Publisher Summary The resurgence of malaria in the past two decades has stimulated a considerable amount of scientific and medical research. Understanding of pathophysiological mechanisms in malaria has advanced considerably in areas, such as the pathogenesis of metabolic dysfunction, the molecular processes involved in cytoadherence, and the causes of anaemia. However, in other areas progress has been slow. Much of the recent research has been conducted either with animal models or with cultured P. fakiparum parasites. The relevance of the observations, and the hypotheses they generate, to disease in man still needs to be established in many cases. The roles of cytoadherence, rosetting, and cytokine release have come to the fore, whereas the parts played by immune damage, intravascular coagulation, and increased vascular permeability have receded. Clinical investigation has taken some of the mystery out of malaria, but still relatively little is known for certain. The next challenge is to translate these advances in understanding of pathophysiology into improved treatments.

The pathophysiology of malaria.

Evidence is presented here that tumor necrosis factor/cachectin (TNF), is of crucial importance in the pathogenesis of cerebral malaria. First, the central lesion of CM, hemorrhagic necrosis of cerebral vessels, corresponds to lesions observed during other pathological conditions associated with high serum TNF levels, such as endotoxemic shock or administration of TNF. Second, in both mouse and human, there is a close correlation between high serum TNF levels and CM. At least in mouse, high TNF levels and CM depend upon T lymphocytes of the CD4+ phenotype. Third, passive immunization against mouse TNF significantly prolongs the survival of P. berghei-infected CBA/Ca mice, and prevents the development of neurologic signs. Treatment with the anti-TNF antibody also prevents hemorrhagic necrosis of brain vessels. Fourth, in the mouse model, a cytokine cascade including at least GM-CSF, IL-3 and IFN-gamma is required for the elevation of TNF level. This cascade appears to involve two components: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Fifth, metabolic parameters of CM and its main lesion in both mouse and human, i.e. the hemorrhagic necrosis of small brain vessels, correspond to the known properties of TNF.

Tumor-Necrosis Factor and other Cytokines in Cerebral Malaria: Experimental and Clinical Data

Red cell surface changes and erythrophagocytosis in children with severe plasmodium falciparum anemia.

Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.

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The Plasmodium bottleneck: malaria parasite losses in the mosquito vector.

Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood-stage malaria.

A total of 32 patients with Plasmodium falciparum malaria were studied. Of these, 23 had benign infections, and 9 had typical cerebral malaria. Cryoglobulins, circulating immune complexes detected by a C1q-binding assay, and hypocomplementemia were found in eight of nine patients with cerebral malaria. Raised levels of complement component 3 breakdown products (C3d) were found in the seven patients tested. Peak levels of circulating immune complexes and C3d were associated with thrombocytopenia. In contrast, in patients with benign Plasmodium falciparum malaria, cryoglobulins and circulating immune complexes were found only in 3 of 23 patients. Similarly, hypocomplementemia was detected only in 5 of 23 patients. These observations suggest that the intensity of the immune response and of the associated complement activation may be important factors in the pathogenesis of cerebral malaria.

https://iai.asm.org/content/iai/31/2/530.full.pdf

Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria.

The relation between the duration of bacterial infection and circulating immune complexes (CIC) level was evaluated using the C1q binding assay in a group of patients with well defined clinical sepsis. Fifty-four patients with endocarditis and 35 with post-open heart surgery mediastinitis were prospectively studied over a period of 2 years. CIC were detected in 42% of patients studied. Interindividual variations were observed but it was found that the level of CIC increased statistically with time (P less than 0.001). CIC were statistically linked with cryoglobulinemia (P less than 0.001), rheumatoid factor (P less than 0.001) and a decreased CH50 (P less than 0.05). CIC were more frequent in patients with endocarditis (53%) than in patients with mediastinitis (24%). However, when the duration of the infection was taken into account the difference was no longer significant. No relation could be evidenced between the incidence of CIC and clinical symptoms including prognosis and renal signs. In our experience, determination of CIC does not have a critical clinical value.

C Gibert

Papers

Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria.

Circulating immune complexes and severe sepsis: duration of infection as the main determinant.