Haemosporida Plasmodium falciparum Plasmodium vivax Plasmodium malariae Plasmodium ovale.
Plasmodium falciparum-infected mice: more than a tour de force
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Plasmodium falciparum-infected mice:more than a tour de forceAlicia Moreno1,2,3, Jean Louis Perignon4, Serban Morosan5, Dominique Mazier1,2,3
and Agustin Benito6
1 Universite Pierre & Marie Curie-Paris 6, UMR S511, Paris F-75013, France2 Inserm, U511, Paris F-75013, France3 AP-HP, Groupe hospitalier Pitie-Salpetriere, Service Parasitologie-Mycologie, Paris F-75013, France4 Unite de Parasitologie Biomedicale, Institut Pasteur, Paris 75015, France5 Centre d’Experimentation Fonctionnelle, Faculte de Medecine Pitie-Salpetriere, F-75013 Paris, France6 Centro Nacional de Medicina Tropical, Instituto de Salud Carlos III, C/Sinesio Delgado 6, Madrid 28029, Spain
Opinion TRENDS in Parasitology Vol.23 No.6
Up until recently, the relevance of Plasmodiumfalciparum-infected humanized mice for malaria studieshas been questioned because of the low percentage ofmice in which the parasite develops. Advances in thegeneration of new immunodeficient mouse strains com-bined with the use of protocols that modulate the innateimmune defenses of mice have facilitated the harvestingof exoerythrocytic and intraerythrocytic stages of theparasite. These results renew the hope of working withP. falciparum in a laboratory animal and indicate thatthe next challenge (i.e. a complete parasite cycle in thesame mouse, including transmission to mosquito) couldbe reached in the future.
Experimental models for falciparum malariaMalaria caused by Plasmodium falciparum is difficult tomodel in the laboratory because of the specificity of thisparasite for its human host, the complexity of its life cycleand the substantial diversity of parasite strains. Despitemajor progress achieved by in vitro culture of the erythro-cytic [1] and liver forms [2] of the parasite, some questions,particularly in the fields of immunology and pathophysiol-ogy, can only be addressed in in vivo models. Nonhumanprimates have provided experimental models for P. falci-parum malaria [3]; nevertheless, their use has been diffi-cult because of economic and ethical considerations, alimited supply of monkeys, the narrow range of parasitelines that are adapted to primate infection and the differ-ent pathology that is seen in these models. Consequently,most experimental in vivo studies on malaria have reliedon different combinations of various murine strains andPlasmodium spp. of rodent [4,5] but biological differencesbetween parasite species remain a major limitation. Forexample, there are many indications that in humancerebral malaria, the preferential sequestration of para-sitized erythrocytes in the brain capillaries is the centralprecipitating step [6], whereas this phenomenon is muchless evident in rodent models [7].
Limitations of experimentalmodels have also hamperedthe evaluation of the impact of new drugs or vaccines prior
Corresponding author: Moreno, A. ([email protected]).Available online 16 April 2007.
www.sciencedirect.com 1471-4922/$ – see front matter � 2007 Elsevier Ltd. All rights reserve
to clinical trials. During the preclinical screening of a newdrug, its activity has to be evaluated first against thedevelopment of P. falciparum in vitro, then against theinfection of a rodent Plasmodium in a mouse model and,finally, against P. falciparum infection in a monkey model[8]. Similar difficulties are encountered in assessing theactivity of vaccines against the real target: the humanparasite. These complex, long and expensive processes,which contrast with the limited financial perspectives ofthe drug market in malaria-endemic countries, have con-tributed to a decrease in the interest of pharmaceuticalcompanies in the development of antimalarial drugs orvaccines. New initiatives between different public sectorsand private industries have recently revived their interest[8] but an adequate model is still needed to drive researchon new tools that are aimed at reducing mortality andmorbidity caused by malaria.
Towards P. falciparum infection in immunodeficientmiceThe discovery of mice with different immunodeficiencies,which enable them to accept human cell grafts, has pavedthe way for the in vivo study of P. falciparum in humanhepatocytes (Hhep) and/or human red blood cells (HRBCs)(Table 1). Initially, the immunodeficient CB-17 mousestrain that displayed severe combined immunodeficiency(SCID) (Box 1) was used to obtain the graft of HRBCs [9,10]or Hheps [11] that were infected with the parasite [12].However, only a few chimeras accepted the parasite infec-tion, which raised doubts about the relevance of thesemodels [13,14]. Later studies were mainly focused onthe intraerythrocytic (IE) phase of P. falciparum and wereaimed at determining the key factors that are involved inparasite development. The first factor studied was thegenetic background of the mice. Various mouse strainswith higher immunodeficiency levels, such as mice bearingthe beige, nude and xid mutations (BNX) [15] or nonobesemice with the SCID mutation (NOD/SCID) [16] (Box 1),were tested but with only modest success. A second factorthat was considered is the different hematological environ-ment between mice and humans but this seemed not to berelevant [17]. Indeed, neither the treatment of mice withhuman sera [12] nor the adaptation of the parasites to
d. doi:10.1016/j.pt.2007.04.004
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Table 1. Mouse–human chimeras for the study of Plasmodium falciparum malaria
Mouse
background
Graft Immunomodulation protocol Advantages Limitations Refs
EE stages SCID Hhep No protocol Parasite EE forms and evaluation
of antiparasite invasion therapy
Low reproducibility [11,13,14]
SCID/Alb-uPA Hhep Treatment against macrophages
and NK cells
Parasite EE forms and good
reproducibility
Availability of Hhep [18,19]
IE stages SCID HRBC Splenectomy, radiation,
elimination of mouse cells and
human serum treatment
Reconstitution of mice with HRBC
and IE parasite development
IE stages obtained in a
low percentage of mice
[12]
NOD/SCID HRBC
(every
day)
Splenectomy, infection with
parasites that are adapted to
mouse serum and ascites
Asexual and sexual IE stages
obtained in mouse blood and
transmission to mosquito
IE stages obtained in a
low percentage of mice
[16]
BNX HRBC
(every
three
days)
Treatment against macrophages
and neutrophils
Asexual IE stages obtained in
mouse blood, and application to
chemotherapy and defense
mechanisms studies
IE stages obtained in a
low percentage of mice
[15]
NOD/SCID HRBC
(every
three
days)
Treatment against macrophages
and neutrophils
Asexual and sexual IE stages
obtained in a high percentage of
mice with different parasite
populations
Lack of cytoadherence
of IE stages to mouse
endothelium
[20,21]
Cytoadherent
IE stages
CB-17/SCID Human
skin
No protocol Cytoadherence of IE stages and
evaluation of antiadhesive
therapies
Highly specialized
manipulation and lack
of pathology
[27–29]
Box 1. From immunodeficient mice to mouse–human
chimeras
In vivo study of human cells has been helped by the availability of
an increasing number of mouse strains that express mutations that
cause immunological deficiencies. BNX mice, which have the Beige,
Nude and Xid mutations, exhibit a combination of deficiencies that
alter cell-mediated immunity, granulocyte and natural-killer (NK)
cell functions, and immunoglobulin deficiency [32]. CB-17 mice that
have the SCID mutation have few functional lymphocytes [33]. Both
strains were initially used for the generation of human chimeras but
their remaining innate immunity limited engraftment of human
cells. The backcross of the SCID mutation onto NOD mice generated
the NOD/SCID strain, which has a low number of functional
lymphocytes, functionally immature macrophages, an abnormally
low NK cell activity and a deficiency in the complement system [34].
These mice were later backcrossed with mouse strains with RAG-1
or RAG-2 mutations to prevent further development of mouse
lymphocytes [35,36] or with mice that have the B2m�/� and Prf1�/�
mutations, which prevent the development of mouse NK cells [37].
Despite their high level of immunodeficiency, a residual NK activity
seemed to restrain survival of human cells. This problem has been
overcome in recently generated NOD/SCID mice that have the Il2rg�/
� mutation, which prevents the expansion of NK cells [38]. A
difference in microenvironments between mice and humans, and
the absence of crossreactivity between growth factors from the two
species also seem to be limiting factors in obtaining a correct
xenograft. Consequently, efforts were directed to humanize the
lymphohematopoietic microenvironment of NOD/SCID mice. Genet-
ic engineering technologies have generated NOD/SCID mice that
express human interleukins such as IL-3 [39] or granulocyte–
macrophage colony stimulating factor [40]. Another line of research
has examined whether the graft of human cells could be improved
after a previous reduction of the homologous mouse cells. Studies
have shown that the expression of the urokinase-type plasminogen
activator transgene controlled by an albumin promoter (Alb-uPA)
was toxic to mouse hepatocytes, so that a high percentage of the
litter died from bleeding disorders [41]. A series of experiments
showed that in surviving mice some hepatocytes had sponta-
neously deleted a portion of the transgene. These nontransgenic
hepatocytes began to proliferate and replace the diseased hepatic
parenchyma with ‘normal’ functioning hepatocytes, an advantage
that could be shared by transplanted Hheps. The generation of a
SCID mouse that carries the transgene Alb-uPA as a homozygote
has enabled the graft and repopulation of the mouse liver by Hheps
[42].
Opinion TRENDS in Parasitology Vol.23 No.6 255
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mouse serum [16] increased the number of infected mice.Other studies used different immunomodulation protocolsto control the remaining innate immunity in the mice(Table 1), which proved to be a major factor that wasimplicated in the clearance of the parasite infection.Initially, in an attempt to control splenic macrophagesand neutrophils, different immunosuppressive protocolssuch as splenectomy or irradiation were used [12,16].Unfortunately, these protocols did not improve the rateof infection. A real improvement was obtained when pha-gocytes from other parts of the host, such as the perito-neum, spleen, liver and bone marrow, were controlledusing a chemical protocol that selectively targeted bothneutrophils (using a monoclonal antibody) and macro-phages (using clodronate-loaded liposomes) [15]. However,the percentage of infected mice was still low, which pre-vented the use of these models in large studies and con-firmed the skepticism of many laboratories about theirpotential use. Indeed, P. falciparum-infected chimeraswere at risk of being removed from the list of experimentalanimals for the study of this parasite.
In this context, new perspectives appeared when it wasrealized that neither the choice of the mouse strain alonenor that of the immunomodulatory protocol was sufficientbut that the key strategy to obtain the IE or exoerythro-cytic (EE) stages in mice was the concomitant use of thecorrect immunodeficient mouse strain with the correctimmunomodulation protocol (Table 1).
Following this strategy, theEEstageofP. falciparumhasbeen obtained in a reproducible manner using a new immu-nodeficient and transgenic mouse, the CB-17/SCID mousebearing a urokinase-type plasminogen activator transgenecontrolled by an albumin promoter (SCID/Alb-uPA) (Box 1).In these mice, the removal of mouse hepatocytes using alethal transgene has enabled the repopulation of the mouseliver with Hhep and their subsequent infection withP. falciparum [18,19] (Figure 1). The combination of achemical immunomodulation protocol with the use of thesehumanized SCID/Alb-uPA mice seems to improve the
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Figure 1. Generation of chimeras for Hheps. (a) Hheps are obtained after collagenase perfusion method. (b) Intrasplenic transplant of Hhep is carried out in 10–14 day old
mice. (c) After transplantation, to evaluate the percentage of chimerism, human albumin and human a-1 antitrypsin are measured in mouse serum samples. (d) Chimeric
mice are infected by retroorbital injection of 5–6 � 105 sporozoites of Plasmodium falciparum.
256 Opinion TRENDS in Parasitology Vol.23 No.6
human chimerism and the hepatic infection. Indeed, P.falciparum sporozoites, when injected intravenously, canmature in theHheps grafted into thesemice, as indicated bymorphologicalandantigen studiesof the liver schizonts [19].
Development of the IE phase of P. falciparum has beensuccessfully obtained in 75% of mice [20] using the com-bination of the NOD/SCID mouse strain with a chemicalprotocol [15]. Additional improvements to this model havebeen carried out by injecting mice with 1 ml of HRBCs(9 � 109 cells) every two days during the 15 days prior to P.falciparum infection. [21]. This protocol has led to infec-tions in 90–100% of mice inoculated, not only with labora-tory-maintained parasite lines but also with clinicalisolates without the necessity for the lengthy adaptationprocess that is required in primate models. Hematologicaland histopathological studies performed in P. falciparum-infected NOD/SCID mice have led us to propose a schemefor the development of IE in this model (Figure 2). In spiteof the fact that intraperitoneal mouse infection differs fromthat in humans, parasite development andmorphology aresimilar to that observed in humans. The main differencelies in the maturation process of the sexual and asexualforms. In humans, parasite maturation takes place only indeep vessels of organs such as the brain, lungs, spleen orbone marrow. In mice, however, all the sexual and asexualerythrocytic forms at any stage of maturation circulate inthe peripheral blood, which indicates that parasites areable to mature in this environment. This difference couldbe due to a lack of interaction of parasite antigens withmouse receptors on the vascular endothelium. The lack of
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parasite sequestration, together with the lack of afunctional immune system, could also explain why thepathology that is observed in P. falciparum-infected micewas less severe than that observed in humans [21]. Prob-ably, the study of malaria pathology in humans wouldrequire a new transgenic immunodeficient mouse modelthat expresses human adhesion molecules.
What can be expected from P. falciparum-infectedmouse–human chimeras?The fact that parasite development in different chimericmouse models mimics parasite development in humansopens a new opportunity to study human–parasite relation-shipsandnew therapies ina small laboratory animalmodel;from a realistic point of view, though, all these animalmodels remain challenging and time consuming. Optimalrepopulation of amouse requires transplantationwith high-qualityHhepsorHRBCs,whichmightbea real challenge formany laboratories, andrepopulation tohigh levels cannot beobtained in all strains of mice. So, what questions can beresolvedwhenworkingwithP. falciparum inmouse–humanchimeras that cannot be addressed with classic experimen-tal models? Mainly, those that relate to in vivometabolism.Although rodent Plasmodium models introduce two vari-ables at once (host and parasite species), the low cost andeasy handling of these models justify their use as the firststep inmetabolismor pharmacokinetic studies. By contrast,P. falciparum-infected mouse–human chimeras introduceonly one variable, the host (mouse), and enable studieswhereby P. falciparum resides inside its real host cell, the
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Figure 2. A possible interpretation of Plasmodium falciparum IE stage development in infected mice. (a) Normal populations of phagocytes in mouse tissues.
(b) Phagocytes from different organs are depleted using liposomes that contain clodronate [43] and monoclonal antibodies [44], which will permit the intraperitoneal (ip)
graft of HRBCs. Some HRBCs might reach the peripheral blood but some of them will be sequestered into the peritoneum. (c) After parasite ip infection, HRBCs blocked in
the peritoneum enable parasites to develop in situ where HRBCs are closer than they would be in mouse blood, which improves the rate of infection. This situation could
represent the parasite sequestration in deep vessels that is observed in humans. There is a slow passage of infected HRBCs to the peripheral blood. Genetically defective
macrophage function of NOD/SCID mice enables the development of initial parasitemias in mouse peripheral blood. However, parasite development induces proliferation
of bone marrow and the repopulation of tissues by newly recruited macrophages, which counterbalances the macrophage depletion induced by liposome treatment.
(d) Phagocytosis of HRBCs that contain mature schizonts and malarial pigment reduces the phagocytic capacity of macrophages. This enables parasitemia to increase,
which in turn will alter the functions of newly recruited macrophages. Finally, there must be a balance between the recruitment of new macrophages and the parasite
development. If the balance moves toward macrophage arrival, mice will control the infection; whereas, if it moves toward parasite development, there will be a saturation
of the macrophage phagocytic function and an exponential parasite multiplication, which will eventually lead to the death of the animal. Abbreviations: Lp, liposomes;
LpMp, liposomes laden macrophages; M, monocytes; Mp, macrophages; mpMp, malarial pigment laden macrophages; MRBC, mouse red blood cells; N, neutrophils; Pf,
P. falciparum-infected HRBC.
Opinion TRENDS in Parasitology Vol.23 No.6 257
Hhep or HRBC. This model should, therefore, betterpredict the efficacy of a new therapy in humans that areinfected with P. falciparum compared with the classicalrodent models. Furthermore, P. falciparum-infectedmouse–human chimeras offer the opportunity to assess,in the same animal, the activity of prodrugs or drugsthat target specific pathways of P. falciparum, in additionto their pharmacokinetics or toxicity, which are essentialparameters to determine their potential. The usefulness of
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this model for antimalarial-drug studies has been initiallyprovenwith studies thatuseBNX chimeras andusing drugswhose effects in humans are well established [22]. Indeed,antimalarial effects observed in infectedmice showedagoodcorrelation with those described in studies with humans,which confirms the potential of thismodel for chemotherapystudies.
P. falciparum-infectedmouse–human chimeras can alsoanswer questions related to the in vivo study of immune
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258 Opinion TRENDS in Parasitology Vol.23 No.6
mechanisms against IE stages that, until now, could onlybe studied in vitro. Reconstitution ofP. falciparum-infectedBNX mice with human monocytes has shown in vivocollaboration between these human cells and passivelytransferred sera from hyperimmune individuals, whichresults in an inhibition of parasite development [23].The model has subsequently permitted examination ofthe protective effect of various antibodies, in addition tosera from volunteers who were immunized with themalaria-vaccine candidateP. falciparummerozoite surfaceprotein 3 [24]. The fact that the mice are immunodeficientprevents the use of currently available chimeras for activeimmunization or for the direct study of complex immuneresponses that could have key roles in malaria in humans.However, this limitation should be overcome in the nearfuture because of the generation of new immunodeficientand transgenic mice that express human leukocyte antigenclass I and II and are, thus, able to accept the graft ofhuman stem cells and support the complete development ofthe human immune system and erythropoiesis [25].
Probably themost innovative advantage of thesemodelsis that they enable studies of in vivo shear forces. Untilnow, parasite–human microvasculature interactions couldbe studied only in in vitro conditions, although it wasknown that the highest shear stress used in vitro is atthe low end of the shear forces found in vivo [26]. Thegeneration of a new chimera for human skin, which wasestablished by grafting split-thickness human skin [27](Table 1), has facilitated direct visualization of howHRBCsroll and adhere not only to postcapillary venules but also toarterioles [28], thus reproducing the in vivo shear forces.Consequently, antiadhesive therapies can be more accu-rately assessed in this new model, as was already demon-strated for various antibodies directed against CD36 orintercellular adhesion molecule 1 (ICAM-1) [28] and forrecombinant peptides [29]. Most interestingly, resultsobtained in this model indicate that attachment of infectedHRBCs to CD36 seems to trigger a Src-family kinase-dependent intracellular signal that is responsible forincreasing subsequent adhesion of infected HRBCs [30].In view of the potential value of this model, it would beinteresting to carry out further hematological and histo-logical studies to determine the characteristics of thesetissues in the mouse environment. Unfortunately, thismodel, where human skin is only grafted in the thoraxof the mice, is not designed to reproduce human pathology.The generation of a transgenic mouse model with adhesionmolecules from humans could overcome this constraint.Because a correlation has been found between ICAM-1expression in brain blood vessels and the presence ofinfected HRBCs in samples from clinical cases of cerebralmalaria [31], an immunodeficient and transgenic mousemodel for human ICAM-1 would be a useful tool to studythe phenomenon of P. falciparum cytoadherence in vivoand its implication in the development of cerebral andsevere malaria.
In addition, the lack of an in vivomodel that accepts theparasite infection without a previous period of adaptationhas hampered the study of the correlation between definedgenes and phenotypic parameters and the function oftarget genes using transgenic parasite lines. This research
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can now take place because chimeric mice with HRBCs canbe infected with different parasite populations without anyprior adaptation [21]. Furthermore, because gametocyto-genesis is a consistent finding in this model, it should bepossible to study the effect of drugs not only on parasitemultiplication but also on its transmission, in addition tothe investigation of fundamental aspects of the switch fromthe asexual cycle of P. falciparum to its sexual develop-ment.
The concomitant graft of Hheps and HRBCs in the samemouse has not yet been obtained but preliminary resultsindicate that it should be possible [18]. This wouldrepresent a major tool for preclinical studies and couldprovide the opportunity to evaluate in the same model theeffect of new therapeutic strategies on the EE and IEstages of the parasites.
Concluding remarksDespite their limitations, we believe that mouse–humanchimeras can now be expected to provide valuable tools forthe study of malaria in humans. Clearly, more develop-ment and refinement of this model is needed to facilitatebroader application in the research community but we areconfident that new immunodeficient mouse strains, suchas the NOD/SCID interleukin 2 receptor g knockout(Il2rg�/�) (Box 1), will overcome these limitations. Finally,the fact that the different stages of the complex life cycle ofP. falciparum have been obtained in different mousemodels indicates that the next challenge, which is tocomplete the whole parasite cycle in the same animalincluding transmission to mosquito, could be reached inthe near future.
AcknowledgementsWe thank Edgar Badell, Francois Nosten and Georges Snounou. Thiswork has been supported by an intramural program grant (MPY-1118/03)from the Instituto de Salud Carlos III by a research project grant(SAF2003–08720) from the Spanish Minister of Science and Technology,by a grant from the Seneca Foundation and by a second grant from theResearch Network of Tropical Diseases Centres in Spain (RICET).
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