Combination therapy protects the brain from malaria infection

Anti-malarial drugs are highly effective if they’re administered before serious clinical symptoms strike. However, they presently don’t target some of key the damage caused by malaria, such as brain and tissue damage caused by the body’s own immune response.

Now researchers at the Walter and Eliza Hall Institute have shown that a new anti-inflammatory drug can prevent serious brain and tissue damage in mice with malaria.

This raises the possibility of a combination therapy including the anti-inflammatory alongside conventional anti-malarials to combat the parasite and its damaging effects.

The team was led by Associate Professor Louis Schofield along with Dr Ariel Achtman and Dr Sandra Pilat-Carotta, and investigated a new class of anti-inflammatory agents, called IDR (innate defense regulator) peptides.

They used IDR-1018, which is currently used by veterinarians to treat infections in large animals, in mice infected by the Plasmodium berghei parasite.

The aim was to reduce the inflammation in the brain, which is part of the body’s immunological response to the malaria parasite, yet is the case of the brain and tissue damage.

They found that co-administration of IDR-1018 with standard first-line anti-malarials increased survival of infected mice by reducing inflammation.

“In this study, we showed that a new class of drugs could prevent inflammation in the brains of mice with malaria and improve their survival,” said Dr Pilat-Carotta. “This is an example of a ‘host-directed’ therapy – a treatment intended to act on the host not the parasite,” she said.

“On their own, antimalarial drugs fail in approximately one out of every four cases of severe clinical malaria, because by the time the patient arrives at a hospital they are already very sick and inflammation caused by the immune response to the parasite is causing major organ damage,” said Professor Schofield.

IDR peptides are a new class of anti-inflammatory agent developed by Professor Robert Hancock and colleagues at the University of British Columbia, Canada, which enhance beneficial aspects of the initial immune response while dampening harmful inflammation, Schofield said.

“IDR peptides are also relatively cheap to produce and easy to use, making them a good option for medical treatments in developing countries,” he said.

Dr Achtman said the development of preclinical models of severe malaria could improve pre-clinical drug screening and potentially prevent some of the drug failures that happen at the human clinical trial stage.

“Professor Gordon Smyth and Ms Charity Law from the institute’s Bioinformatics division used sophisticated bioinformatics-driven analyses to identify early changes to inflammatory processes, days before the mice show visible changes in malaria disease symptoms.

“Host-directed therapies are a good treatment option because parasites are less likely to evolve resistance, and we believe they will eventually increase the number of successful treatment interventions in the short time window between hospitalisation with severe malaria and death,” Dr Achtman said.

The study was published in Science Translational Medicine today.