Investigation of Plasmodium vivax Relapses in Humanized Mice

• Applicant: Dr. Carola Schäfer
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322877348

Plasmodium vivax, the causative agent of almost half the malaria-associated deaths outside Africa, shows a distinct biology of forming dormant liver stages termed hypnozoites. These can be reactivated by unknown mechanisms months or even years after primary infection, leading to new symptomatic blood stage infections that are called relapses. It is believed that reactivation of hypnozoites can be influenced by different mechanisms. Globally distinct populations show different relapse patterns. Also, P. falciparum co-infections are thought to trigger P. vivax relapses. Furthermore, there is some evidence that histone modifying agents can influence hypnozoite reactivation (Dembele et al., 2014). Unfortunately, all of these phenomena, as well as hypnozoite biology in general, could not be properly investigated up to date, due to the lack of suitable model systems for relapsing malaria.Since P. vivax parasites exclusively infect human cells, they are problematic to study in an animal model. Mice transplanted with human cells or tissue offer a great opportunity to study human-specific parasites. Recently it was shown that a liver-humanized mouse model (FRG huHep mouse) supports Plasmodium vivax liver stage development, hypnozoite formation, persistence and reactivation (Mikolajczak et al., 2015). The transition of liver-stage to blood-stage infection relies on inoculation of the mice with human reticulocytes, a cumbersome process that must be repeated approximately every three days to capture reactivated hypnozoites emerging from the liver. Still, it cannot be ensured that all hypnozoites are being captured by this method. Thus, it is highly desirable to develop a model that would not rely on reticulocyte inoculation and could be monitored for blood stage relapse at any time point.The proposed project is subdivided into two aims. In the first aim, the influence of global differences, P. falciparum co-infections and histone modifying enzymes on P. vivax relapse patterns will be addressed experimentally for the first time in malaria research history using the already established FRG huHep mouse. This will show whether these observations hold true in the mouse model and will therefore give new insights on P. vivax relapse patterns. In the second aim, an improved humanized mouse model for vivax malaria research will be created. This newly created mouse will be infected with P. vivax sporozoites in order to investigate whether the full Plasmodium vivax life cycle takes place, including transition from liver- to blood stage malaria. The establishment of this novel mouse model will be a major contribution to the field of malaria research. This small animal model of P. vivax infection will for the first time allow for the biological study of relapsing malaria as it occurs naturally and serve as a novel, human immunocompetent model for preclinical drug and vaccine studies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Stefan Kappe