IMPORTED PEDIATRIC MALARIA IN THE U.S. AND THE ESSENTIAL ROLE OF HSP40 IN MALARIA PARASITE BLOOD STAGE REPLICATION AND THERMOTOLERANCE

Malaria is a persistent global health concern that has impacted the human population for centuries.Children under the age of five are the most vulnerable to severe disease and death. While most cases occur in subtropical regions of the world, due to international travel and immigration, the U.S. treats approximately 2,000 cases of malaria each year. In humans, Plasmodium falciparum is the intracellular parasite responsible for the most severe manifestations of malaria. To replicate and cause pathology, P. falciparum must survive febrile temperature shifts, a characteristic clinical feature of malaria infection. As a result, P. falciparum has evolved an expanded set of heat shock proteins to protect itself from thermal stress, which provide potential biological targets for the development of novel antimalarials. With increasing rates of antimalarial drug resistance worldwide, multidisciplinary approaches are required to improve the care and treatment of malaria. In this dissertation, we integrate epidemiological approaches with fundamental molecular biology research to further our understanding of malaria. We conduct a retrospective chart review to describe the pediatric patient population treated for malaria in the U.S. from 2016-2023. A total of 171 pediatric patients were treated for malaria across the nine hospitals included in our study. Most patients acquired malaria while traveling to visit friends and relatives in West African countries. We find misdiagnosis in the U.S. to be common and was associated with an increased risk for severe malaria. For our molecular biology investigations, we employ a conditional knockdown approach to define the essential role of a heat shock protein, HSP40, in malaria parasite blood stage replication, thermotolerance, and drug sensitivity. We find HSP40 expression is required for malaria parasite blood stage replication and survival of febrile temperature shifts. We show that reduced HSP40 expression corresponds to a cell cycle progression defect, reduced nuclear replication, and disruption of DNA replication and repair pathways. This work integrates epidemiological and molecular approaches to advance knowledge of malaria in traveling U.S. pediatric patients and provide mechanistic insights into parasite biology with the potential to inform future antimalarial design.

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Background: Malaria is a persistent global health concern that has impacted the human population for centuries. Children under the age of five are the most vulnerable to severe disease and death. While most cases occur in subtropical regions of the world, due to international travel and immigration, the U.S. treats approximately 2,000 cases of malaria each year. In humans, Plasmodium falciparum is the intracellular parasite responsible for the most severe manifestations of malaria. To replicate and cause pathology, P. falciparum must survive febrile temperature shifts, a characteristic clinical feature of malaria infection. As a result, P. falciparum has evolved an expanded set of heat shock proteins to protect itself from thermal stress, which provide potential biological targets for the development of novel antimalarials. With increasing rates of antimalarial drug resistance worldwide, multidisciplinary approaches are required to improve the care and treatment of malaria.

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Methods: In this dissertation, we integrate epidemiological approaches with fundamental molecular biology research to further our understanding of malaria. We conduct a retrospective chart review to describe the pediatric patient population treated for malaria in the U.S. from 2016-2023. For our molecular biology investigations, we employ a conditional knockdown approach to define the essential role of a heat shock protein, HSP40, in malaria parasite blood stage replication, thermotolerance, and drug sensitivity.

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Results: We find misdiagnosis in the U.S. to be common and was associated with an increased risk for severe malaria. We find HSP40 expression is required for malaria parasite blood stage replication and survival of febrile temperature shifts. We show that reduced HSP40 expression corresponds to a cell cycle progression defect, reduced nuclear replication, and disruption of DNA replication and repair pathways.

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Data Summary: A total of 171 pediatric patients were treated for malaria across the nine hospitals included in our study. Most patients acquired malaria while traveling to visit friends and relatives in West African countries.

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Conclusions: This work integrates epidemiological and molecular approaches to advance knowledge of malaria in traveling U.S. pediatric patients and provide mechanistic insights into parasite biology with the potential to inform future antimalarial design.

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Practical Significance: These provide potential biological targets for the development of novel antimalarials. This work integrates epidemiological and molecular approaches to advance knowledge of malaria in traveling U.S. pediatric patients and provide mechanistic insights into parasite biology with the potential to inform future antimalarial design.