Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

Abstract

Hernandez-Valladares M, Rihet P, Iraqi FA. Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes. Physiol Genomics 46: 1-16, 2014. First published October 29, 2013 doi:10.1152/physiolgenomics.00044.2013.-There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific hostpathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development. malaria; genetic resistance; human; mouse model; QT mapping PLASMODIUM FALCIPARUM MALARIA remains a major cause of morbidity and mortality in many developing countries. According to the World Health Organization (WHO), the number of cases in 2012 reached 219 million [95% confidence interval (CI) 154 -289 million], among which Ͼ660,000 (95% CI 490,000 -836,000) were fatal (62, 181a). Drug-resistant parasite strains are spreading rapidly across the world, and, despite substantial efforts and encouraging results from recent trials, a fully protective malaria vaccine remains a distant prospect (154). Vaccine development faces major difficulties partly due to the genetic control of immunity to the parasite (155,156,163,176) and/or to the parasitic antigenic variation (146).The outcome of human malaria infection is thought to depend on both parasite and host genetic factors. P. falciparum genotypes have been associated with differences in disease outcome (41) and may be subject to selective pressure (34,55). The influ...

Long-Term Prophylaxis and Pharmacokinetic Evaluation of Intramuscular Nano- and Microparticle Decoquinate in Mice Infected with P. berghei Sporozoites

“…Host contributions to parasite clearance in malaria impact the duration and severity of the initial infection and so are likely to be lowest early in acute infections in previously unexposed individuals. In rodents, it is possible for different mouse strains to have different MICs because the different inbred mouse strains have different genetic backgrounds [19, 20]. …”

Co-infecção Plasmodium falciparum e Schistosoma haematobium: papel dos genes HLA não-clássicos de classe I (HLA-G, -E e -F) na suscetibilidade à malária

“…The best examples are the Fulani, who exhibit greater resistance to malaria infection and mild and severe malaria attacks when compared to other sympatric ethnic groups living in the same villages (Modiano et al 1996(Modiano et al , 1998 (Dolo et al 2005) (Bereczky et al 2006. The genetic component of malaria-related phenotypes was also observed by comparing monozygotic twin pairs with dizygotic pairs as well as siblings (Hernandez-Valladares et al 2014). Two studies have evaluated the genetic influence on susceptibility/resistance to malaria, but only small part was attributed to the hemoglobin S (HbS) and -thalassemia genes, suggesting that other genes may be involved on the resistance to P. falciparum malaria (Mackinnon et al 2005;Phimpraphil et al 2008).…”

“…Two studies have evaluated the genetic influence on susceptibility/resistance to malaria, but only small part was attributed to the hemoglobin S (HbS) and -thalassemia genes, suggesting that other genes may be involved on the resistance to P. falciparum malaria (Mackinnon et al 2005;Phimpraphil et al 2008). Besides the heritability of malaria phenotypes, many studies have identified genes or genomic regions associated with susceptibility to P. falciparum malaria (Driss et al 2011;Hernandez-Valladares et al 2014). WHO advises the rotational use of these insecticides for indoor residual spraying (IRS).…”

“…Specific genetic epidemiology approaches can be used to identify genetic factors influencing host susceptibility/resistance to infectious diseases. Two common approaches are case-control studies and family-based association studies that have revealed many association/linkage between genes mainly coding proteins of immune system or involved in the physiology of host cells and malaria susceptibility/resistance (Garcia et al 2010;Hernandez-Valladares et al 2014;Marquet 2017). Many candidate genes have been located at 5q31-q33 and 6p21-p23 chromosomal regions and have been associated with the control of parasitemia in the context of both, mild and asymptomatic malaria.…”

“…Many candidate genes have been located at 5q31-q33 and 6p21-p23 chromosomal regions and have been associated with the control of parasitemia in the context of both, mild and asymptomatic malaria. The region 5q31-q33 encompasses genes controlling the Th1/Th2 responses and the region 6p21-p23 is the MHC region (including HLA I, II and TNF gene in HLA-III) (Garcia et al 1998(Garcia et al , 2010Milet et al 2010;Driss et al 2011;Hernandez-Valladares et al 2014). The genes closer to TNF region showed significant association with uncomplicated malaria phenotype (Flori et al 2003(Flori et al , 2005.…”