Where malaria prospers most, human societies have prospered least. The global distribution of per-capita gross domestic product shows a striking correlation between malaria and poverty, and malaria-endemic countries also have lower rates of economic growth. There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.

/pdf/the-economic-and-social-burden-of-malaria-18x30ahacx.pdf

The economic and social burden of malaria

The purpose of this article is to provide a compendium of major histocompatibility complex (MHC) peptide motifs and MHC ligands known to date, together with a discussion of the methods used to gain this information. A problem here is the exponential growth of information in this field over the recent years. The number of known MHC ligands was zero in 1989 and three in 1990. This article, written in 1994, lists a couple of hundred such ligands, plus a large number of likely ligands. By the time this work is published, we expect a lot more ligands to be known. On the other hand, the peptide motifs of many of the more important MHC class I molecules are known already, so that this article will still be useful as a source of information. For class II, the situation is a bit different. Only a few allele-specific motifs have been reported, and the data from different authors are partially conflicting. The principles of allele-specific ligand motifs, however, have emerged recently by the combination of information on MHC class II structure, ligand sequencing, and peptide binding assays. Thus, these principles can be applied to further ligands to be identified.

/pdf/mhc-ligands-and-peptide-motifs-first-listing-3wmk826w0h.pdf

MHC ligands and peptide motifs: first listing.

Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage.

Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria.

Malarious patients experience asymptomatic parasitemia; acute febrile illness (with cerebral damage, anemia, respiratory distress, hypoglycemia); chronic debilitation (anemia, malnutrition, nervous system-related sequelae); and complications of pregnancy (anemia, low birth weight, increased infant mortality). These manifestations in patients, communities, and countries reflect intrinsic (human, parasite, mosquito) and extrinsic (environmental, social, behavioral, political, and economic conditions as well as disease-control efforts) determinants. At a minimum, between 700,000 and 2.7 million persons die yearly from malaria, over 75% of them African children. Between 400 and 900 million acute febrile episodes occur yearly in African children under 5 yr of age living in endemic areas. Although about half of these children are parasitemic, all merit consideration of malaria-specific therapy, which is becoming more problematic because of parasite resistance to drugs. These numbers will more than double over the next 20 yr without effective control. Fewer than 20% of these febrile episodes and deaths come to the attention of any formal health system. The relatively few ill patients who have any contact with the health services represent the "ears of the hippopotamus." Greatly intensified research activities and control of the intolerable burden of malaria are mandatory if economic development is to accelerate in Africa. In particular, support should be targeted to understanding and preventing malaria-induced anemia, hypoglycemia, effects on pregnancy, and neurologic and developmental impairment. To decrease and stop transmission of this intolerable scourge, there is an urgent need for malaria vaccines, newer drugs, and better vector control methods as well as the ability to improve current technologies and use them more efficiently.

The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.

Malaria is a major killer of children worldwide and the strongest known force for evolutionary selection in the recent history of the human genome. The past decade has seen growing evidence of ethnic differences in susceptibility to malaria and of the diverse genetic adaptations to malaria that have arisen in different populations: epidemiological confirmation of the hypotheses that G6PD deficiency, α + thalassemia, and hemoglobin C protect against malaria mortality; the application of novel haplotype-based techniques demonstrating that malaria-protective genes have been subject to recent positive selection; the first genetic linkage maps of resistance to malaria in experimental murine models; and a growing number of reported associations with resistance and susceptibility to human malaria, particularly in genes involved in immunity, inflammation, and cell adhesion. The challenge for the next decade is to build the global epidemiological infrastructure required for statistically robust genomewide association analysis, as a way of discovering novel mechanisms of protective immunity that can be used in the development of an effective malaria vaccine.

https://sites.duke.edu/malaria/files/2012/10/Kwiatkowski-1.pdf

How malaria has affected the human genome and what human genetics can teach us about malaria.

The protective association between the human leukocyte antigen HLA-B53 and severe malaria was investigated by sequencing of peptides eluted from this molecule followed by screening of candidate epitopes from pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no HLA-B53-restricted epitopes were identified in other antigens. These findings indicate a possible molecular basis for this HLA-disease association and support the candidacy of liver-stage-specific antigen-1 as a malaria vaccine component.

M. Aidoo

Papers

Molecular analysis of the association of HLA-B53 and resistance to severe malaria.

An HLA-based approach to the design of a CTL-inducing vaccine against Plasmodium falciparum.