gms | German Medical Science

Malaria is still one of most important infectious diseases despite intensive research and decreasing numbers of fatalities. Among the various outcomes caused by different Plasmodium strains, cerebral malaria (CM) caused by Plasmodium falciparum is the most severe and accounts for almost all malaria deaths. The mechanisms involved in CM development are not completely understood but it is widely accepted that an overwhelming inflammatory response also affecting the brain is at least partly responsible for the disease progression. Current treatment recommendations for CM patients focus primarily on fast elimination of the parasites from the blood but do not target the cerebral inflammation.

We addressed the question whether the antibiotics doxycycline was able to interfere with CM development by using the murine experimental model of Plasmodium berghei ANKA infected C57BL/6 mice. To mimic the clinical situations of already infected malaria patients, PbA-infected mice were treated from day 4–6 p.i. with DOX, which successfully prevented experimental CM (ECM) in an IL-10-independent manner [1]. Furthermore, this DOX mediated protection correlated with reduced systemic and local inflammation, resulting in significantly increased survival of the infected mice [1]. However, since DOX treatment led to decreased parasitemia on day 6 p.i., it remained difficult to differentiate between anti-inflammatory effects of DOX and altered inflammation caused by reduced parasite loads.

Here we show that DOX treatment of PbA infected mice that received before a 20fold higher infective dose was still able to prevent death in mice with similar parasitemia 6 days p.i. when compared to control-infected mice that did not receive DOX and developed ECM at this time point. Similarly to the previous experiments, DOX treatment diminished cerebral inflammation as shown by decreased migration of immune cells to the brains of treated mice. Activation markers of cytotoxic immune cells as well as cytokine production from these cells were significantly reduced in brain and spleen after treatment. In addition, we could also show in preliminary experiments that a sub-antimicrobial dose of doxycycline was able to prevent ECM despite increasing parasitemia.

Our newest results support the original hypothesis that DOX targets inflammatory processes in the central nervous system (CNS) and prevents ECM by a combination of anti-inflammatory and anti-parasitic effects. Further research is required to evaluate how inclusion of DOX to standard treatment regimens could improve the outcome of (E)CM even after onset of cerebral symptoms.