What if Malaria Parasite becomes Resistant to all Drugs?
In this last year, the worldwide attention has been on COVID19, however in the souther hemisphere malaria is still the main killer, or at least it still represents a burden for the people becoming ill in terms of lost days of work or other opportunities (WHO 2018–2020). Malaria is an infectious disease spread by mosquitos, which affects humans and other animals causing symptoms that typically include fever, tiredness, vomiting, and headaches, and ultimately death if untreated. There are several recognized treatments and prophylaxis. The most common prophylaxis is Malarone (atovaquone and proguanil), and the most common and effective treatments are derivates of artemisin. The story goes like this: A person is bitten by a mosquito carrying a malaria plasmodium, the plasmodium through the blood travel to liver where a specific form of it (merozoites) infects the red cells. Artemisin kills the parasites inside the red cells. Most of this cycle can be seen animated in the video below from the Howard Hughes Medical Institute:

A recent research paper, titled Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda (Uwimana et al. 2020), was published in Nature Medicine last week. In this work, researchers identified as Pfkelch13 R561H, the new parasite breed showing “early warning signs” of resistance to one of top antimalarial drugs. The study was conducted by researchers of the Rwanda Biomedical Center (RBC), the Ministry of Health, and the World Health Organization (WHO) [1]. Artemisinin, the core component of the bi-therapy drug against malaria used worldwide for the last 15 years (brand name in Africa “Co-artem” and Europe “Riamet”) did not work on the new strain, according to the research. This raises a lot of attention as this is the most common treatment worldwide, and in many European countries we have the mosquitoes vector which can spread the disease.

While the resistance was identified in a laboratory experiment, the researchers reported that it has not yet appeared among humans across the country. Despite resistance to the drug has not been reported yet in Africa in humans, it is better to be prepared to reinforce malaria prevention in anticipation of when Co-artem will not be an effective treatment, as this will represent a major public threat. The reason of concerns is given by the fact that other treatments have also been identified as having resistance at some degree in other regions of the planet. But the “early detection of resistance provides the best chance of minimizing its lethal impact,” as we can start researching new possibilities, and strengthen prophylaxis. Drug resistance can be imported or grow locally in areas with poor disease control measures. According to the research findings, the Rwandan strain is a new local emergence. Malaria P. falciparum strains resistant to artemisinin were previously reported for the first time in western Cambodia in 2009, and then subsequently detected in other parts of Southeast Asia [2], but this is the first time in the African continent. The figure below summarizes the philogenetic distributions of the resistant strains. Each line/color represents a different strain variation.

Genome‐wide phylogenetic tree of the malaria P. falciparum. Image from Uwimana et al. 2020

Subsaharan Africa, is highly endemic to malaria, contributing quite significantly to malaria, and resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) combination drugs has already been reported [3]. Indeed Co-artem came on the rise of compensating resistance to CQ and SP, but it is now threatened by the PfKelch13 strain.

Multiple hypotheses implicate PfKelch13 as a responder to downstream effects of artemisin activation, Birnbaum et al. found that PfKelch13 and its interacting proteins are localized in vesicles close to cytostomes (see picture below), and those vesicles might curb artemisin from killing the malaria parasite inside the red cells [4].

Image from Marapana, D., & Cowman, A. F. (2020). Uncovering the ART of antimalarial resistance. Science, 367(6473), 22–23.

Now, whether artemisin resistance will appear in human soon, whether co-resistance of artemisin and other treatment is also unavoidable are open questions. However, in this perspective it will be beneficial to further investigate the impact of PfKelch13, and in case develop variations of artemisin able to cope with it, or at least be prepared for the upcoming resistance.

If you want to know more about the diagnosis of malaria, check this story about microscopy

or this about genetic testing
['Dr. Alessandro Crimi']
['Pandemic', 'Genetics', 'Science', 'Biology', 'Medicine']