Human malarial disease: a consequence of inflammatory cytokine release

Abstract

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficiency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease.

Figure 1

The proposed influence of differences in thrombomodulin levels on cytokine-induced expression of adhesion molecules on endothelial cells, and monocyte attraction, in different organs. (a) tissues with low endothelial thrombomodulin levels (b) tissues with high levels.

Figure 2

Immunohistochemical staining of the gut wall of malaria patients to detect iNOS. Techniques (DAB, haematoxylin), materials and controls as in reference 71. Cases (a) MP6 and (b) MP21 (see Table 1 of ref. 71) are shown. Unpublished data.

Figure 3

Proposed control of pro-inflammatory cytokines over the influences that limit oxygen delivery, as well as over the capacity of mitochondria to use oxygen.

Figure 4

Immunohistochemical staining of (a) chest wall and (b) diaphragm muscle of malaria patients to detect iNOS. Techniques (DAB, haematoxylin), materials and controls as in reference 71. Cases (a) MP21 and (b) MP39 (see Table 1 of ref. 71) are shown. Unpublished data.

Figure 5

Immunohistochemical staining of cerebrum of (a) African paediatric control (MP41), (b) Salmonella enteritidis (MP12) and (c) P. falciparum (MP6) to detect S100A12. Techniques (DAB, haematoxylin) as in reference 71. Antibody courtesy of Dr Carolyn Geczy. See Table 1 of ref. 71 for case details. Unpublished data.