TY - JOUR
T1 - A microscale human liver platform that supports the hepatic stages of plasmodium falciparum and vivax
AU - March, Sandra
AU - Ng, Shengyong
AU - Velmurugan, Soundarapandian
AU - Galstian, Ani
AU - Shan, Jing
AU - Logan, David J.
AU - Carpenter, Anne E.
AU - Thomas, David
AU - Sim, B. Kim Lee
AU - Mota, Maria M.
AU - Hoffman, Stephen L.
AU - Bhatia, Sangeeta N.
N1 - Funding Information:
We thank the Malaria Research and Reference Reagent Resource Center for access to the polyclonal rabbit antiserum against purified recombinant P. vivax (Sal-1) MSP-1 (MRA-16, deposited by J.H. Adams); NYU for the monoclonal antibody 2A10; NIAID, NIH for R217; and Dr. R. Wirtz (Centers for Disease Control and Prevention) and Dr. F. Zavala (Johns Hopkins University) for PvCSP and HSP70 monoclonal antibodies, respectively. We are grateful to the Sanaria Manufacturing Team for the production of PfSPZ and PvSPZ. We thank R. Schwartz for confocal microscopy help; S. Suresh and M. Diez for aid in establishing RBC cocultures; A. Rodriguez (NYU), D. Wirth, and E. Lund (HSPH) for providing mosquitoes infected with P. yoelii and P. berghei ; J. Prachumsri (Mahidol Vivax Research Center) and J. Adams (University of South Florida) for providing fresh P. vivax ; T. Golub (Broad Institute) for advice with the Luminex-based characterization of drug-metabolism transcripts; H. Green (Harvard University) for providing J2-3T3 fibroblasts; and H. Fleming for manuscript editing. PvSPZ production was supported by a grant from Medicines for Malaria Venture, and PfSPZ production was supported by a Phase II NIAID, NIH Small Business Innovative Research Grant (2R44A1055229) awarded to S.L.H. Software improvements were supported by an NIH grant (R01GM089652) to A.E.C. This work was supported by the Bill & Melinda Gates Foundation (51066). S.N. is supported by an Agency for Science, Technology and Research (A ∗ STAR, Singapore) NSS. S.N.B. is an HHMI Investigator. The authors wish to dedicate this paper to the memory of Officer Sean Collier for his caring service to the MIT community and for his sacrifice.
PY - 2013/7/17
Y1 - 2013/7/17
N2 - The Plasmodium liver stage is an attractive target for the development of antimalarial 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, as well as 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 antimalarial drug screening and vaccine development.
AB - The Plasmodium liver stage is an attractive target for the development of antimalarial 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, as well as 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 antimalarial drug screening and vaccine development.
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U2 - 10.1016/j.chom.2013.06.005
DO - 10.1016/j.chom.2013.06.005
M3 - Article
C2 - 23870318
AN - SCOPUS:84880397868
SN - 1931-3128
VL - 14
SP - 104
EP - 115
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -