A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

Abstract

SUMMARY The Plasmodium liver stage is an attractive target for the development of anti-malarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable and reproducible in vitro liver stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum including the release of infected merozoites and infection of overlaid erythrocytes, and also the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput anti-malarial drug screening and vaccine development.

Current therapies and future possibilities for drug development against liver-stage malaria

“…Using cryopreserved primary human hepatocytes and cryopreserved P. falciparum, March et al (88) achieved higher infection efficiency than with the HC04 cell line infected with freshly harvested P. falciparum, currently the only hepatoma cell line supporting the full development of this species in vitro. Microscale human liver cells have the added advantage of being able to model infections originating from the diverse genetic makeup of human populations, as they are not limited to primary hepatocytes sourced from a small pool of donors (i.e., patients with liver cancer).…”

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

“…Importantly, because 1 liver stage parasite can initiate blood stage infection, our liver stage model system will make it possible to quantify liver stage infection with 1 parasite by measuring the liver stage-to-blood stage transition, the most sensitive detection method of prophylactic liver stage drug efficacy. Current methods to test liver stage efficacy of preclinical compounds utilize an in vitro P. falciparum model to test the effect on invasion and growth (32) or rodent malaria models for testing in vivo causal prophylaxis (33). While these systems are attractive due to scalability and cost effectiveness, they are limited in regards to the applicability of in vitro results and generalizability between rodent and human malaria species.…”

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

“…contributed equally to this work. falciparum and vivax malaria (13,14). We hypothesized that this system would be ideal for modeling HBV infection in vitro.…”