Association of HLA alleles with Plasmodium falciparum severity in Malian children

Pre-erythrocytic immunity to Plasmodium falciparum malaria is likely to be mediated by T-cell recognition of malaria epitopes presented on infected host cells via class I and II major histocompatibility complex (MHC) antigens. To test for associations of human leukocyte antigen (HLA) alleles with disease severity, we performed high-resolution typing of HLA class I and II loci and compared the distributions of alleles of HLA-A, -B, -C and -DRB1 loci in 359 Malian children of Dogon ethnicity with uncomplicated or severe malaria. We observed that alleles A*30:01 and A*33:01 had higher frequency in the group of patients with cerebral disease compared to patients with uncomplicated disease [A*30:01: gf = 0.2031 vs gf = 0.1064, odds ratio (OR) = 3.17, P = 0.004, confidence interval (CI) (1.94–5.19)] and [A*33:01: gf = 0.0781 vs gf = 0.0266, 4.21, P = 0.005, CI (1.89–9.84)], respectively. The A*30:01 and A*33:01 alleles share some sequence motifs and A*30:01 appears to have a unique peptide binding repertoire compared to other A*30 group alleles. Computer algorithms predicted malaria peptides with strong binding affinity for HLA-A*30:01 and HLA-A*33:01 but not to closely related alleles. In conclusion, we identified A*30:01 and A*33:01 as potential susceptibility factors for cerebral malaria, providing further evidence that polymorphism of MHC genes results in altered malaria susceptibility.

[1]  M F del Guercio,et al.  Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules. , 1996, Human immunology.

[2]  Alex Lancaster,et al.  PyPop: A Software Framework for Population Genomics: Analyzing Large-Scale Multi-Locus Genotype Data , 2002, Pacific Symposium on Biocomputing.

[3]  A. Velayati,et al.  HLA-A *3303* and *3301 predispose patients to persistent hepatitis B infection. , 2009, Journal of gastrointestinal and liver diseases : JGLD.

[4]  Alessandro Sette,et al.  Generating quantitative models describing the sequence specificity of biological processes with the stabilized matrix method , 2005, BMC Bioinformatics.

[5]  L. Rénia,et al.  On the Pathogenic Role of Brain-Sequestered αβ CD8+ T Cells in Experimental Cerebral Malaria1 , 2002, The Journal of Immunology.

[6]  K. Cao,et al.  Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. , 2001, Human immunology.

[7]  O. Doumbo,et al.  Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. , 2000, Blood.

[8]  A. Oduro,et al.  HLA-DRB1*04 allele is associated with severe malaria in northern Ghana. , 2008, The American journal of tropical medicine and hygiene.

[9]  R. Vierkant,et al.  Relationship between HLA Polymorphisms and Gamma Interferon and Interleukin-10 Cytokine Production in Healthy Individuals after Rubella Vaccination , 2007, Clinical and Vaccine Immunology.

[10]  H. Rammensee,et al.  Definition of peptide binding motifs amongst the HLA-A*30 allelic group. , 2000, Tissue antigens.

[11]  S. Hoffman,et al.  Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes , 1990, The Journal of experimental medicine.

[12]  L. Luzzatto,et al.  Glucose-6-phosphate dehydrogenase and malaria. Greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant. , 1972, Lancet.

[13]  P. Hedrick,et al.  Estimation of relative fitnesses from relative risk data and the predicted future of haemoglobin alleles S and C , 2003, Journal of evolutionary biology.

[14]  Bjoern Peters,et al.  Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications , 2005, Immunogenetics.

[15]  G. Thomson,et al.  HLA-A, -B, -C, -DRB1 allele and haplotype frequencies in an African American population. , 2007, Tissue antigens.

[16]  K. Cao,et al.  High and intermediate resolution DNA typing systems for class I HLA-A, B, C genes by hybridization with sequence-specific oligonucleotide probes (SSOP). , 1999, Reviews in immunogenetics.

[17]  A. Dicko,et al.  Association of intraleukocytic Plasmodium falciparum malaria pigment with disease severity, clinical manifestations, and prognosis in severe malaria. , 2003, The American journal of tropical medicine and hygiene.

[18]  A. Di Rienzo,et al.  Protection against malaria morbidity: near-fixation of the alpha-thalassemia gene in a Nepalese population. , 1991, American journal of human genetics.

[19]  Ogobara K. Doumbo,et al.  The pathogenic basis of malaria , 2002, Nature.

[20]  A. Valdés,et al.  Conditional genotype analysis: detecting secondary disease loci in linkage disequilibrium with a primary disease locus. , 2007 .

[21]  L. Rénia,et al.  On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. , 2002, Journal of immunology.

[22]  H. Webster,et al.  Interleukin-10 inhibits tumor necrosis factor production but not antigen-specific lymphoproliferation in acute Plasmodium falciparum malaria. , 1995, The Journal of infectious diseases.

[23]  L. Miller,et al.  The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. , 1976, The New England journal of medicine.

[24]  H. Payami,et al.  Relative predispositional effects (RPEs) of marker alleles with disease: HLA-DR alleles and Graves disease. , 1989, American journal of human genetics.

[25]  G Thomson,et al.  Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci. , 2004, Tissue antigens.

[26]  D. Kwiatkowski.  How malaria has affected the human genome and what human genetics can teach us about malaria. , 2005, American journal of human genetics.

[27]  O. Lund,et al.  novel sequence representations Reliable prediction of T-cell epitopes using neural networks with , 2003 .

[28]  Morten Nielsen,et al.  The peptide-binding specificity of HLA-A*3001 demonstrates membership of the HLA-A3 supertype , 2008, Immunogenetics.

[29]  Richard J. Challis,et al.  Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia , 2006, Molecular and biochemical parasitology.

[30]  M. Molyneux,et al.  Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis , 2003, Malaria Journal.

[31]  S. Hoffman,et al.  Human lymphocyte proliferative response to a sporozoite T cell epitope correlates with resistance to falciparum malaria. , 1989, Journal of immunology.

[32]  O. Doumbo,et al.  Serum Levels of the Proinflammatory Cytokines Interleukin-1 Beta (IL-1β), IL-6, IL-8, IL-10, Tumor Necrosis Factor Alpha, and IL-12(p70) in Malian Children with Severe Plasmodium falciparum Malaria and Matched Uncomplicated Malaria or Healthy Controls , 2004, Infection and Immunity.

[33]  M. Aidoo,et al.  Cytotoxic T-Lymphocyte Epitopes for HLA-B53 and Other HLA Types in the Malaria Vaccine Candidate Liver-Stage Antigen 3 , 2000, Infection and Immunity.

[34]  A. Dicko,et al.  Impact of preseason treatment on incidence of falciparum malaria and parasite density at a site for testing malaria vaccines in Bandiagara, Mali. , 2002, The American journal of tropical medicine and hygiene.

[35]  P. Druilhe,et al.  Plasmodium falciparum malaria: evidence for an isotype imbalance which may be responsible for delayed acquisition of protective immunity , 1992, Infection and immunity.

[36]  R. Sauerwein,et al.  Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease , 1997, Parasitology.

[37]  A. Dicko,et al.  Incidence of severe Plasmodium falciparum malaria as a primary endpoint for vaccine efficacy trials in Bandiagara, Mali. , 2004, Vaccine.

[38]  M. Aidoo,et al.  Molecular analysis of the association of HLA-B53 and resistance to severe malaria , 1992, Nature.

[39]  M. Busson,et al.  HLA-DRB1 and DQB1 allele distribution in the Muong population exposed to malaria in Vietnam. , 2002, Tissue antigens.

[40]  D. Rubin,et al.  Maximum likelihood from incomplete data via the EM - algorithm plus discussions on the paper , 1977 .

[41]  K. Tokunaga,et al.  Polymorphisms of the HLA-B and HLA-DRB1 genes in Thai malaria patients. , 2005, Japanese journal of infectious diseases.

[42]  Tzong-Shyuan Lee,et al.  Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice , 2002, Nature Medicine.

[43]  O. Doumbo,et al.  HLA-A2 Supertype-Restricted Cell-Mediated Immunity by Peripheral Blood Mononuclear Cells Derived from Malian Children with Severe or Uncomplicated Plasmodium falciparum Malaria and Healthy Controls , 2005, Infection and Immunity.

[44]  Andrew J. McMichael,et al.  Common West African HLA antigens are associated with protection from severe malaria , 1991, Nature.

[45]  Y. Imai,et al.  T lymphocyte-dependent development of cerebral symptoms in WM/Ms rats infected with Plasmodium berghei. , 1994, Annals of tropical medicine and parasitology.

[46]  O. Doumbo,et al.  Community permission for medical research in developing countries. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  B. Lell,et al.  HLA-DQB1*0501-restricted Th1 type immune responses to Plasmodium falciparum liver stage antigen 1 protect against malaria anemia and reinfections. , 2001, The Journal of infectious diseases.