Prevention of Experimental Severe Malaria

Background: Severe malaria, including cerebral malaria and malaria-associated acute respiratory distress syndrome, remains associated with high mortality despite anti-plasmodial and supportive therapies. This study evaluates whether a drug combination can prevent severe malaria complications in a well-defined experimental model. The combination includes an anti-plasmodial artemisinin derivative, a tyrosine kinase inhibitor originally developed for anti-angiogenic cancer therapy, and the general immunosuppressant dexamethasone. Methods: C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA sub1a strain). Disease progression was assessed using MRI, histology, and liver enzyme analysis and by monitoring parasitemia and survival. The drugs administered included the anti-plasmodial agent artemisone (Art), dexamethasone (Dex), a systemic immunosuppressant, and apatinib (Apa) and sunitinib, both angiogenesis inhibitors. Additional experiments were performed in infected Ncr1-deficient and Tigit-KO transgenic mice (which show decreased or increased activation of NK cells, respectively). Results: PbA infection in C57bl/6 mice induced mild cerebral pathology, severe pulmonary inflammation with edema and microhemorrhages, and elevated liver enzymes, followed by death within a week post-infection, despite relatively low parasitemia on the day of death. Early treatment with Art, starting two- or three days post-infection (PI), killed the parasites and led to complete recovery. Dex, Apa, and sunitinib, initiated at the same early time points PI, prevented acute mortality. However, about two weeks later, these mice developed high parasitemia and succumbed to the disease. Late treatment (starting five days PI) with the individual compounds was ineffective. In contrast, late combined treatment with Dex, Apa, and Art eliminated the plasmodia and rescued most mice. Infection of Ncr1-deficient or Tigit-KO mice resulted in rapidly fatal disease with a course similar to that in mice with the same genetic background, indicating that partial immunosuppression or immune enhancement is insufficient to inhibit malaria progression and that NK cells do not necessarily play a role in the pathology. Conclusions: Multi-target therapy using anti-plasmodial, immunomodulatory, and anti-angiogenic agents has the potential to prevent severe malaria complications and improve survival outcomes.