Malaria is caused by a parasitic protozoan called plasmodium that is transmitted by anopheles mosquitoes. Of the five main species that infect humans, plasmodium falciparum is the most virulent, meaning it is the most deadly, and is extremely common in impoverished countries. Malaria fatalities have fallen in recent years, which owes some credit to the efforts of the UN, which decided that malaria was a critical issue in 2021 and began a global initiative to reduce global fatalities to malaria. As the project went on, more money was raised and global mortality dropped from an estimated 895,709 in 2000 to 608,000 in 2022, 95% of whom lived in the WHO African Region. Malaria has plagued humanity for much of human history; its ancient presence in Africa likely resulted in the popularity of sickle-cell anemia and thalassemia in endemic areas, which provide resistance to malaria. Malaria’s terrorization of Africa is further exemplified by the prevalence of the Duffy antigen, a genetic trait that provides resistance to plasmodium vivax, which had been endemic in Africa when the gene was estimated to have evolved 42,000 years ago. As a result, p. vivax is not common in Africa, especially in comparison to p. falciparum, which the Duffy antigen does not protect against.

Malaria is not a contagious disease because the life cycle of plasmodium relies on both its host organism and its vector, anopheline mosquitoes. When a mosquito takes a blood meal from an infected individual, it ingests gametocytes, which are the reproductive cells of plasmodium. Inside the midgut lumen of the mosquito, the gametocytes differentiate and fertilize to form a zygote, which contains the genetic information of a female and male gametocyte. The zygote then transforms into an ookinete, which burrows into the wall of the mosquito’s midgut and forms an oocyst on the other side. Inside the oocyst, sporozoites multiply until the oocyst ruptures and the sporozoites flood to the salivary glands so they can be transmitted to a new host. Once inside the new host, sporozoites travel to the organism’s liver and multiply, differentiating and multiplying until some eventually turn into gametocytes, which are ingested by mosquitoes when they take a blood meal and the cycle continues. 

Even after malaria seems to have left a patient, the disease can return in two ways: recrudescence and relapse. Recrudescence occurs when faint levels of parasites remain in the host, which can happen when a balance is formed by the immune system where the parasites aren’t completely eliminated, but condition doesn’t worsen, and that balance can be kept for long periods of time. The problem arises when the host’s immune system is disrupted by another ailment and parasite populations are no longer controlled, allowing them to reestablish and cause the illness to return. Relapse can occur even after all parasites seem to be absent in human hosts, as plasmodium vivax has been observed to form hypnozoites, dormant cells that differentiate from sporozoites, which can colonize in the liver, and can survive even as other p. vivax cells have been wiped out by antimalarial treatment. Patients can also be asymptomatic, which is particularly common in endemic regions because immunity is acquired, meaning they carry plasmodium gametocytes without experiencing symptoms. This is actually dangerous because if they move to an area with little or no cases of malaria, they can unknowingly cause a resurgence of cases if a mosquito takes a blood meal from them and transmits it to other individuals, or if they donate blood or organs, as undetected parasite populations can grow and cause illness in the new host.

There are a variety of methods in use and being researched to reduce the rates of cases and deaths from malaria, including the application of insecticides, bed nets, treatments, vaccines, and various other tools. One of the first known treatments for malaria is quinine, a compound found in the bark of the cinchona tree native to South America used in the 1600s. Since then, chemotherapy and five classes of antimalarial drugs have been developed that inhibit plasmodium in different ways, but over time, strains of plasmodium have evolved resistance to all of them. Strains of p. falciparum resistant to several antimalarial drugs often have defects in DNA mismatch repair, which means they experience a higher rate of mutations. This is usually harmful for fitness, but under the strong selection pressure of new treatments, the likelihood of mutating resistant genes is increased, which can render new drugs ineffective. 

One mechanism under current investigation is the MEP pathway in plasmodium, which produces IPP, isopentenyl pyrophosphate, a molecule the parasite needs to survive. A chemical called fosmidomycin inhibits this pathway, which prevents the production of IPP and therefore inhibits the development of p. falciparum, which provides a potential new mechanism for fighting malaria. However, concerns have arisen because of one related species that also relies on the production of IPP in the MEP pathway, which has resistance to fosmidomycin. This species, cryptosporidium, gets its IPP from its host, so if plasmodium mutates and evolves to use the same system, it also will be resistant to fosmidomycin. Malaria is a lethal disease that infects hundreds of millions of people every year, especially in Africa, and warrants serious attention for the study of new mechanisms to fight it. As plasmodium gains resistance to treatments and anopheline mosquitoes gain resistance to insecticides, the importance of new methods to stop the spread of this disease is apparent. Application of fosmidomycin has potential to kill parasites and limit the spread, but other tools such as genetic modification should be looked into to avoid a selection pressure that encourages evolution of resistance.

I have spent basically half of my spring break trying to finish reading all of the malaria articles I want to cover for my honors project, as I was hoping to complete that amongst many other things this week, but I’ve honestly barely made a dent and still have several articles left. It takes me a really long time to get through these things, but I am really satisfied with what I’ve learnt. It was also nice that I included information from several sources in this post, which is kind of what I wanted to do in the beginning, but each scientific report contains way too much information too cram multiple into one post. With this post, most of the information came from the NIH’s Brief History of Malaria, with some supporting details from the WHO and ourworldindata.org.

In a lot of the experiments involved in the articles I’ve read, they measure the success of plasmodium by the amount of oocysts that are created on the midgut wall, and before I wrote this post, I wasn’t really sure what that meant. I decided it made sense to do a background of plasmodium before I continued, both for my sake and yours, dear reader, because you probably have even less of an idea what an oocyst is. But you do now! At least I hope. That tasty morsel of information and much more coming in future articles, so stay tuned to learn with me!

Institute of Medicine (US) Committee on the Economics of Antimalarial Drugs; Arrow KJ, Panosian C, Gelband H, editors. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Washington (DC): National Academies Press (US); 2004. 5, A Brief History of Malaria. Available from: https://www.ncbi.nlm.nih.gov/books/NBK215638/

https://www.who.int/news-room/fact-sheets/detail/malaria

https://ourworldindata.org/malaria