Journal Article

Further Improvements of the P. falciparum Humanized Mouse Model

Gleeson, James, Meija, Pedro, Tyagi, Rajeev Kumar, Druilhe, Pierre, Swetman, Claire, Arnold, Ludovic, Pérignon, Jean-Louis

2011

Overview

It has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines. We investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2Rγ deficiency (NSG mice). We demonstrate here the role of aging, of inosine and of the IL-2 receptor γ mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent. The combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Aging / Analysis / Animal models / Animals / Antimalarials / B cells / Bacterial infections / Biology / Bisphosphonates / Cells, Cultured / Clodronic acid / Combination drug therapy / Drug development / Drugs / Erythrocytes / Erythrocytes - immunology / Erythrocytes - parasitology / Humans / Immune response / Immunity, Innate - drug effects / Immunodeficiency / Immunosuppressive agents / Immunosuppressive Agents - therapeutic use / Infections / Inflammation / Inflammatory response / Injections, Intravenous / Inosine - therapeutic use / Interleukin 12 / Interleukin 2 / Interleukin 2 receptors / Interleukin Receptor Common gamma Subunit - genetics / Intravenous administration / Liposomes / Malaria / Mice / Mice, Inbred BALB C / Mice, Inbred NOD / Mice, SCID / Mutation / Parasitemia / Parasitemia - drug therapy / Parasitemia - parasitology / Parasites / Plasmodium / Plasmodium falciparum / Plasmodium falciparum - drug effects / Plasmodium falciparum - immunology / Plasmodium falciparum - pathogenicity / Reproducibility / Rodents / Vaccines / Vector-borne diseases