Pathogenesis of malaria and clinically similar conditions - PubMed (original) (raw)

Review

Pathogenesis of malaria and clinically similar conditions

Ian A Clark et al. Clin Microbiol Rev. 2004 Jul.

Abstract

There is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. This is also true of certain noninfectious states, such as the tissue injury syndromes. This review discusses the historical origins of these ideas, which began with tumor necrosis factor (TNF) and spread from their origins in malaria research to other fields. As well the more established proinflammatory mediators, such as TNF, interleukin-1, and lymphotoxin, the roles of nitric oxide and carbon monoxide, which are chiefly inhibitory, are discussed. The established and potential roles of two more recently recognized contributors, overactivity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the escape of high-mobility-group box 1 (HMGB1) protein from its normal location into the circulation, are also put in context. The pathogenesis of the disease caused by falciparum malaria is then considered in the light of what has been learned about the roles of these mediators in these other diseases, as well as in malaria itself.

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Figures

FIG. 1.

FIG. 1.

The proposed central role of HMGB1 in the amplification and perpetuation of inflammation. As well as excessive TNF and IL-1 inducing HMGB1 secretion, they can be predicted to run down cellular energy through overactivating PARP-1, thus favoring necrosis, which releases HMGB1 from the nucleus, over apoptosis, which is energy dependent and does not cause HMGB1 release. By increasing the expression of RAGE (a receptor for which HMGB1 is one of several ligands) and then activating it, HMGB1 induces a further wave of inflammatory cytokines, including the TNF and IL-1 that induced it in the first place. Thus, HMGB1 is thought to amplify and extend inflammatory reactions.

FIG. 2.

FIG. 2.

The shared ability of cytokine-induced NO and CO to inhibit TNF production and therefore provide a negative-feedback loop to inhibit the illness and pathology in cytokine-release syndromes. Reprinted from reference with permission from the publisher.

FIG. 3.

FIG. 3.

HO-1 staining of liver tissue, showing a representative field of the three cases in which death was not associated with severe systemic infection or coma (A) and and a representative field from the 37 malaria or sepsis patients who had been comatose before death. Biotin-conjugated secondary antibody and streptavidin-conjugated horseradish peroxidase from an LSAB+ kit (DAKO) were applied to sections to amplify the antigen signal for subsequent 3,3′-diaminobenzidine staining, which produces a permanent brown color. Magnification, ×400.

FIG. 4.

FIG. 4.

HO-1 staining of brain (A to C) and liver (D to F) tissue of each of the three categories used to group the 32 clinically defined cases of cerebral malaria, on the basis of their histological and immunohistochemistry findings, as CM(A), (A and D), CM(B), (B and E); and CM(C) (C and F). Panel A typifies the 11 cases with isolated or undetectable parasites or HO-1-stained monocytes in brain sections. Panels B and C are examples from the 7 and 14 cases, respectively, with increasing parasite and cellular involvement in cerebral blood vessels: Panel B shows an influx of young intraerythrocytic malaria parasites (para) but negligible monocytes, and panel C illustrates the more mature parasites, monocyte accumulations (mono), and microhemorrhages (hemorrh) typical of CM(C). All three categories showed systemic inflammation, as demonstrated by strongly staining Kupffer cells (D to F). Dilution of primary anti-HO-1 antibody (StressGen) was 1:1,000. Staining was done as described for Fig. 3. Magnification, ×200 in all cases.

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