Plasmodium falciparum utilizes proteins of the complement and fibrinolysis pathway for red blood cell invasion

The intracellular parasite Plasmodium falciparum causes malaria tropica, the severest form of malaria in the WHO African region. With over 619,000 deaths in 2022, malaria is still one of the deadliest diseases worldwide. The symptomatic phase includes fevers, head- and body aches, and diarrhea. In erythrocytes, the parasite develops via the ring, then trophozoite stages into mature schizonts, which form up to 32 daughter merozoites (MZs) that are released and invade new red blood cells (RBCs). In the bloodstream, the extracellular MZs are susceptible to the human complement system. To avoid complement-mediated lysis, the parasites bind to the complement inhibitor factor H (FH) or to plasminogen, a protein in the fibrinolysis system. There is currently little information on how these proteins influence MZ invasion of RBCs. Therefore, we performed MZ invasion assays to investigate how proteins of the FH family, plasminogen, and other key alternative pathway proteins influence their entry into RBCs. We found that in the presence of C3b but also under FHR1-depleted conditions, the numbers of intraerythrocytic parasites increased. Furthermore, under plasminogen-deficient conditions, RBC infection by MZs was reduced, while the addition of plasminogen led to increased invasion rates independent of active complement. In conclusion, we hypothesize that MZs utilize proteins of the complement and the fibrinolysis system to facilitate erythrocyte attachment for efficient and successful invasion and intraerythrocytic replication.