Development of humanized mouse models to study human malaria parasite infection

Seattle Biomedical Research Institute, WA 98109, USA.
Future Microbiology (Impact Factor: 4.28). 05/2012; 7(5):657-65. DOI: 10.2217/fmb.12.27
Source: PubMed


Malaria is a disease caused by infection with Plasmodium parasites that are transmitted by mosquito bite. Five different species of Plasmodium infect humans with severe disease, but human malaria is primarily caused by Plasmodium falciparum. The burden of malaria on the developing world is enormous, and a fully protective vaccine is still elusive. One of the biggest challenges in the quest for the development of new antimalarial drugs and vaccines is the lack of accessible animal models to study P. falciparum infection because the parasite is restricted to the great apes and human hosts. Here, we review the current state of research in this field and provide an outlook of the development of humanized small animal models to study P. falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future.

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    • "These include studies of viral pathobiology, innate and adaptive immunity, and therapeutics (Dash et al., 2012, 2011; Gorantla et al., 2012; Nischang et al., 2012). Human mycobacterial (tuberculosis) (Calderon et al., 2013; Lee et al., 2013; Leung et al., 2013) and parasite infections (for example, malaria) (Kaushansky et al., 2014; Vaughan et al., 2012) can also be studied in these mice (Brehm et al., 2014). However, hematologic, metabolic and behavioral characteristics of these animals remain limited. "
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    ABSTRACT: Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization.
    Biology Open 09/2015; DOI:10.1242/bio.013201 · 2.42 Impact Factor
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    • "Nevertheless, this good targeting has not been able to provide improvements in drug efficacy above 10-fold [12], and parasitemia could not be completely eliminated from the cultures. In vivo assays in mice grafted with human erythrocytes and subsequently infected with P. falciparum [13] showed that some iLP-encapsulated antimalarials had a clearly improved efficacy (Fig. 1A). However, as in in vitro assays, Plasmodium parasites could not be completely cleared despite the continuous presence of iLPs in the blood of mice during the entire length of four-day tests (Fig. 1B). "
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    ABSTRACT: One of the most important factors behind resistance evolution in malaria is the failure to deliver sufficiently high amounts of drugs to early stages of Plasmodium-infected red blood cells (pRBCs). Despite having been considered for decades as a promising approach, the delivery of antimalarials encapsulated in immunoliposomes targeted to pRBCs has not progressed towards clinical applications, whereas in vitro assays rarely reach drug efficacy improvements above 10-fold. Here we show that encapsulation efficiencies reaching >96% are achieved for the weak basic drugs chloroquine (CQ) and primaquine using the pH gradient loading method in liposomes containing neutral saturated phospholipids. Targeting antibodies are best conjugated through their primary amino groups, adjusting chemical crosslinker concentration to retain significant antigen recognition. Antigens from non-parasitized RBCs have also been considered as targets for the delivery to the cell of drugs not affecting the erythrocytic metabolism. Using this strategy, we have achieved unprecedented complete nanocarrier targeting to early intraerythrocytic stages of the malaria parasite for which there is a lack of specific extracellular molecular tags. Immunoliposomes studded with monoclonal antibodies raised against the erythrocyte surface protein glycophorin A were capable of targeting 100% RBCs and pRBCs at the low concentration of 0.5 μM total lipid in the culture, with >95% of added liposomes retained on cell surfaces. When exposed for only 15 min to Plasmodium falciparum in vitro cultures of early stages, free CQ had no significant effect on the viability of the parasite up to 200 nM, whereas immunoliposomal 50 nM CQ completely arrested its growth. In vivo assays in mice showed that immunoliposomes cleared the pathogen below detectable levels at a CQ dose of 0.5 mg/kg, whereas free CQ administered at 1.75 mg/kg was, at most, 40-fold less efficient. Our data suggest that this significant improvement is in part due to a prophylactic effect of CQ found by the pathogen in its host cell right at the very moment of invasion. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 05/2015; 210. DOI:10.1016/j.jconrel.2015.05.284 · 7.71 Impact Factor
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    • "When SCID/Alb-uPA mice are depleted in NK cells and macrophages, the level of human hepatocytes chimerism and consequently of P. falciparum liver-stage development improves (Morosan et al., 2006). Nevertheless, the human liver chimeric SCID/Alb-uPA mouse model presents some drawbacks, mainly due to the severe liver injury induced by the uPA transgene expression and to mice hypofertility (Vaughan et al., 2012). These weaknesses, and the need for high-quality adult human hepatocytes for transplantation, make this model extremely costly and timeconsuming , which drastically limits the number of experimental mice and consequently the strength of the conclusions. "
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    ABSTRACT: Malaria imposes a horrific public health burden - hundreds of millions of infections and millions of deaths - on large parts of the world. While this unacceptable health burden and its economic and social impact have made it a focal point of the international development agenda, it became consensual that malaria control or elimination will be difficult to attain prior to gain a better understanding of the complex interactions occurring between its main players: Plasmodium, the causative agent of disease, and its hosts. Practical and ethical limitations exist regarding the ability to carry out research with human subjects or with human samples. In this review, we highlight how rodent models of infection have contributed significantly during the past decades to a better understanding of the basic biology of the parasite, host response and pathogenesis.
    Journal of Immunological Methods 05/2014; 410. DOI:10.1016/j.jim.2014.05.001 · 1.82 Impact Factor
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