Receptors, innate immunity and host genetics

Malaria is a major global health burden, with roughly half the world's population at risk of contracting the disease. Malaria is caused by the intracellular protozoan parasite of the genus Plasmodium; it has two stages of infection in the human host, the first is liver stage (LS) which is clinically silent and is the gateway to second stage, blood-stage infection, where symptoms develop. Targeting LS for malaria eradication would not only prevent the clinical presentation of the disease but inhibit further transmission of the parasite within populations, making it an appealing target. The understanding of LS infection has been hampered by a lack of appropriate in vitro culture systems and adequate animal models. To address this, we developed the ectopic huLiver mouse model using the HC-04 cell, one of the reported cell lines to support complete LS development. We showed that the model can be infected with P. falciparum, in which LS can be successfully completed and transition to blood-stage can occur. Thus, proving to be a biologically relevant model to study LS infection and for drug development research. We hypothesized that receptor expression on the cell surface, as well as innate immune sensing, were two main determinants of P. falciparum infectivity. Using in vitro studies, we examined the effect of receptor expression and observed an increased P. falciparum entry to the HC-04 cells when cell surface receptor expression was increased. However, parasite replication appeared to stay constant, suggesting cells are using alternative methods for controlling infection. Additionally, we showed in vivo, using the FRG-huHep mouse model, that P. falciparum infection is sensed by the host, and interferon stimulated genes (ISGs) are produced in response. We also showed that in Kenyan children type III interferon (IFN) genetic background influences malaria disease development. Overall, our results suggest that an interplay between receptor expression and host innate immune response is what permits the parasite to successfully infect hepatocytes and disease progression.