For decades now, combination therapies with Artemisinin, a potent anti-malarial drug, have been the cornerstone of malaria treatment worldwide. It has always vexed scientists that some malaria patients failed to clear the parasite and went into relapse despite receiving the right treatment.

This happened even when scientists could not detect any genetic mutations in the parasite (Plasmodium falciparum) which might have rendered it resistant to drugs

Researchers at the Rajiv Gandhi Centre for Biotechnology (RGCB) might just have unravelled this mystery with their discovery that it was host factors rather than genetic mutations acquired by the parasite which led to drug resistance and treatment failure.

Christeen Davis and colleagues at the RGCB, established through their research that malaria parasites were able to withstand or resist artemisinin because of the protective biochemical environment created by the immature or young red blood cells known as reticulocytes in the patient’s own blood.

These findings may add an entirely new dimension to how scientists may think about drug resistance and offer a new perspective on how host biology influences a disease and its treatment.

The study, titled “Host Reticulocyte Redox Attenuation Creates a Protective Niche for Artemisinin Tolerance in Plasmodium falciparum”, was published in the latest (June 16) issue of the Journal of Infectious Diseases as an Editor’s Choice article.

Artemisinin kills the parasite by a biochemical assault. It generates a flood of free radicals which lead to oxidative damage inside the parasite.

Reticulocytes, the new, freshly minted red blood cells released from the bone marrow, are loaded with antioxidants, nutrients and protective enzymes, capable of neutralising oxidative stress.

Preference for reticulocytes

Researchers demonstrated that the malaria parasite P. Falciparum had a preference for reticulocytes and actively sought out these young cells. In the antioxidant-rich environment of reticulocytes, the parasites multiplied faster and could withstand and rebound from the artemisinin-induced oxidative and protein damage far more efficiently than in mature red blood cells.

They also demonstrated that this protective effect disappeared when the parasites were transferred back into mature cells, a clear proof that resistance to artemisinin was driven by the host cell environment rather than permanent genetic changes in the parasite.

In fact, the host’s own biology is providing a protective shield so that the malaria parasite can survive the biochemical assault by artemisinin.

Research so far has largely focussed on the genetic changes within the parasite that lead to drug resistance

“Our findings demonstrate that the biology of the host cell can significantly influence how malaria parasites respond to treatment. The parasite is not acting alone. It exploits the natural antioxidant defences present in young blood cells to protect itself from drug-induced stress,” said Rajesh Chandramohanadas, senior author of the study and principal investigator at RGCB.

Clinical relevance

The study has clinical relevance as children, anaemic patients, and individuals recovering from blood loss or infection, often have elevated levels of reticulocytes in circulation and these are the patients in whom the malaria parasite may persist, despite treatment.

The researchers believe that future malaria therapies may benefit from targeting host-parasite interactions in addition to the parasite itself. Understanding how parasites exploit antioxidant pathways within reticulocytes could open new avenues for improving the effectiveness of existing antimalarial drugs and reducing treatment failures.