger for toxic products of host origin. As a final twist, low concentrations of these host-derived "toxins" are not only harmless, but necessary for normal biological functions. They are deleterious only when overproduced.
Anemia, Hemolytic↗
Malaria mimicry with tumor necrosis factor. Contrasts between species of murine malaria and Plasmodium falciparum.
Because Plasmodium berghei ANKA induces cerebral malaria and P. vinckei does not, the former has often been studied as a model for human falciparum malaria. It lacks, however, many of the systemic changes seen in the human disease. Because both of these murine models and the human disease have now been defined in terms of excess tumor necrosis factor (TNF) production, the authors have more closely examined the two murine models in this light to see which provides the better overall model for falciparum malaria. Administering TNF to malaria-infected mice did not cause cerebral symptoms nor breakdown of the blood-brain barrier, which is the hallmark of P. berghei ANKA cerebral malaria and is generally absent in human cerebral malaria. Tumor necrosis factor did, however, induce hypoglycemia and liver injury, pathology that is seen in terminal P. vinckei and falciparum malaria, but is absent in terminal P. berghei ANKA malaria. Plasma TNF and interleukin-6 (IL-6) also were found to be consistently higher in infections caused by P. vinckei than in those caused by P. berghei ANKA. The pathology of P. vinckei malaria is thus consistent with raised systemic levels of TNF and other cytokines, as is falciparum malaria. The authors therefore conclude that P. vinckei malaria, although lacking a cerebral component, is the better model for the human disease.
Animals↗
Role of TNF in cerebral malaria.
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Brain Diseases↗
Proposed link between cytokines, nitric oxide and human cerebral malaria.
Nitric oxide (NO), also known as endothelial-derived relaxing factor (EDRF), is generated by a range of cell types including endothelial cells, smooth muscle cells and neurons, and mediates a range of different physiological functions, such as maintenance of vascular tone and neuro-transmission. In this article, Ian Clark, Kirk Rockett and Bill Cowden propose that when vascular generation of NO is particularly high (for example, if local intravascular levels of tumour necrosis factor (TNF) are markedly increased) this mediator could diffuse to nearby neurons, be misinterpreted as being of synaptic origin and thus interfere with orderly neuro-transmission. NO of vascular origin could also, through vasodilation of cerebral vessels, contribute to increased intracranial pressure and thus to certain of the clinical signs seen in cerebral malaria. As well as contributing to cerebral malaria, these phenomena could also lead to the neurological changes observed in certain other systemic diseases.
Journal Article↗
Flavins as potential antimalarials. 2. 3-Methyl-10-(substituted-phenyl) flavins.
A series of 3-methyl-10-(substituted-phenyl)flavins was prepared and tested for antimalarial activity against the lethal parasite Plasmodium vinckei in mice. Several of these analogues were found to be effective antimalarial agents. A quantitative structure-activity relationship study was undertaken with 44 analogues and no satisfactory relationship could be established.
Animals↗
Killing of Plasmodium falciparum in vitro by nitric oxide derivatives.
We have investigated the in vitro susceptibility of the human malaria parasite Plasmodium falciparum to killing by nitric oxide and related molecules. A saturated solution of nitric oxide did not inhibit parasite growth, but two oxidation products of nitric oxide (nitrite and nitrate ions) were toxic to the parasite in millimolar concentrations. Nitrosothiol derivatives of cysteine and glutathione were found to be about a thousand times more active (50% growth inhibitory concentration, approximately 40 microM) than nitrite.
Animals↗
TNF and inhibition of growth of Plasmodium falciparum.
The mechanism of intra-erythrocyte death of Plasmodium chabaudi in vivo has not yet been elucidated. Here we summarise recent experiments in which serum from mice undergoing a successful immune response to this parasite did not inhibit Plasmodium falciparum in vivo unless the P. chabaudi infection and TNF levels were high enough to cause illness in the host. This was true for the 556KA and DS strains of P. chabaudi in intact mice, but not for 556KA in nude mice, which did not generate inhibitory activity at any parasitaemia. Tumour necrosis factor (TNF) inhibits malaria parasites via some undefined secondary mediator. 10 mg of r hu TNF generated this inhibitory activity, as measured against P. falciparum in vitro, in the serum of mice only if they were pretreated with Corynebacterium parvum, which activates macrophages and sensitises the mice to the toxic effects of TNF. This implies a role for activated macrophages downstream from TNF in the process involved in intra-erythrocytic death of parasites.
Animals↗
TNF and Plasmodium berghei ANKA-induced cerebral malaria.
The cerebral pathology observed in Plasmodium berghei ANKA-infected CBA mice has been attributed to overproduction of TNF, the mice in which this syndrome is seen being those with the highest serum TNF levels. To investigate this further, we injected recombinant human TNF into malaria-primed mice to see if we could reproduce the cerebral changes observed in P. berghei ANKA infections. A range of doses, administered as a single or repeated injections, or via osmotic pumps, failed to reproduce these changes, but did induce hypoglycaemia, midzonal liver necrosis and neutrophil adhesion in pulmonary vessels. This pathology is seen in terminal Plasmodium vinckei infections, but absent in terminal P. berghei ANKA. In addition, the permeability of the blood-brain barrier to Evan's blue, which is present in P. berghei ANKA but not in normal or P. vinckei-infected mice, was not induced by exogenous TNF. Serum levels of TNF were measured in an ELISA assay, and found to be consistently higher in P. vinckei rather than P. berghei ANKA terminal infections. This is consistent with the pathological changes we could reproduce by injecting TNF. For these reasons we suggest that the cerebral pathology seen in mice infected with P. berghei ANKA may be governed by TNF produced locally by monocytes sequestered within the cerebral blood vessels, not simply by systemic levels of this cytokine.
Animals↗
SLE and malaria: another look at an old idea.
An alternative view of the relationship between autoimmune disease and malaria is provided in the following article by Geoff Butcher and Ian Clark. Here they reassess the evidence that favours an earlier suggestion that where parasitic infections are common, autoimmune disease is rare. They suggest that malaria may exert a protective effect against the autoimmune nephritis in systemic lupus erythematosus (SLE).
Journal Article↗