Download Host susceptibility to malaria in human and mice: compatible

Articles in PresS. Physiol Genomics (October 29, 2013). doi:10.1152/physiolgenomics.00044.2013
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Host susceptibility to malaria in human and mice: compatible approaches to
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identify potential resistant genes
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Maria Hernandez-Valladares1, Pascal Rihet2,3 and Fuad A. Iraqi4*
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Biomedical Research/Public Health Operations, Granada, Spain
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UMR1090 TAGC, INSERM,, 163 av, Luminy, 13288 Marseille, CEDEX 09, France
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Aix-Marseille University, Marseille, F-13288, France
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Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv
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University, Ramat Aviv, 69978 Tel Aviv, Israel
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Running title: Genetic resistance to Malaria in human and murine
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Correspondence to: Prof. Fuad A. Iraqi
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Department of Clinical Microbiology and Immunology
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Sackler Faculty of Medicine
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Tel-Aviv University
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Ramat Aviv, Tel-Aviv 69978
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Israel
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Phone: +972-3-6409321
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Fax: +972-3-6409160
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[email protected]
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All the authors contributed equally to the preparation of this review
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Copyright © 2013 by the American Physiological Society.
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Abstract
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There is a growing evidence for human genetic factors controlling the outcome of malaria infection,
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while molecular basis of this genetic control still poorly understood. Case-control and Family-based
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studies have been carried to identify genes underlying host susceptibility to malarial infection.
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Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and
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6p21.3, and several immune genes located within those regions have been associated with malaria
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related phenotypes. Association and linkage studies of resistance to malaria are not easy to carryout in
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human populations, due to the difficulty to survey a significant number of families. Murine models
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were proven to be excellent genetic tool for studying host response to malaria, that allowed mapping
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fourteen resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria.
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Once QTL or genes have been identified then may human ortholoug can be identified. Comparative
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mapping studies showed that couple of human and mouse might share similar genetic-controlled
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mechanisms of resistance. In this way, char8 that controls parasitemia was mapped on chromosome 11;
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char8 corresponds to human chromosome 5q31-q33, and contains immune genes, such as Il3, Il4, Il5,
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Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might
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differ in both hosts due to specific host-pathogen interactions. Finally, novel genetic tools including
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animal model were recently developed and will offer new opportunities for identifying genetic factors
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underlying host phenotypic response to malaria, which will help in better therapeutic strategies
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including vaccine and drug development.
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Introduction
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Plasmodium falciparum malaria remains a major cause of morbidity and mortality in many developing
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countries. According to WHO, the number of cases in 2012 reached 219 millions (95% CI 154-289
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million), among which over 660 000 (95% CI 490 000-836 000) were fatal (62, 178). Drug-resistant
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parasite strains are spreading rapidly across the world and, in spite of substantial efforts and
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encouraging results from recent trials, a fully protective malaria vaccine remains a distant prospect
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(154). Vaccine development faces major difficulties partly due to the genetic control of immunity to the
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parasite (155, 156, 163, 176) and/or to the parasitic antigenic variation (146).
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The outcome of human malaria infection is thought to depend on both parasite and host genetic factors.
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P. falciparum genotypes have been associated with differences in disease outcome (41) and may be
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subject to selective pressure (34, 55). The influence of host genetic factors has been demonstrated in
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animal models (156, 47, 49), and there is accumulating evidence of human genetic control in malarial
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infection and disease. The development of efficient control measures calls for a better knowledge of
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human genes controlling the infection and the disease. Genetic epidemiology studies are aimed at
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estimating the heritability of phenotypes related to malaria, at localizing and at identifying genes
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involved in susceptibility or resistance to malaria. Herein we will review the current knowledge in the
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field of genetics of human malaria. We will particularly discuss the results of case-control studies and
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family-based and the animal model studies.
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Several malaria phenotypes have been considered in genetic epidemiology studies and summarized in
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Table 1. The purpose of such studies is to identify genetic factors that control parasitemia, and those
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that determine the risk of developing either mild malaria or severe malaria. Although the phenotypes
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are related, the study of each phenotype should give a particular insight into the understanding of
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malaria physiopathology.
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Severe malaria is mainly composed of three sub-phenotypes: cerebral malaria, severe anemia, and
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respiratory distress (102). Separate or combined phenotypes have been considered in association
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studies. The studies of severe malaria phenotypes are based on recruitment in hospital. For mild
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malaria, composed of parasitemia and fever attacks sub-phenotypes, the ascertainment is based on
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population living in an endemic area. A binary phenotype and quantitative phenotypes can be used for
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both severe and mild malaria: the presence or absence of malarial disease is a binary phenotype, while
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the risk of developing malarial disease is a quantitative phenotype. The calculation of the quantitative
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phenotype is generally based on a logistic regression model that takes into account significant
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covariates, such as age.
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Asexual blood stages are responsible for mild and severe malaria. Parasitemia without clinical
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symptoms frequently occur in endemic area, but high parasitemia strongly increased the risk of
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developing mild malaria attacks. This has been clearly demonstrated in longitudinal studies in Africa
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(147). High parasitemia is often observed in case of severe malaria, and is a WHO criteria for severe
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malaria diagnosis (182, 62, 113). However, in case of severe malaria, infected red blood cells are
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sequestered at high levels, and low parasitemia can be observed (137, 138). In addition, it is
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conceivable that two individuals with the same parasitemia differently respond to the parasite infection
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mounting different pro-inflammatory responses, and whereas one could develop severe malaria, the
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other could develop only mild malaria. Nevertheless, malaria pathogenesis is incompletely understood
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and the study of parasitemia, which is a risk factor, should be helpful in understanding mechanisms
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involved in clinical malaria. Since parasitemia fluctuate considerably, only one measurement will not
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reflect the parasitic load of individuals. Therefore, cross-sectional studies (studies are based on data
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collected by measuring a parameter in many subjects at the same time point, or without regarding
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differences in time. Thus, a cross-sectional parasitemia survey is based on one parasitemia
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measurement), that are designed to test association of polymorphisms with severe malaria are generally
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not appropriate to the study of parasitemia. Conversely, longitudinal studies (in this study, subjects are
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surveyed over time with continuous or repeating monitoring of a parameter. Thus, a longitudinal
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parasitemia survey looks at parasitemia measured several times in the same subjects, examines
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how
parasitemia
changes
over
the
course
of
time,
and
how
subjects
differ
in
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parasitemia), that take into account more than ten parasitemia measurements will be more appropriate
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for studying the influence of host genetic factors on parasitemia.
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Additional phenotypes have been used in genetic studies. Since immunoglobulins G (IgG) have been
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shown to inhibit the growth of parasites in cooperation with effector cells in vitro and to protect
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humans in vivo (24), IgG levels were considered as pertinent phenotypes. The levels of IgG-subclasses
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were also assessed: the levels of cytophilic IgG that have been associated with protection from mild or
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severe malaria are the most interesting phenotypes (12, 13). IgG1 and IgG3 that bind to Fc receptors,
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and IgG2 that binds to FcRIIA-H131, which is frequent in Africa, likely kill the parasite in cooperation
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with cells such as monocytes, while IgG4 may block this antibody-dependent cell cytotoxicity
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mechanism (Figure 1).
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The heritability of phenotypes related to malarial infection and disease
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Comparisons of three sympatric West African ethnic groups showed that the Fulani had lower blood
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infection levels and fewer clinical malaria attacks than the Mossi and the Rimaibe living in the same
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area in Burkina Faso (110). In addition, the Fulani had higher levels of IgG against malaria antigens
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(111). Similar ethnic differences in resistance to malaria have been observed in Mali (39) and in Nepal
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(160). Interestingly, the low frequency of protective globin variants in the Fulani group suggested that
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unknown genetic factors were involved in malaria resistance (112). Although such differences may be
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a result of differences in lifestyle, it is thought that the Fulani resistance to malaria had a genetic basis.
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Furthermore, twin studies have shown that mild malaria and antibody responses to parasite antigens
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were more concordant within monozygotic twin pairs than in dizygotic pairs (72, 73, 152). The results
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of several family studies have shown conclusively a familial aggregation of blood infection levels (1,
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52, 142), malaria attacks (72), severe malaria (141), and anti-malarial immune responses (12, 155,
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158). Segregation analyses of parasitemia yielded significant sibling correlation coefficients, which
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ranged from 0.16 to 0.24 (1, 52, 142). Similarly, several studies have found significant sibling
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correlation of IgG and IgG sub-class responses to parasite antigens (12, 157, 158); sibling correlation
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coefficients ranged from 0.13 to 0.39. Although an initial study detected a major gene controlling
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parasitemia in Cameroun, segregation analyses of both parasitemia and antibody levels rather
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evidenced a complex genetic model in Cameroun, in Burkina Faso, and in Papua New Guinea (1, 52,
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142, 157). The odds of having cerebral malaria were 2.49 for a child whose sibling had a history of
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cerebral malaria than the odds for a child whose sibling had no history of cerebral malaria (34, 141).
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Similar results have been obtained for mild malaria and severe anemia (72, 141). In addition,
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Mackinnon et al. (97, 98) found that genetic factors explained approximately 25% of the variation in
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the incidence of mild malaria episodes. Interestingly, the studies attributed a small proportion of the
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variation of mild malaria incidence to hemoglobin S (HbS) and α-thalassemia, and pointed out that
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other genes were involved in malaria resistance (97, 98).
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Case-control association studies have mainly identified genes associated with severe malaria
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Case-control studies have been carried out to investigate the role of candidate genes in clinical malaria
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and these studies are summarized in Table 1. Such studies test whether case and control groups differ
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in marker allelic frequencies. Case-control studies are based on candidate genes, which have been
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chosen on the basis of the high frequency of deleterious alleles at the homozygous stage, or their
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function. Fifty years ago, Haldane and Allison reported a similarity in geographical distribution of
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hemoglobinopathologies (thalassemia and sickle disease) and P. falciparum malaria, and proposed that
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thalassemia and HbS might confer protection against malaria (10, 59). Thus, genes encoding alpha-
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globin and beta-globin have been considered as candidate genes. Other genes involved in erythrocyte
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surface, in immune responses that likely affect the outcome of infectious diseases, in the sequestration
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of P falciparum-infected erythrocytes or in erythrocyte metabolism have also been analyzed in
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association studies.
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Erythrocyte polymorphisms and severe malaria
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HbS carriers are strongly protected against severe malaria (2, 4, 8, 67). This clearly supports that there
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is a significant impact of malaria in selecting HbS as a protective allele, in spite of the deleterious effect
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of HbS at the homozygous state. Another hemoglobin variant named HbC was shown to be associated
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with protection against severe malaria (3, 107, 112). Strikingly, the HbC and the HbS mutations occur
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in the 6th position in the beta-globin gene, and both mutations coexist in several populations in West
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Africa. Since HbC is clinically less severe than HbS in the homozygote state, it has been suggested that
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HbC would replace HbS in West Africa (161). Other beta-globin and alpha-globin variants that cause
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the thalassemias have also been shown to protect against severe malaria (7, 108, 179). In addition,
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association studies have provided consistent evidence of a protective effect of glucose-6-phosphate
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dehydrogenase (G6PD) deficiencies against severe malaria (56, 149) and haplotype analyses support
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the hypothesis of recent positive selection (150, 164). Other red blood cell polymorphisms, such as the
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deletion of glycophorin C (GYPC) exon 3 or a 27 bp-deletion in band 3 gene (SLC4A1) have also been
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associated with protection from severe malaria (9, 54, 133, 134).
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Cytoadherence genes, immune genes and severe malaria
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Several studies have detected the association of CD36 antigen (CD36), complement receptor 1 (CR1),
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intercellular adhesion molecule 1 (ICAM1) and platelet/endothelial cell adhesion molecule 1 (PECAM1)
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variants with either resistance or susceptibility to severe malaria. However, the results have been highly
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variable in different geographical locations. For instance, ICAM1-Kilifi allele was found to be
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associated with protection from severe malaria in Gabon and with susceptibility in Kenya, while a large
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study in the Gambia failed to detect any association (18, 42, 81). In the same way, the CD36-1264G
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variant was associated with susceptibility to cerebral malaria in populations living in the Gambia and in
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Kenya (6), and with protection against severe malaria in another Kenyan population (132). Similar
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findings were obtained for the other candidate cytoadherence genes and variants. It has been suggested
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that parasite factors may profoundly influence the pattern of association, since the sequestration of the
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parasite depends on the constant switch between different forms of P. falciparum erythrocyte
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membrane protein 1 (PfEMP-1) (146).
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The nitric oxide synthase type 2A (NOS2A)-954C variant has been associated with protection against
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severe malaria in Gabon, while no association was detected in the Gambia and in Tanzania (26, 80, 90).
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Similarly, the human leukocyte antigen HLA-B53 was associated with protection against severe
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malaria, but not in Kenya (67, 68). In contrast, several tumor necrosis factor (TNF) alleles have been
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associated with severe malaria in different studies: these include TNF-308A and TNF-238A (5, 104,
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105, 175). The Fc gamma receptor IIa (FCGR2A)-H131 variant was also found to be associated with
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susceptibility to severe malaria in two different studies in Thailand and the Gambia (35, 129).
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The association of erythrocyte genetic variants with severe malaria seems to be well established, while
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the pattern of associations of cytoadherence and immune responses with severe malaria is less clear and
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remains indicative of ongoing research. Strikingly, most of erythrocyte genetic variants that protect
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against severe malaria have been associated also with protection against mild malaria, erythrocyte
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resistance to invasion by the parasite or a reduced parasitemia, while a few genes involved in immune
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responses, such as TNF and NOS2A, have been found to be associated with mild malaria or parasitemia
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(Table 1). The absence of association with parasitemia may be partly due to the cross-sectional study
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design, which is less appropriate than the longitudinal study design. Candidate immune genes
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associated with severe malaria may also weakly influence parasitemia and/or mild malaria, and other
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immune genes may be more important for these phenotypes. Nevertheless, it remains possible that the
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association of some genes with severe malaria arise from statistical artifacts, such as biases due to
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population stratification or population admixture.
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Family-based association and linkage studies test whether a particular allele of the marker is
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transmitted from parents to affected offspring in families more often than expected by chance. To date,
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most of the candidate genes have not been analyzed by using family-based studies. Nevertheless, such
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studies recently confirmed the association of HbAS and interferon gamma receptor 1 (IFNGR1)+2200C
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with protection against severe malaria (2, 77) and revealed the association of IFNG-183T with reduced
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risk of cerebral malaria (76, 29). In addition, HbC that protects from severe malaria has also been
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shown to protect also against mild malaria (144).
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Linkage analyses do not focus on a particular allele, and alleles co-inherited with disease may vary
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from one family to another), led to the localization of genes controlling parasitemia and mild malaria
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on chromosome 5q31-q33 (44, 53, 143) and chromosome 6p21-p23 (45, 74). Chromosome 5q31-q33
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contains several candidate genes implicated in the regulation of immune responses (Figure 1). These
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include genes involved in the Th1 and Th2 balance, such as interleukin 4 (IL4) and IL12B, and genes
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involved in the activation of effector cells, such as IL3, IL5, colony stimulating factor 2 (CSF2), and
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colony stimulating factor 1 receptor (CSF1R), and genes involved in the production of antibodies, such
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as IL4 and IL13. Chromosome 6p21-p23 corresponds to the MHC region, and the peak of linkage was
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found to be close to TNF (45). A systematic polymorphism-screening revealed a family-based
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association of TNF-308, TNF-238, TNF-851 and TNF-1304 polymorphisms with mild malaria or
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parasitemia (46).Nevertheless, TNF genetic variation did not completely explain the linkage of the
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MHC region with mild malaria. More recently, results have shows that the natural cytotoxicity
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triggering receptor 3 (NCR3) that is close to TNF, and we showed that a NCR3 polymorphism located
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within the promoter was associated with mild malaria, and that this association was not due to the
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association of TNF with mild malaria (36).
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Interestingly, recent studies were shown that mouse resistance to P. chabaudi linked to mouse
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chromosome 11 and mouse chromosome 17 (63, 65), which carry regions homologous to chromosome
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5q31-q33 and the MHC region, respectively. These findings might help to dissect the human loci and to
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demonstrate the effect of candidate genes in vivo. So far, only the effect of Tnf on resistance to P.
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chabaudi has been demonstrated by using Tnf-deficient mice (66), which were more susceptible to the
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infection with higher parasitic levels and mortality rates.
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Current lessons from human genetic studies of resistance to malaria
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Case-control studies have clearly shown the protective effect of red blood cell polymorphisms on
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malaria (14, 40, 43, 89, 123, 140). A number of case-control studies have also detected association of
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genes involved in cytoadherence or immune responses. However, most of these studies yielded
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conflicting results, suggesting a possible role for hitherto unknown traits associated but not examined
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in these studies. Family-based studies that avoid biases due to population stratification (refers to a
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situation in which the study population includes two sub-populations genetically different. In this case,
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the two sub-populations differ in allele frequencies at a number of genetic markers located within
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different chromosomal regions (20, 25, 69, 75, 76, 82, 95, 96, 105, 108, 124, 125, 130, 165, 180).
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These differences can be due to different population histories), should be useful to clarify this point. To
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date, very few family-based association studies have been conducted, and they have confirmed the
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protective effect of hemoglobin variant and some immune gene variants.
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Linkage and association analyses can be viewed as a more general approach to localize and to identify
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genes involved in malaria resistance (15, 23, 78, 114, 115, 151, 169). The first studies have identified
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two chromosomal regions that contain malaria resistance genes (Figure 1), and these results were
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confirmed in linkage replication studies in humans. Two genes, TNF and NCR3, which are located on
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chromosome 6p21.3, have been shown to be independently associated with mild malaria, indicating
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that there are at least two genes located on the central region of MHC involved in the genetic control of
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human malaria. Preliminary analysis suggests that chromosome 5q31-q33 also contains several genes
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controlling parasitemia (P. Rihet, unpublished data). To date, those malaria resistance genes have not
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been identified. It is well known that the identification of genes underlying complex traits is a
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challenging task, and strategies combining mouse and human studies may be helpful in identifying
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malaria resistance genes. In this way, two mouse loci have been mapped to chromosomal regions that
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correspond to human chromosomes 5q31-q33 and 6p21.3 (see the section of mouse genetic studies of
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malaria resistance in this chapter). This suggests that mouse models might help to identify malaria
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resistance genes in humans.
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Mouse Models for Studying Malaria
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The mouse is a leading model for studying biological processes in mammals and provides models of
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particular importance in the study of the host response to infectious disease and understanding why
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some naturally occurring genotypes are dramatically more sensitive to disease than others. This clearly
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applies to the malaria disease. Human and mouse genomes are very similar. Mouse strains show
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different degree of susceptibility and resistance to malaria as observed in human cases. There are a
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number of different parasites infecting the laboratory mouse and while none of these behaves like P.
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falciparum, the deadly strain of human malaria, they do model parts of the disease. There are also
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significant inter-strain variations, which have been exploited to study host responses. Therefore, the
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mouse model offers a powerful tool for dissecting and understanding the host response mechanism to
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malaria, and through comparative genomics it may be possible to identify the orthologous genes in
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humans.
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Mouse populations for gene mapping studies
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In crosses between genetically well-defined strains of mice, chromosomal regions responsible for the
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genetic variance of quantitative traits (i.e. parasitemia) can be mapped to a large genetic interval as
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quantitative trait loci (QTL) in experimental resource populations (F2 or backcross –BC- generation)
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(87, 135). A QTL is defined as a region of DNA that is associated with a particular phenotypic trait.
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Knowing the number of QTL that explains variation in the phenotypic trait tells us about the genetic
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complexity of a trait. QTL mapping is the statistical study of the alleles which occur in a locus and the
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phenotypes that they produce. Due to limit of recombination events in F2 and BC populations, QTL
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usually maps within 20-30cM genomic regions, which may consist hundreds if not thousands of genes.
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1 cM represents approximately 2000 Kb of DNA in the mouse genome.
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Subsequently, fine mapping of the QTL can be achieved by a number of approaches including
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advanced intercross lines (AIL), recombinant inbred lines (RIL), congenic strains (CS), using single
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nucleotide polymorphisms (SNPs) (181) haplotype mapping (58), and Collaborative Cross (CC) was
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designed (33, 162, 166). They are unquestionably providing an opportunity to identify host genetic
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factors that influence disease progression.
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Once QTL or genes have been identified, genetic analysis may then be extended successfully to
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humans (167). For example, the genetic basis of total and HDL cholesterol concentrations was
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examined in experimental crosses involving various pairs of inbred mouse strains maintained on
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regular chow and high-fat diet (71, 79, 99, 171). Although these experiments discovered more than 27
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QTL, they could explain only a fraction of the total genetic variance in cholesterol metabolism.
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Importantly, however, comparative mapping showed that the majority of murine QTL and candidate
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genes have known correspondents in the human genome emphasizing the relevance of QTL analysis in
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the mouse model for understanding complex disease in humans (172).
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Murine malaria parasites
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Since more than 20 years, laboratory mice have been exposed to a wide range of health-threatening
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conditions, infected with all kind of microorganisms, phenotyped, cured with testing drugs and
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immunized with potential vaccines. The availability of mouse genetic markers (e.g. microsatellites and
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single nucleotide polymorphisms), new mouse genomes resources (see Box 1) and the published initial
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sequencing of the mouse C57BL/6J genome by the Mouse Genome Sequencing Consortium (117) have
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highly encouraged the study of the genetic bases of resistance to diseases in mouse. Four mouse
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Plasmodium species (P. chabaudi, P. berghei, P. yoelii and P. vinckei) were found to infect rodents and
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mosquitoes from several Central African regions several decades ago (31, 32, 84, 85). Thereafter,
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numerous studies described the morphological and developmental characteristics and iso-enzyme
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patterns from the different species (86, 170). The malaria mouse models became popular laboratory
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tools to study the drug (mainly pyrimethamine, cloroquine and sulphonamide) resistance issues that
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were alarmingly worrying in the affected human communities (131, 153, 174, 184).
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Among the four species, P. chabaudi has provided a remarkable experimental tool with many
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similarities to human P. falciparum, such as analogous blood-stage antigens, invasion of red blood
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cells, suppression of cell-mediated immune responses and parasite sequestration in target organs (159).
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Two subspecies of P. chabaudi have been described: P. chabaudi chabaudi and P. chabaudi adami.
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The latter is known to induce a severe form of the disease characterized with more pronounced
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pathologies when compared to the infections by P. chabaudi. P. yoelii was a common experiment
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model of mouse cerebral malaria some decades ago. However, it has been extensively used in the
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development and characterization of vaccine candidates in the last decade (119). Three subspecies have
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been defined: P. yoelii yoelii, P. yoelii killicki and P. yoelii nigeriensis. P. berghei is the preferred
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mouse parasite to study cerebral malaria and its lethal pathologies currently (93). Researchers have
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available five different isolates: k173, SP11, LUKA, NK65 and ANKA, although most of the mouse
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cerebral malaria investigations have been carried out with P. berghei ANKA. Four subspecies of P.
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vinckei are recognized: P. vinckei vinckei, P. vinckei petteri, P. vinckei lentum and P. vinckei
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brucechwatti. Despite being the most distributed mouse parasite in nature, P. vinckei is the least
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characterized mouse parasite. P. vinckei petteri has been used in the identification of new antimalarial
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drugs (21).
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Common laboratory mouse strains used in malaria studies
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In the last few decades, up to thirteen different inbred mouse strains have been infected with several
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Plasmodium species and their susceptibility to malaria (and to other infectious diseases) has been
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characterized (83, 126, 136). Most of the mouse strains are susceptible to the infections by the four
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murine parasites. However, C57BL/6J and DBA/2J mice are resistant to infections by P. chabaudi and
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P. berghei parasites, respectively, and are commonly used to investigate the molecular basis of mouse
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resistance to malaria. Susceptible and resistant mice to P. chabaudi infections suffer from severe
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anemia after two weeks post infection. Susceptible animals die with high parasitic levels and low red
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blood cell concentrations whereas resistant animals clear parasites from the bloodstream and recover
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the pre-infection red blood cell values. Moreover, the outcomes from susceptible and resistant mice
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after infection with mouse parasites can differ substantially. While P. berghei-susceptible mice die
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from cerebral malaria after few days post infection, resistant animals die from severe anemia after
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several weeks post infection. Table 2 summarizes the current information about the susceptibility of
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laboratory mouse to malaria induced by the most common murine parasites in mouse studies, P.
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chabaudi, P. berghei and P. yoelii. Since 1997, a remarkable number of publications have described
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more than a dozen genetic loci linked to murine malaria resistance (47, 48, 92, 100).
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Genetic loci linked to murine malaria parasitemia
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One of the first published studies crossed two mouse strains, C3H/He and SJL, susceptible to P.
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chabaudi adami DS-induced malaria with a common resistant strain, C57BL/6J, to produce a F2
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generation of animals (47). Two loci on chromosome 9 (chabaudi resistance char1) and chromosome 8
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(char2) linked to the parasite-induced death were found in both crosses. Char1 was also found in F2
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animals from both crosses when testing for QTL contributing to peak parasitemia whereas char2 was
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only found in animals originated from the C3H/HexC57BL/6J cross. Although the 95% confidence
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interval of their positions spanned a wide genomic region comprised of several hundreds of genes,
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some candidate genes were suggested to control the phenotypic traits: haptoglobin (Hp), encoding a
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protein that functions in the binding of free hemoglobin in the bloodstream, and erythrocyte antigen 1
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(EaI), encoding for the protein that define MN blood groups in humans, on chromosome 8; transferrin
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(Trf), encoding a key iron transport protein, and two retinol-binding proteins (Rbp1 and Rbp2), on
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chromosome 9.
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Simultaneously, char2 was also mapped in a separate study using a different susceptible mouse strain,
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A/J (49). Despite the width of the 95% confidence interval, three new genes were presented as
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attractive candidates for char2: glycophorin A (GypA), encoding for an erythrocyte membrane protein,
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interleukin 15 (Il15) and macrophage scavenger receptor 1 (Msr1), encoding for key proteins involved
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in the phagocytosis of microbes by mononuclear phagocytes. Thus, char2 was a common locus to
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control parasitic levels in two independent studies, which used different susceptible mouse strains and
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mouse parasite subspecies to induce the infection.
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Later on, an independent BC study with susceptible NC/Jic and resistant 129/SvJ mice using P. yoelii
353
17XL (148) mapped a locus on chromosome 9, pymr (Plasmodium yoelii malaria resistance),
354
controlling survival and parasitemia after infection at the same position as char1 localized in a previous
355
study using P. chabaudi adami DS (47). Since P. yoelii prefers to invade reticulocytes whereas P.
356
chabaudi invades both reticulocytes and mature red blood cells, pymr (char1) might represent a
357
relevant common locus controlling malaria traits induced by different species. The locus position is
358
homologous to the human region 3q24-26 that contains two genes involved in immune responses,
359
cytokine-inducible SH-2-containing protein (Cish) and chemokine receptor 4 (Cmkbr4).
360
Further studies with the promising loci, char1 and char2, could aim the identification of the key gene.
361
In fact, five years later, a CS approach was used to generate char2-CS using C3H/HeJ and C57BL/6J
362
as parental inbred lines (28). At each generation, mice carrying the genotype of interest at char2 locus
363
were selected for subsequent backcrosses to the parental mice to fix the background genome. A total of
364
ten char2-CS, each carrying different recombination outputs around char2, were originated from
365
intercrosses of lines at the N7 or N8 generation. Genetic analysis of P. chabaudi adami DS-infected
366
animals from each line suggested a large congenic interval on chromosome 8, which conferred
367
susceptibility on background of resistant parental mice (the CS was named Char2-7). The interval was
368
most likely comprised of several genes that could interact to control survival and parasitic levels. One
369
of them was mapped to the distal region of the chromosome when compared congenic intervals from
370
non-susceptible animals of resistant background. Because char2 was localized in the central region on
371
chromosome 8 in previous studies (47, 49), these congenic studies strongly supported the existence of
372
several genes at this locus, sufficient to decrease the survival to malaria. In order to refine the map
373
positions of the char2 genes, a series of recombinant lines from the Char2-7 CS has been recently
374
derived (91) by crossing back to the parental line C57BL/6J. Nine Char2-7 recombinant CS, targeting
375
the distal region of chromosome 8, were inbred, infected with P. chabaudi adami DS and tested for
376
susceptibility to malaria. Due to changes of the parasite lethality and the difficulties to discriminate
15
377
phenotypes among the recombinant CS, mortality rates from each strain were normalized and a
378
statistical model was used to predict the position of a single locus or multiple loci. Results from the
379
different models were compared and two critical regions showed the highest likelihood of containing
380
the char2 genes. One, on the proximal portion of chromosome 8 (35-42.6 cM), was mapped on the
381
same position as in the original studies (47, 49). The other, on the distal portion of the chromosome
382
(68.9-75.4 cM), was suggested in the first congenic study (28) and it could be now confirmed as the
383
second char2 locus controlling susceptibility to malaria.
384
A different approach to refine the position of char2 in the proximal region of chromosome 8 was
385
carried out using an F11 AIL from an F1 cross of A/J and C57BL/6J mice (63). The power of the AIL
386
approach in fine mapping resistance loci has been reported in murine trypanosomiasis and pulmonary
387
adenoma studies (70, 173), reducing 95% confidence intervals of loci positions up to 7-fold in
388
comparison with those observed in F2 studies. However the 95% confidence interval of char2 location
389
(between 13 and 16 cM) could not be narrowed down as expected from the AIL approach. This was
390
most likely due to the little phenotypic differences found in the parental mouse strains infected by P.
391
chabaudi chabaudi 54X when compared to the well distinguished phenotypes observed in infections by
392
P. chabaudi chabaudi AS (156). As it has been shown in later studies, environmental factors as well as
393
parasite polymorphisms among isolates might influence the severity of malaria between susceptible and
394
resistant mice (64). Moreover, the AIL study did not detect the presence of linked loci on the proximal
395
region of chromosome 8 as suggested by the first congenic line study (28) and supporting the results
396
from the second congenic line study (91) which, showed the location of the second char2 locus on the
397
distal region of the chromosome. Two more candidate genes were presented to control parasitemia in
398
the AIL study: chondroitin sulfate proteoglycan 3 (Cspg3), a major constituent in blood vessels, and
399
interleukin 12 receptor beta 1 (il12rb1).
16
400
While many efforts towards the positional cloning of char2 genes have been performed, refinement
401
studies on the map position of char1 have not been unfortunately carrying out in spite of the relevance
402
of the locus found in two separated studies with different mouse and parasite species.
403
The first evidence of H2 locus involved in the control of survival to malaria infections in mouse
404
appeared two decades ago (183). However, the H2 locus was not significantly linked to either survival
405
or peak parasitemia in BC and BC-F2 combined studies (49). A new study using an F2 generation of
406
C3H/HeJ and C57BL/6J mice was carried out to detect loci responsible for the control of daily
407
parasitemia levels (27). A significant locus at the proximal end of chromosome 17 (a region harboring
408
the H2 complex), named char3, was identified to control parasite clearance from the blood stream after
409
peak parasitemia, whereas char1 and char2 controlled peak parasitemia levels confirming previous
410
results (47, 49). Because char3 did not play any role in the control of the peak parasitemia, but it was
411
critical in the eradication of parasites, this locus might represent the complex H2 locus that could
412
modulate T-cell responses required for the clearance of primary and secondary parasitemias (Figure 2)
413
(88). Interestingly, human MHC alleles have been involved in the protection of West African children
414
from severe malaria (67) and TNF, a gene harbored within the H2 loci, was implicated in the immune
415
response to cerebral malaria (46). The char3 region has also been involved in the control of TRBV4
416
CD8+ T cells during mononucleosis induced by γ-herpes virus (60).
417
The AIL study with an (A/JxC57BL/6J) F11 population infected with P. chabaudi chabaudi 54X
418
resolved this locus into two loci in coupling phase, one of them was mapped near the H2 region (char3)
419
whereas the other, named in this study char7, mapped within a region containing interesting candidates
420
genes, i.e. complement component 3 (C3), interleukin 25 (Il25) and immune response 5 (Ir5). Further
421
linkage studies of both loci using daily parasitemia traits revealed that char3 and char7 acted in early
422
stages of the infection before peak parasitemia, in disagreement with previous mapping studies using P.
423
chabaudi adami DS parasites. These controversial results showed that different P. chabaudi subspecies
424
and mouse-specific parasitemia development might influence the mode of action of the resistant loci.
17
425
Another remarkable effort to narrow down the positions of char1 and char2 loci and map new malaria
426
resistance loci was carried out using a set of 37 recombinant CS derived from A/J and C57BL/6J
427
parental mice (50) The individual AcB strains, created from (F1xA/J)xA/J double backcrosses,
428
contained on average 13% of the C57BL/6J genome and the total AcB set contained almost 80% of the
429
resistant genome. Susceptibility phenotypes to P. chabaudi chabaudi AS infection and genotypes at
430
char1 and char2 loci were studied in all the AcB strains (51). In particular, the AcB55 strain was found
431
to be resistant to infection (low parasitic levels and 0% mortality), despite carrying susceptibility alleles
432
at char1 and char2 loci, indicating the presence of a novel resistance locus transferred by a small
433
C57BL/6J chromosomal region into the A/J genomic background. An (AcB55xA/J)F2 population was
434
monitored for parasitic levels and mortality and genotyped at a maximum spacing of 10 cM covering
435
all murine chromosomes containing C57BL/6J genomic segments. While genetic linkage was not
436
detected when using mortality as phenotypic trait, a significant locus was detected on chromosome 3
437
(char4) when using peak parasitemia as phenotype. A second, less significant, locus (not named in this
438
study) was mapped on chromosome 10. Both loci explained 18% of the variance of the peak
439
parasitemia. The size of char4 locus was estimated between 6 and 10 cM, a region narrow enough to
440
transfer into A/J genomic background and create congenic lines for further dissection of the traits. The
441
char4 segment, syntenic with the human 4q21-q25, contained interesting candidate genes: lymphoid
442
enhancer binding factor 1 (Lef1), a transcription factor that regulates gene expression in T
443
lymphocytes; complement component factor I (Cfi) and the p105 subunit of NfκB1, an essential
444
regulator for B cell functions.
445
Further clinical examinations of two malaria resistant AcB congenic lines, AcB55 and AcB61 (the
446
latter carried susceptibility alleles at char1 and char2 but did not carry resistance allele at char4) were
447
carried out to detect possible biochemical mechanisms that could have conferred resistance to the
448
infection (106). In fact, mice from both CS showed significant splenomegaly caused by the expansion
449
of the red pulp at the time of necropsy, a higher expression of erythroid-specific (globin, transferrin
18
450
receptor and solute carrier family 11 member 2) and cell cycle genes, and abnormal higher reticulocyte
451
concentrations. Genetic analysis of (AcB55xA/J)xF2 and (AcB55xDBA/2J)xF2 populations using
452
reticulocytosis as the quantitative trait mapped a new A/J-derived locus proximal to char4 region.
453
Liver- and cell-specific pyruvate kinase (pklr) gene was selected as a strong candidate in the new locus
454
for playing essential roles in the synthesis of ATP in red blood cells and cause hemolytic anemia in
455
humans when it is mutated. DNA sequence analysis detected an isoleucine-to-asparagine substitution at
456
aminoacid 90 of the pklr protein in both AcB55 and AcB61 congenic mice. Moreover, association
457
studies demonstrated that homozygous pklr mutants had reduced peak parasitemia and mortality rates
458
when compared with heterozygous mice. These spectacular results showed that inactive Pklr269A
459
mutants were protected against P. chabaudi chabaudi AS malaria and that splenomegaly and an
460
enhanced erythropoiesis and reticulocytosis played as compensatory mechanisms to overcome the
461
infection. These investigations proved that the recombinant CS approach can successfully be used for
462
genetic dissection of complex malaria traits. The Pklr269A mutation controlling hemolytic anemia in
463
mice affected the related and more complex parasitic level trait, which might be controlled by
464
additional not yet detected genetic factors. Epidemiological studies have not detected a selective
465
pressure on piruvate kinase deficiency by the malaria parasites, as in the cases of sickle cell trait and
466
thalassaemias, but a possible protective role of this deficiency against the different malarias in humans
467
cannot be ruled out. Currently, the impact of pyruvate kinase deficiency in humans infected with
468
malaria parasites is being studied. So far, the finding of the Pklr269A mutant as a resistant gene in mice
469
represents the most remarkable achievement from genetic studies of malaria resistance in mouse
470
models and shows the optimal strategy that it should be carried out towards a successful identification
471
of more candidate genes from preliminary F2 or BC studies
472
An additional pair of loci of opposite additive effects, char5 and char6, controlling parasitemia curves
473
was mapped on chromosome 5 in the AIL F11 study (63). A previous study with a BC population of A/J
474
and C57BL/6J as parental mice detected char6 (49), although F2 and combined BC and F2 studies
19
475
could not confirm the presence of the locus. The lack of confirmation in the latter studies could have
476
been due to the use of software to perform genetic analysis to detect single loci, possibly missing the
477
detection of linked loci, as in this case, on chromosome 5. As in the case of linked char3 and char7 loci
478
on chromosome 17, the 95% confidence interval of char5 and char6 positions could not be determined.
479
Analysis of char5 and char6 for daily parasitemia traits showed that both loci seemed to act in the days
480
of highest parasitemia, in agreement with the results from the suggestive linkage to peak parasitemia in
481
the BC study. Linked char5 and char6 regions contained a substantial number of potential candidates
482
genes: blood antigen acetylcholinesterase (Ache), erythropoietin (Epo), heat shock 27-kDa protein 1
483
(Hspb1), correlation in cytokine production 1 (Cora1), NADPH oxidase subunit (Ncf1) and actin-
484
related gene 1 (Act1).
485
The comparative approach with human and mouse genomes
486
Human homologous genes may be detected by comparative mapping of human and mouse genomic
487
regions (22, 177). However, it is also possible to perform an inversed strategy and study the role of
488
homologous human loci of resistance to malaria in mouse models. The identification of genetic factors
489
involved in the malarial disease in both humans and mice could reveal common genes controlling
490
similar mechanisms of infection from different mammalian malarias (101).
491
Several association and linkage analysis of P. falciparum parasitemia mapped pfbi (Plasmodium
492
falciparum blood infection) locus on the 5q31-q33 chromosome region (see Table 1), flanked by DNA
493
microsatellite D5S642 and interleukin 12 gene (IL12B) (143). The segment contained several candidate
494
genes involved in the regulation of the immune TH1 and TH2 responses to the infection such as
495
interleukin 4 (IL4), IL12B and interferon regulatory factor 1 (IRF1). Interestingly, the 5q31-q33 region
496
has also been identified to control Schistosoma mansoni infections (161) and regulating
497
immunoglobulin E levels (101). In an attempt to find novel murine loci for control of parasitemia on
498
regions homologous to human chromosome 5q31-q33 (Figure 3), the (A/JxC57BL/6J)F11 population of
499
mice was genotyped on chromosomes 11 and 18, but not on chromosome 13 (65). A new locus, named
20
500
char8, was found on chromosome 11 controlling parasitic levels. The locus was more significant for
501
the trait with parasitemia scores up to day 11 post infection than for the trait with parasitemia scores up
502
to day 7 post infection, indicating that char8 might act from early to late stages of the parasitemia
503
curve. Although more than 300 genes were found within the 95% confidence interval of char8, Il3, Il4,
504
Il5, Il12b, Il13, Irf1, granulocyte-macrophage colony-stimulating factor 2 (Csf2), growth differentiation
505
factor 9 (Gdf9), heat shock protein 4 (Hspa4), T-cell phenotype modifier (Tcpm1), T-cell-specific
506
transcription factor 7 (Tcf7), il2-inducible T-cell kinase (itk) and T-cell immunoglobin domain and
507
mucin domain containing genes (Tim1 and Tim3) were presented as interesting candidate genes with
508
homologues in human chromosome 5q31-q33.
509
Moreover, one of them Csf2, has been involved in the development of splenomegaly, leukocytosis, and
510
granulocyte-macrophage hematopoiesis, controlling the resistance to P. chabaudi infections (145).
511
Because any genetic factor controlling the malaria infection was not found on mouse chromosome 18,
512
this locus comparative approach might lead further dissection studies to map pfbi gene(s) on
513
chromosome 5q31-q33.
514
Genetic loci linked to murine cerebral malaria resistance
515
P. berghei ANKA induces the symptoms that can mimic some of the aspects of human cerebral malaria
516
in susceptible mouse strains. These aspects include respiratory distress syndrome, low body
517
temperature, ataxia, paralysis and coma, followed by death. Histopathological studies showed that
518
sequestration of parasitized red blood cells in brain vessels and damage of endothelial tissues were
519
involved in the irreversible effects of the infection (120, 121, 139). Based on the percentage of
520
mortality derived from cerebral malaria, laboratory strains of mouse can be divided into highly
521
susceptible (e.g. C57BL/6J, CBA/J and 129/SvJ), weakly susceptible (e.g. BALB/cJ and C3H) and
522
resistant (e.g. DBA/2J) (16). Interestingly, susceptible mice died from neurological damages with low
523
parasitemia whereas resistant mice died with severe anemia and high parasitic levels.
21
524
The first genetic study of resistance to cerebral malaria in mouse used an F2 population of susceptible
525
C57BL/6J and resistant DBA/2J mice (118). Animals surviving to day 14 post infection were
526
phenotyped as resistant whereas those dying before that day were phenotyped as susceptible. The
527
analyses showed a significant locus (unnamed in this study) in the middle region of chromosome 18
528
controlling mortality to cerebral malaria. Less significant loci were found on chromosomes 5, 8 and 14.
529
Strikingly, the position of the locus on chromosome 8 mapped within the char2 region, suggesting a
530
common segment involved in two different malaria phenotypes, parasitemia and cerebral malaria.
531
Several candidate genes on chromosome 18 were suggested to control cerebral malaria: colony-
532
stimulating factor 1 receptor (Csf1r), the platelet-derived growth factor receptor, beta peptide (Pdgfrb)
533
and the CD14 antigen (Cd14). Interestingly, the expression of the latter appeared to increase in acute
534
respiratory distress syndrome, one of the features associated with the fatalities from cerebral malaria
535
(94).
536
In order to find out new strains of mouse resistant to cerebral malaria and make use of more genetic
537
polymorphisms, several wild-derived mouse strains from Asia, Western and Eastern Europe and
538
Northern Africa were challenged with P. berghei ANKA. Six of the twelve strains tested were resistant
539
to cerebral malaria (16). WLA, a Mus musculus domesticus strain, has been used as the resistant mouse
540
line in subsequent genetic resistance studies. In fact, a (WLAxC57BL/6J)F1 population was
541
backcrossed to C57BL/6J. The resulting animals were infected with P. berghei ANKA, genotyped
542
covering the entire genome and phenotyped as susceptible when dying with typical neurological
543
symptoms between day 5 and 12 post infection (17). Genetic analysis found two loci located on
544
chromosomes 1, berr1 (Berghei resistance locus 1), and 11, berr2, controlling cerebral malaria
545
resistance. It was noted that transforming growth factor β2 (Tgfb2), a gene known to control the
546
severity of mouse infections by P. chabaudi and P. berghei (38,128) is located 0.5 cM apart from the
547
marker with the highest significance for genetic linkage on chromosome 1. A new linkage analysis
548
genotyping for Tgfb2 showed equal association strength, suggesting this gene as a potential candidate
22
549
for cerebral malaria control. A parallel study with a series of recombinant inbred mice from susceptible
550
BALB/cJ (non mammary tumor virus 7, Mtv-7, gene carriers) and resistant DBA/2J (Mtv-7 carriers),
551
showed that animals with the Mtv-7 gene inserted in their genomes were resistant where those without
552
the insert were susceptible to cerebral malaria (57). However, because Mtv-7 was not mapped within
553
the most significant linked segment on chromosome 1 to the cerebral malaria phenotypes, this gene was
554
not presented as a potential candidate.
555
A new cerebral malaria susceptibility locus, cmsc (cerebral malaria susceptibility), within the H2
556
region on chromosome 17 was found in a BC population bred from susceptible CBA and resistant
557
DBA/2 animals infected with P. berghei ANKA (127). This study did not find previously reported loci
558
such as berr1, berr2 or the unnamed locus on chromosome 18, raising the possibility of the existence
559
of different susceptible loci that contribute to the cerebral malarias of CBA and C57BL/6 mice. In
560
agreement with a previous study on susceptibility of different mouse strains to P. berghei ANKA-
561
induced cerebral malaria (146), which showed that H2 haplotypes were not highly involved in the
562
control of the pathogenesis, cmsc could not be identified as an H2 susceptible haplotype since resistant
563
mice such as C3H/HeJ and AKR share the same CBA-susceptible haplotype. However, as char3, cmsc
564
mapped near attractive candidate genes such as Tnf and lymphotoxin a (Lta) which, are critical
565
mediators of the pathogenesis induced by cerebral malaria. Recently, a gene knock-out study has
566
shown that Tnf-deficient C57BL/6J mice had higher peak parasitemias and mortality rates than
567
proficient animals (66). The multiple roles of Tnf in the different malaria pathologies as its different
568
modes of action during the parasitic infection still remain to be fully understood. Current sequence
569
analysis of both Tnf and Lta genes from CBA and DBA/2 mice might suggest the identity of the
570
causative genetic variant within the cmsc locus in the near future.
571
Previous genetic studies to find novel loci associated with resistance to cerebral malaria used the
572
reported (WLAxC57BL/6J)F2 population of mice (30). Using survival time and cure as cerebral malaria
573
phenotypes, a resistant locus on distal chromosome 1 was found, mapping within the previously
23
574
reported berr1. Two more loci, berr3 and berr4, were mapped on chromosome 9 and 4, respectively.
575
Interestingly, berr3 mapped near to previously reported char1 and pymr loci, involved in the resistance
576
to infections by P. chabaudi and P. yoelii. This region has gained a special interest since it might
577
harbor a common resistant gene to the infections of several murine Plasmodium species and it might
578
represent a universal mechanism of defense against different parasites. Recently, a deficiency in
579
chemokine receptor Ccr5 (encoding gene is located within the berr3 region) has been associated to
580
reduced susceptibility of P. berghei cerebral malaria (19). The attractive genes in the berr4 segment are
581
a toll-like receptor (Tlr4) and the complement component 8 beta subunit.
582
Conclusions and Future Directions
583
A mapping experiment using the human parasite requires the use of mosquitoes to infect chimpanzees
584
with P. falciparum gametocytes. Murine malarias make possible to work entirely in the mouse, a far
585
more tractable and cost-effective model. Such studies have focused on increasing our understanding of
586
the parasite, including the development of drug resistance, antigenic variation, and erythrocytic
587
invasion pathways. Mouse models have also been extensively used to dissect the host response to
588
disease including the innate and adaptive immune responses. This review has shown the use of mouse
589
models to map genetic regions controlling malaria traits that need to be further dissected to find the
590
resistant genes. In the immediate future, many research groups will generate congenic lines for the
591
known QTL and the results from examinations of the biological features of these lines will be
592
presented. These could give some interesting insights into associated phenotypes ahead of the
593
identification of the underlying genes.
594
The development of microarray technology with the spotting of mouse genes on chips is presently
595
being used to follow changes in expression of all mouse genes as a response to infection. In particular
596
we now are able to contrast the response of resistant and susceptible genotypes. Recently, Delahaye et
597
al. (37) were successful in using this technology to identify gene expression profiles discriminating
598
resistant and susceptible mouse during cerebral malaria infection. It is hoped that this will illuminate
24
599
the differences between the cascades of events in the two mouse strains, and determine which genes,
600
within the QTL, participate in such pathways. This will be of particular interest to those loci isolated as
601
congenic donor interval with available isogenic control lines, and will help to identify host resistance
602
genes. Indeed, the approach will lead to identify genes that are differentially expressed between
603
resistant and susceptible mice, and that will be considered strong candidates to be tested by using gene
604
targeting. Bioinformatics and experimental analyses will further identify cis-regulatory polymorphisms
605
causing changes in expression levels; these include the analysis of the sequence to search for
606
transcription binding sites and experimental methods exploring DNA-proteins interactions, such as
607
chromatin immuno-precipitation or electro mobility shift assay. Finally, with the development of the
608
new technology, namely the next generation sequence (NGS) it may be possible to determine the gene
609
expression variations of the whole genome (11, 122, 168), and combining this technology with the
610
mouse and human genetic resources, may help in identifying both genes and gene networks involved in
611
host resistance.
612
Expanding the mapping studies to larger human populations (cohorts) in malaria endemic areas will
613
provide further statistical power for identifying genetic factors underlying human phenotypic variations
614
to the disease. Combining and conduct new of analysis of the accumulated human studies can offer
615
new tool for fine mapping and identifying host genes associated with the disease.
616
617
The novel genetic reference population, namely the Collaborative Cross (CC) mice will eventually
618
comprise a set of approximately 500 recombinant inbred lines (RIL) created from full reciprocal
619
matings of 8 divergent strains of mice, including five classical inbred lines (A/J, C57BL/6J,
620
129S1/SvImJ, NOD/LtJ, and NZO/HiLtJ) and three wild-derived strains, will offer a new opportunity
621
of mapping and subsequently indentifying new genetic factors underlying variations of host
622
susceptibility to malaria (33, 162, 166). It was shown that CC mice are promising GRP, which will
623
allow identifying genes underlying complex traits, which can be applicable to malaria.
25
624
The convergent results of linkage studies in humans and in mouse models encourages to perform a
625
genome-wide screening in humans, and to compare the identified chromosomal regions in humans with
626
those previously identified in mouse models. The identification of human polymorphisms associated
627
with resistance to malaria, and the evaluation of candidate genes in the mouse model should provide
628
consistent new insights into the mechanisms of malaria resistance. This information will open the doors
629
for understanding the communication, which must occur between host and parasite.
630
Finally, it is expected that we identifying further genetic factors underling host susceptibility to
631
malaria, it will open the venue for personalized medicine application, which will benefits a significant
632
percentage of human populations, which may not response to specific drug or future vaccines.
633
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1135
1136
1137
1138
1139
37
1140
1141
Figure Legends:
1142
1143
Figure 1. Immunological mechanisms directed against asexual blood stages and genes located within
1144
chromosome 5q31-q33 (red) and chromosome 6p21.3 (green).
1145
1146
Figure 2. Mapping of the H2 region and candidate genes Tnf and Lta on mouse chromosome 17 (the
1147
design of mouse chromosome 17 was taken from the mouse genome resources at the Ensembl site).
1148
1149
Figure 3. Location of the 5q31-q33 region on chromosome 5 linked to the control parasitic levels in
1150
human malaria. Candidate genes and their homologous locations in the mouse genome are shown on
1151
the right side of the figure. The figure was drawn with the chromosome design and information based
1152
on the NCBI (177) and Ensembl (22) data.
1153
1154
1155
38
1156
1157
Table 1. Loci reported at least once to show linkage or association with P. falciparum malaria.
Locus
Functiona
Location
Type of study
Phenotype
HbA1
HbA2
HbB
A
16pterp13.3
11p15.5
Case-control
Severe malaria
Mild malaria
Severe malaria
Mild malaria
Antibody levels
A
Case-control
Family-based
(linkage and
association)
References
(7,108,179)
(2,3,4,8,67,107,
112,123,144)
ABO
A
9q34
Case-control
Severe malaria
(43,89)
G6PD
A
Xq28
Case-control
Severe malaria
(56,149)
SCLC4A1
HP
ICAM1
CD36
CR1
PECAM1
NOS2A
A
A
B
B
B
B
C
17q21-q22
16q22
19p13
7q11.2
1q32
17q23
17cen-q11.2
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
(9,54,133,134)
(14,40)
(18,42,81)
(6,132,130)
(20)
(75)
(24,25,69,80,82,1
24)
TNF
C
6p21.3
Case-control
Family-based
Severe malaria
Severe malaria
Severe malaria
Severe malaria
Severe malaria
Severe malaria
Severe malaria
Mild malaria
Severe malaria
Mild malaria
(linkage and
association)
NCR3
MALSb
C
6p21.3
Family-based
(5,46,76,165,
175)
Mild malaria
(36)
Mild malaria
(45,74)
Severe malaria
Severe malaria
Severe malaria
Severe malaria
Antibody levels
Parasitemia
(67)
(67)
(115)
(125)
(95)
(44,53,143)
Severe malaria
Severe malaria
Severe malaria
Severe malaria
(169)
(151)
(15)
(77)
Severe malaria
(29,78)
(linkage and
association)
C
6p21.3
Family-based
(genetic linkage)
HLA-B
HLA-DR
IL12B
IL13
IL4
PFBIb
C
C
C
C
C
C
6p21.3
6p21.3
5q33
5q31
5q31
5q31-q33
Case-control
Case-control
Case-control
Case-control
Case-control
Family-based
(linkage and
association)
IL1B
CD40L
IFNRA1
IFNGR1
C
C
C
C
2q14
Xq26
21q22.1
6q23-q24
Case-control
Case-control
Case-control
Case-control
Family-based
(linkage and
association)
IFN
C
12q14
Case-control
Family-based
(linkage and
39
association)
FCGR2A
C
C
1q31-q32
1q21-q23
Case-control
Case-control
TLR4
MBL2
C
C
9q32-q33
10q11-q21
Case-control
Case-control
IL10
Severe malaria
Severe malaria
Antibody levels
Severe malaria
Severe malaria
Parasitemia
(180)
(35,123,129)
(151)
(23,96,114)
1158
1159
a
1160
and C, respectively.
1161
b
1162
Infection levels and mild Malaria Susceptibility, respectively. Accession numbers are 248310 (PFBI)
1163
and 609148 (MALS).
Loci involved in red blood cell physiology, cytoadherence, and immune responses are encoded A, B,
Loci are referenced in OMIM database. PFBI and MALS mean Plasmodium falciparum Blood
1164
1165
40
1166
1167
Table 2. Susceptibility of inbred mouse strains to malaria after infection with 3 Plasmodium subspecies
1168
(83,136).
Inbred mouse strain
P. chabaudi
P. berghei
P. yoelii
A/HeJ
Susceptible
Susceptible
ND
A/J
Susceptible
Susceptible
ND
AKR/J
Susceptible
Resistant
ND
BALB/cJ
Susceptible
Susceptible
Susceptible
CBA/J
Resistant
Susceptible
ND
C3H/HeJ
Susceptible
Resistant
ND
C57BL/6J
Resistant
Susceptible
Susceptible
C57L/J
Resistant
Susceptible
ND
C58/J
ND
Resistant
ND
DBA/1J
Susceptible
Resistant
ND
DBA/2J
Resistant
Resistant
ND
SJL/J
Susceptible
ND
ND
ST/bJ
ND
Susceptible
ND
1169
1170
ND: not done
1171
41
1172
Table 3. Mouse genetic loci controlling parasitemia (P) and cerebral malaria (CM). aP.c. stands
1173
for Plasmodium chabaudi, bP.c.c. stands for Plasmodium chabaudi chabaudi and cP.b. stands for
1174
Plasmodium berghei.
Phenotype
Locus
Chromosome
P
char1
9
Murine parasite
Candidate
genesa
Trf, Rbp
Gene
identifiedb
?
P. c. adami DS
GypA,
?
P. c.c. ASb
Cspg3
P. c. adami DSa
P. yoelii 17XL
P
char2
8
P.c.c. 54X
P
char3
17
P. c. adami DS
Tnf, Lta
?
P.c.c. 54X
Pklr269A
P
char4
3
P. c.c. AS
Lef1, Cfi
P
char5
5
P.c.c. 54X
Ache, Epo
?
P
char6
5
P.c.c. 54X
Cora1,
?
Ncf1
1175
a
1176
b
P
char7
17
P.c.c. 54X
C3, Il25
?
P
char8
11
P.c.c. 54X
Il4, Csf2
?
CM
unnamed
18
P. b. ANKAc
Csf1r, Cd14
?
CM
cmsc
17
P. b. ANKA
Tnf, Lta
?
CM
berr1
1
P. b. ANKA
Tgfb2
?
CM
berr2
11
P. b. ANKA
-
?
CM
berr3
9
P. b. ANKA
Ccr5, Rbp
?
CM
berr4
4
P. b. ANKA
Tlr4, C8b
?
Genes initially proposed as candidates
Genes
the
variation
of
which
42
alters
the
phenotype
1177
Box 1. Web sites to find mouse genome resources
http://www.ncbi.nlm.nih.gov/genome/guide/mouse/
http://www.ensembl.org/Mus_musculus/
http://genome.ucsc.edu/
http://www.informatics.jax.org/
43
NKp3
+
NK
TNF
IL-18
NKp3
IFN
+
NK
Mo
IRF1
Elimination of the
parasite:
phagocytosis
and/or
Th
Eo
ILA
+
Th
IL-4
IFN
IL-10
HLA-DR
ILTh
Parasitized
erythrocyte
IL-
IL-3
GMIL-5
IL-4 IL-6
IL-5 IL-10
IL- IL-9
+
IgG1
cytophilic IgG IgG2
B FcJRIIA
IgG3
noncytophilic
1
IgG2
IgG4
1
Human Chromosome 5
1