How FHR-1 deficiency affects the infection with the malaria pathogen Plasmodium falciparum

The obligate intracellular parasite Plasmodium falciparum causes malaria tropica, the most severe form of malaria, which is particularly acute in the WHO African region. With more than 247 million cases and 619,000 deaths each year, malaria is still one of the deadliest infectious diseases in the world. Malaria infection is characterized by multiple symptoms, like fever, head- and body aches, and diarrhea. Severe complications further include anemia, shock, cerebral malaria, multiple organ failure, and ultimately death. During evolution, P. falciparum has developed various mechanisms to evade attack by human complement, such as binding of the human complement regulator Factor H. In previous studies, we have shown that the Factor H-Related Protein 1 (FHR-1) competes with Factor H for binding sites and thereby prevents Factor H-mediated complement evasion. Furthermore, FHR-1, when binding to malaria-lysed erythrocytes, activates neutrophils and thus contributes to inflammation. Remarkably, up to one third of the African population harbors a chromosomal deletion of the FHR-1 gene. To investigate a potential link between FHR-1 deficiencies and malaria severity, we investigated two cohorts of malaria tropica-infected African patients. All individuals gave informed consent to participate in a clinical trial. From the study participants, serum was collected and used to detect the FHR-1 protein by Western blot analysis. In addition, other protein concentrations, such as inflammation markers, were measured using in-house and commercial ELISA. We show that FHR-1 deficient patients are less likely to suffer from severe malaria. In addition, these patients have less signs of anemia compared to FHR-1 expressing individuals. Further, we measured inflammation markers. Both in FHR-1-deficient patients and in patients with a mild course of malaria, we were able to demonstrate a significant decrease in the concentration of inflammation markers. Our data underline the potent role of FHR-1 in inflammation, which likely enhances the immune response in malaria infections and the risk of severe malaria anemia.