Elucidating the Malaria Unfolded Protein Response

Malaria is the most prevalent mosquito-borne disease, affecting a wide swathe of the human population across the globe. In 2019 alone, there were over 200 million reported cases of malaria, and this disease kills about 400,000 people annually. The parasite Plasmodium falciparum causes malaria and is found on the continents of Asia, Africa, and South America. This parasite needs both a mosquito host and a human host. Within humans, the parasite first lives and reproduces in the liver, and then migrates to live and reproduce in red blood cells. It is during its residence in red blood cells that the parasite causes symptoms associated with malaria, prompting patients to seek treatment. Thus, most antimalarial drugs target parasites when they are within the red blood cell. Reducing the numbers of parasites within the blood alleviates the severity of symptoms experienced. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat falciparum malaria. Alarmingly, resistance to artemisinin has arisen and is widespread in Southeast Asia. In addition, a few cases have been reported in greater Asia, Africa, and South America. The potential for the U.S. to have a military presence or to be conducting active military operations in these malarious areas is significant. To combat artemisinin resistance, it is imperative to understand how artemisinin works. Artemisinin requires heme to be activated. Heme is a byproduct of parasite-mediated digestion of host hemoglobin, which it obtains from the red blood cell. Once activated within the parasite, artemisinin reacts non-specifically with nearby proteins. In essence, the drug is like a bomb that, when activated, indiscriminately injures all nearby items. This damages many proteins and activates a stress response called the unfolded protein response (UPR). This is a signaling system that is found in many organisms ranging from humans to malaria parasites. In contrast to the UPR in humans, which is well-characterized, the parasite UPR remains poorly characterized. What we do know is that in response to artemisinin, parasites turn on the UPR and that artemisinin-resistant parasites have a more robust UPR. A deeper understanding of the parasite UPR can allow us to design therapeutics that target this essential parasite process and eliminate artemisinin resistant parasites. This proposal seeks to identify previously unknown proteins involved in the parasite UPR and to use this knowledge to kill artemisinin-resistant parasites. One of the biggest threats to the gains made against this disease is antimalarial drug resistance. Targeting an essential parasite process will lessen the ability of parasites to mutate to achieve drug resistance. The near-term impact of this research is identification of key proteins involved in the UPR that can then be used in reporter systems to screen for drugs targeting this process. The long-term impact of this research is we could have novel antimalarial therapeutics that can combat artemisinin-resistant parasites. Furthermore, due to the universal nature of this signaling process, insights gained from understanding the malaria UPR can impact our understanding of the UPR in other parasites such as Toxoplasma gondii, which causes toxoplasmosis and which can be fatal in immunocompromised individuals. Knowledge gained could even inform our understanding of the UPR in humans, which is dysregulated in a multitude of diseases that range from diabetes to Parkinson’s disease.

Enabling Technologies & Assays

Jan 2022 — Jan 2024

$309,000

United States