A team of scientists has identified two molecular pathways that can lead to new therapeutic targets for cerebral malaria and also, discovered a novel link between food intake during the early stages of infection and the outcome of the disease.
Cerebral malaria, which is a severe form of the disease, is the most serious consequence of infection by the parasite Plasmodium falciparum, resulting in seizures, coma, and death.
Senior author James Mitchell from Harvard T. H. Chan School of Public Health said that they have known for a long time that nutrition can affect the course of infectious disease, but they were surprised at how rapidly a mild reduction in food intake could improve outcome in a mouse malaria model.
However, the real importance of this work is the identification of unexpected molecular pathways underlying cerebral malaria that they can now target with existing drugs, added Mitchell.
Lead authors Pedro Mejia and J. Humberto Trevino-Villarreal found that leptin, a hormone secreted from fat tissue with roles in suppressing appetite, but also in activating adaptive immune and inflammatory responses, is increased upon infection in a mouse model of cerebral malaria, and turns out to be a major bad actor in promoting neurological symptoms and death.
Researchers showed that reducing leptin using a variety of means, either genetically, pharmacologically, or nutritionally by reducing food intake during the first two days of infection, protected against cerebral malaria.
The researchers also found that leptin acted primarily on cytotoxic T cells by turning on the well-studied mTOR protein, for which pharmacologic inhibitors are readily available. In their animal model, treating mice with the mTOR inhibitor rapamycin protected them against the neurological complications of cerebral malaria.
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Protection was due in part to a preservation of the blood brain barrier, which prevented the entry of blood cells carrying the parasites into the brain. As rapamycin is already FDA-approved for use in humans, trials in humans for cerebral malaria treatment with this drug may be possible, according to the researchers.
The study appears online in Nature Communications.
