Pathogenesis of Malaria and Clinically Similar Conditions

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

Shared features in the pathobiology of babesiosis and malaria

“…Tumor necrosis factor (TNF) was soon identified as a probable candidate and also recognized as causing pathology if produced in excess in mice infected by Plasmodium vinckei [25]. Administration of recombinant TNF to human volunteers induces most of the symptoms of babesiosis and malaria, including fever, sweats, chills, headache, myalgia, abdominal pain, nausea, vomiting and diarrhea [26,27]. Markedly elevated serum concentrations of TNF, IFN-g, IL-2, IL-6, E-selectin (expressed in the endothelium), vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) occur during the acute phase of human B. microti infection and return to baseline a month after resolution of infection [28].…”

“…Evidence has accumulated that whereas moderate production of TNF might help to eradicate Babesia and Plasmodium spp. parasitemia, excessive production of TNF and related proinflammatory cytokines is primarily responsible for symptoms associated with these infections [24,26,[29][30][31][32][33][34][35].…”

“…Arguments have emerged that erythrocytic-associated changes following babesial or malarial infection, including erythrocyte lysis, adherence to endothelial cells and restriction of blood flow in the microvasculature, seem less likely to account for the typical symptoms associated with these diseases [26,29]. The synchronous release of Plasmodium spp.…”

“…Thus, events associated with erythrocyte lysis (such as release of parasites into the bloodstream), rather than lysis of the erythrocyte itself, seem to be responsible for these symptoms. Although erythrocyte adherence to endothelial cells might occur in mild to moderate malaria, as evidenced by the absence of mature forms of the parasite in the circulation, sequestration of large numbers of erythrocytes with subsequent restriction of blood flow to microvessels has only been linked with severe malarial disease and is absent in people experiencing asymptomatic persistent malaria [26]. Similarly, erythrocyte adherence occurs in cattle that are chronically infected by Babesia bigemina but remain asymptomatic [37].…”

“…The pathogenesis of severe P. falciparum infection is complex and incompletely understood, but major pathologic events include: (i) overproduction of inflammatory cytokines triggered by the parasite; (ii) microvascular obstruction and tissue hypoxia caused by adherence of erythrocytes to vascular endothelium; (iii) anemia and tissue anoxia caused by lysis of erythrocytes; (iv) hypoglycemia and lactic acidemia caused by anaerobic metabolism of glucose; (v) tissue hemorrhage owing to alteration in hemostasis; and (vi) cerebral, pulmonary, renal and hepatic impairment caused by the cumulative effects of these pathologic processes [6,26].…”