Malaria immunopathology: Signaling and cellular mechanisms involved in hemozoin -inducible proinflammatory events

Malaria, caused by the protozoan parasite Plasmodium falciparum , is the most important parasitic disease worldwide. There are 300 to 500 million clinical cases every year, and between 1 and 3 million deaths, mostly of children, are attributable to this infection. Although it is widely accepted that an exacerbated immunological response contributes to the pathogenesis of severe malaria, the parasite components responsible for such activation and the underlying mechanisms remain largely unexplored. Hemozoin (HZ), a parasitic waste product of hemoglobin digestion, was previously considered an inert metabolite. However, several lines of evidence, including its rapid phagocytosis, its accumulation inside various organs and its ability to modulate macrophage (M&phis;) functions, along with the production of anti-HZ antibodies by malaria patients, suggest that HZ might play a role in malaria immunopathology. Therefore, in the current study we attempted to better define the contribution of HZ to the proinflammatory events associated to malaria, and to identify the mechanisms underlying its upregulatory effects in M&phis;. HZ was found enhance IFN-γ-inducible iNOS transcription and subsequent NO production and to increase the expression of various chemokine transcripts through specific second messengers (oxygen radical generation, phosphatase downregulation, MEK1/2-ERK1/2 phosphorylation and NF-κB activation). These data indicate that by triggering specific intracellular signals, HZ induces and enhances important M&phis; responses, which may help to exacerbate the immunological response. Importantly, the proinflammatory activity of HZ was demonstrated in vivo, including its ability to induce leukocyte recruitment as well as chemokine, chemokine receptor, and cytokine production. Altogether, these findings support the idea that HZ participates in inflammatory mediator overproduction during malaria and therefore, it might be a key component in the development of severe disease. Although a causal link between HZ and the clinical manifestations of malaria remains to be established, our data warrants further investigation of HZ as an immunomodulator. A better understanding of the antigenic properties of HZ as well as the analysis of the local and temporal effects of HZ in vivo will be helpful in the design of future immune treatments against malaria to prevent millions of deaths.