Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2013

Open Access 01-12-2013 | Research

Identification of the Plasmodium berghei resistance locus 9 linked to survival on chromosome 9

Authors: Selina ER Bopp, Evelyn Rodrigo, Gonzalo E González-Páez, Mary Frazer, S Whitney Barnes, Clarissa Valim, James Watson, John R Walker, Christian Schmedt, Elizabeth A Winzeler

Published in: Malaria Journal | Issue 1/2013

Login to get access

Abstract

Background

One of the main causes of mortality from severe malaria in Plasmodium falciparum infections is cerebral malaria (CM). An important host genetic component determines the susceptibility of an individual to develop CM or to clear the infection and become semi-immune. As such, the identification of genetic loci associated with susceptibility or resistance may serve to modulate disease severity.

Methodology

The Plasmodium berghei mouse model for experimental cerebral malaria (ECM) reproduces several disease symptoms seen in human CM, and two different phenotypes, a susceptible (FVB/NJ) and a resistant mouse strain (DBA/2J), were examined.

Results

FVB/NJ mice died from infection within ten days, whereas DBA/2J mice showed a gender bias: males survived on average nineteen days and females either died early with signs of ECM or survived for up to three weeks. A comparison of brain pathology between FVB/NJ and DBA/2J showed no major differences with regard to brain haemorrhages or the number of parasites and CD3+ cells in the microvasculature. However, significant differences were found in the peripheral blood of infected mice: For example resistant DBA/2J mice had significantly higher numbers of circulating basophils than did FVB/NJ mice on day seven. Analysis of the F2 offspring from a cross of DBA/2J and FVB/NJ mice mapped the genetic locus of the underlying survival trait to chromosome 9 with a Lod score of 4.9. This locus overlaps with two previously identified resistance loci (char1 and pymr) from a blood stage malaria model.

Conclusions

Survival best distinguishes malaria infections between FVB/NJ and DBA/2J mice. The importance of char1 and pymr on chromosome 9 in malaria resistance to P. berghei was confirmed. In addition there was an association of basophil numbers with survival.
Appendix
Available only for authorised users
Literature
1.
Schofield L, Grau GE: Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005, 5: 722-10.1038/nri1686.CrossRefPubMed
2.
Aikawa M, Brown A, Smith CD, Tegoshi T, Howard RJ, Hasler TH, Ito Y, Perry G, Collins WE, Webster K: A primate model for human cerebral malaria: Plasmodium coatneyi-infected rhesus monkeys. Am J Trop Med Hyg. 1992, 46: 391-397.PubMed
3.
Ibiwoye MO, Howard CV, Sibbons P, Hasan M, van Velzen D: Cerebral malaria in the rhesus monkey (Macaca mulatta): observations on host pathology. J Comp Pathol. 1993, 108: 303-310. 10.1016/S0021-9975(08)80293-9.CrossRefPubMed
4.
Gysin J, Aikawa M, Tourneur N, Tegoshi T: Experimental Plasmodium falciparum cerebral malaria in the squirrel monkey Saimiri sciureus. Exp Parasitol. 1992, 75: 390-398. 10.1016/0014-4894(92)90252-6.CrossRefPubMed
5.
Curfs JH, van der Meide PH, Billiau A, Meuwissen JH, Eling WM: Plasmodium berghei: recombinant interferon-gamma and the development of parasitemia and cerebral lesions in malaria-infected mice. Exp Parasitol. 1993, 77: 212-223. 10.1006/expr.1993.1078.CrossRefPubMed
6.
Rest JR: Cerebral malaria in inbred mice. I. A new model and its pathology. Trans R Soc Trop Med Hyg. 1982, 76: 410-415. 10.1016/0035-9203(82)90203-6.CrossRefPubMed
7.
de Souza JB, Riley EM: Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect. 2002, 4: 291-300. 10.1016/S1286-4579(02)01541-1.CrossRefPubMed
8.
Penet MF, Viola A, Confort-Gouny S, Le Fur Y, Duhamel G, Kober F, Ibarrola D, Izquierdo M, Coltel N, Gharib B, Grau GE, Cozzone PJ: Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J Neurosci. 2005, 25: 7352-7358. 10.1523/JNEUROSCI.1002-05.2005.CrossRefPubMed
9.
Lackner P, Beer R, Helbok R, Broessner G, Engelhardt K, Brenneis C, Schmutzhard E, Pfaller K: Scanning electron microscopy of the neuropathology of murine cerebral malaria. Malar J. 2006, 5: 116-10.1186/1475-2875-5-116.PubMedCentralCrossRefPubMed
10.
Wassmer SC, Combes V, Grau GE: Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion. Ann N Y Acad Sci. 2003, 992: 30-38. 10.1111/j.1749-6632.2003.tb03135.x.CrossRefPubMed
11.
von Zur MC, Sibson NR, Peter K, Campbell SJ, Wilainam P, Grau GE, Bode C, Choudhury RP, Anthony DC: A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI. J Clin Invest. 2008, 118: 1198-1207.
12.
Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P: Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987, 237: 1210-1212. 10.1126/science.3306918.CrossRefPubMed
13.
Pais TF, Chatterjee S: Brain macrophage activation in murine cerebral malaria precedes accumulation of leukocytes and CD8+ T cell proliferation. J Neuroimmunol. 2005, 163: 73-83. 10.1016/j.jneuroim.2005.02.009.CrossRefPubMed
14.
Grau GE, Piguet PF, Engers HD, Louis JA, Vassalli P, Lambert PH: L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol. 1986, 137: 2348-2354.PubMed
15.
Bopp SE, Ramachandran V, Henson K, Luzader A, Lindstrom M, Spooner M, Steffy BM, Suzuki O, Janse C, Waters AP, Zhou Y, Wiltshire T, Winzeler EA: Genome wide analysis of inbred mouse lines identifies a locus containing Ppar-gamma as contributing to enhanced malaria survival. PLoS ONE. 2010, 5: e10903-10.1371/journal.pone.0010903.PubMedCentralCrossRefPubMed
16.
Driss A, Hibbert JM, Wilson NO, Iqbal SA, Adamkiewicz TV, Stiles JK: Genetic polymorphisms linked to susceptibility to malaria. Malar J. 2011, 10: 271-10.1186/1475-2875-10-271.PubMedCentralCrossRefPubMed
17.
Foote SJ, Burt RA, Baldwin TM, Presente A, Roberts AW, Laural YL, Lew AM, Marshall VM: Mouse loci for malaria-induced mortality and the control of parasitaemia. Nat Genet. 1997, 17: 380-381. 10.1038/ng1297-380.CrossRefPubMed
18.
Fortin A, Belouchi A, Tam MF, Cardon L, Skamene E, Stevenson MM, Gros P: Genetic control of blood parasitaemia in mouse malaria maps to chromosome 8. Nat Genet. 1997, 17: 382-383. 10.1038/ng1297-382.CrossRefPubMed
19.
Lin E, Pappenfuss T, Tan RB, Senyschyn D, Bahlo M, Speed TP, Foote SJ: Mapping of the Plasmodium chabaudi resistance locus char2. Infect Immun. 2006, 74: 5814-5819. 10.1128/IAI.01690-05.PubMedCentralCrossRefPubMed
20.
Fortin A, Cardon LR, Tam M, Skamene E, Stevenson MM, Gros P: Identification of a new malaria susceptibility locus (Char4) in recombinant congenic strains of mice. Proc Natl Acad Sci U S A. 2001, 98: 10793-10798. 10.1073/pnas.191288998.PubMedCentralCrossRefPubMed
21.
Hernandez-Valladares M, Naessens J, Gibson JP, Musoke AJ, Nagda S, Rihet P, Ole-MoiYoi OK, Iraqi FA: Confirmation and dissection of QTL controlling resistance to malaria in mice. Mamm Genome. 2004, 15: 390-398. 10.1007/s00335-004-3042-4.CrossRefPubMed
22.
Hernandez-Valladares M, Rihet P, Iraqi FA, ole-MoiYoi OK: Mapping of a new quantitative trait locus for resistance to malaria in mice by a comparative mapping approach with human Chromosome 5q31-q33. Immunogenetics. 2004, 56: 115-117. 10.1007/s00251-004-0667-0.CrossRefPubMed
23.
Min-Oo G, Fortin A, Pitari G, Tam M, Stevenson MM, Gros P: Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus. J Exp Med. 2007, 204: 511-524. 10.1084/jem.20061252.PubMedCentralCrossRefPubMed
24.
Min-Oo G, Willemetz A, Tam M, Canonne-Hergaux F, Stevenson MM, Gros P: Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9. Genes Immun. 2010, 11: 113-123. 10.1038/gene.2009.78.CrossRefPubMed
25.
Laroque A, Min-Oo G, Tam M, Radovanovic I, Stevenson MM, Gros P: Genetic control of susceptibility to infection with Plasmodium chabaudi chabaudi AS in inbred mouse strains. Genes Immun. 2012, 13: 155-163. 10.1038/gene.2011.67.CrossRefPubMed
26.
Bagot S, Campino S, Penha-Goncalves C, Pied S, Cazenave PA, Holmberg D: Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain. Proc Natl Acad Sci U S A. 2002, 99: 9919-9923. 10.1073/pnas.152215199.PubMedCentralCrossRefPubMed
27.
Nagayasu E, Nagakura K, Akaki M, Tamiya G, Makino S, Nakano Y, Kimura M, Aikawa M: Association of a determinant on mouse chromosome 18 with experimental severe Plasmodium berghei malaria. Infect Immun. 2002, 70: 512-516. 10.1128/IAI.70.2.512-516.2002.PubMedCentralCrossRefPubMed
28.
Ohno T, Nishimura M: Detection of a new cerebral malaria susceptibility locus, using CBA mice. Immunogenetics. 2004, 56: 675-678. 10.1007/s00251-004-0739-1.CrossRefPubMed
29.
Campino S, Bagot S, Bergman ML, Almeida P, Sepulveda N, Pied S, Penha-Goncalves C, Holmberg D, Cazenave PA: Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity. Genes Immun. 2005, 6: 416-421. 10.1038/sj.gene.6364219.CrossRefPubMed
30.
Berghout J, Min-Oo G, Tam M, Gauthier S, Stevenson MM, Gros P: Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19. Genes Immun. 2010, 11: 310-318. 10.1038/gene.2009.79.CrossRefPubMed
31.
Torre S, van Bruggen R, Kennedy JM, Berghout J, Bongfen SE, Langat P, Lathrop M, Vidal SM, Gros P: Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice. Genes Immun. 2013, 14: 249-257. 10.1038/gene.2013.16.CrossRefPubMed
32.
Gonçalves LA, Almeida P, Mota MM, Penha-Gonçalves C: Malaria liver stage susceptibility locus identified on mouse chromosome 17 by congenic mapping. PLoS ONE. 2008, 3: e1874-10.1371/journal.pone.0001874.PubMedCentralCrossRefPubMed
33.
Sepulveda N, Paulino CD, Carneiro J, Penha-Goncalves C: Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits. Heredity (Edinb). 2007, 99: 173-184. 10.1038/sj.hdy.6800979.CrossRef
34.
Fortin A, Diez E, Rochefort D, Laroche L, Malo D, Rouleau GA, Gros P, Skamene E: Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics. 2001, 74: 21-35. 10.1006/geno.2001.6528.CrossRefPubMed
35.
Wiltshire T, Pletcher MT, Batalov S, Barnes SW, Tarantino LM, Cooke MP, Wu H, Smylie K, Santrosyan A, Copeland NG, Jenkins NA, Kalush F, Maual RJ, Flynne RJ, Kay SA, Adams MD, Fletcher CF: Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse. Proc Natl Acad Sci U S A. 2003, 100: 3380-3385. 10.1073/pnas.0130101100.PubMedCentralCrossRefPubMed
36.
Franke-Fayard B, Trueman H, Ramesar J, Mendoza J, van der Keur M, van der Linden R, Sinden RE, Waters AP, Janse CJ: A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle. Mol Biochem Parasitol. 2004, 137: 23-10.1016/j.molbiopara.2004.04.007.CrossRefPubMed
37.
Broman KW, Wu H, Sen S, Churchill GA: R/qtl: QTL mapping in experimental crosses. Bioinformatics. 2003, 19: 889-890. 10.1093/bioinformatics/btg112.CrossRefPubMed
38.
Neill A, Hunt N: Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice. Parasitology. 1992, 105: 165-175. 10.1017/S0031182000074072.CrossRefPubMed
39.
Perlmann P, Troye-Blomberg M: Malaria immunology. Edited by: rev. and enl. 2002; 2007, Switzerland: Karger, 2CrossRef
40.
de Souza JB, Hafalla JC, Riley EM, Couper KN: Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology. 2010, 137: 755-772. 10.1017/S0031182009991715.CrossRefPubMed
41.
Franke-Fayard B, Janse CJ, Cunha-Rodrigues M, Ramesar J, Buscher P, Que I, Lowik C, Voshol PJ, den Boer MA, van Duinen SG, Febbraio M, Mota MM, Waters AP: Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci U S A. 2005, 102: 11468-11473. 10.1073/pnas.0503386102.PubMedCentralCrossRefPubMed
42.
Renia L, Potter SM, Mauduit M, Rosa DS, Kayibanda M, Deschemin JC, Snounou G, Gruner AC: Pathogenic T cells in cerebral malaria. Int J Parasitol. 2006, 36: 547-554. 10.1016/j.ijpara.2006.02.007.CrossRefPubMed
43.
Ohno T, Ishih A, Kohara Y, Yonekawa H, Terada M, Nishimura M: Chromosomal mapping of the host resistance locus to rodent malaria (Plasmodium yoelii) infection in mice. Immunogenetics. 2001, 53: 736-740. 10.1007/s00251-001-0390-z.CrossRefPubMed
44.
45.
Neill AL, Chan-Ling T, Hunt NH: Comparisons between microvascular changes in cerebral and non-cerebral malaria in mice, using the retinal whole-mount technique. Parasitology. 1993, 107 (Pt 5): 477-487.CrossRefPubMed
46.
Thumwood CM, Hunt NH, Clark IA, Cowden WB: Breakdown of the blood–brain barrier in murine cerebral malaria. Parasitology. 1988, 96 (Pt 3): 579-589.CrossRefPubMed
47.
Hunt NH, Grau GE: Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol. 2003, 24: 491-499. 10.1016/S1471-4906(03)00229-1.CrossRefPubMed
48.
Kossodo S, Monso C, Juillard P, Velu T, Goldman M, Grau GE: Interleukin-10 modulates susceptibility in experimental cerebral malaria. Immunology. 1997, 91: 536-540. 10.1046/j.1365-2567.1997.00290.x.PubMedCentralCrossRefPubMed
49.
Sokol CL, Barton GM, Farr AG, Medzhitov R: A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008, 9: 310-318. 10.1038/ni1558.PubMedCentralCrossRefPubMed
50.
Kim S, Shen T, Min B: Basophils can directly present or cross-present antigen to CD8 lymphocytes and alter CD8 T cell differentiation into IL-10-producing phenotypes. J Immunol. 2009, 183: 3033-3039. 10.4049/jimmunol.0900332.CrossRefPubMed
Metadata
Title
Identification of the Plasmodium berghei resistance locus 9 linked to survival on chromosome 9
Authors
Selina ER Bopp
Evelyn Rodrigo
Gonzalo E González-Páez
Mary Frazer
S Whitney Barnes
Clarissa Valim
James Watson
John R Walker
Christian Schmedt
Elizabeth A Winzeler
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2013
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-12-316

Other articles of this Issue 1/2013

Malaria Journal 1/2013 Go to the issue

Research

Mutational analysis of Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in the interior division of Sabah, Malaysia

Research

Clustering of host-seeking activity of Anopheles gambiae mosquitoes at the top surface of a human-baited bed net

Research

Prevalence of gestational, placental and congenital malaria in north-west Colombia

Research

Microsatellite genotyping of Plasmodium vivax infections and their relapses in pregnant and non-pregnant patients on the Thai-Myanmar border

Research

Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02D malaria vaccine in infants living in a malaria-endemic region

Case study

Integrated vector management: a critical strategy for combating vector-borne diseases in South Sudan
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits