Genes expressed in red cells could shape a malaria attack
Authors: Lucio Luzzatto
Journal: The Lancet Haematology (2018)

Within the classic dichotomy of acquired and inherited disorders, malaria is unquestionably acquired. Yet, since Haldane's seminal malaria hypothesis,1Haldane JBS Disease and evolution.Ric Sci. 1949; 19: 68-76Google Scholar we have come to realise that genetic factors are very important in influencing the outcome of malarial infection. Indeed, from the standpoint of Darwinian selection, what matters is not whether an individual acquires malaria (from which they might recover) but whether that person dies from the infection. Thus, the tiny protozoon Plasmodium falciparum is implicated in two major public health problems: first, the morbidity and mortality from malaria itself; and second, the burden from serious inherited blood diseases—ie, thalassaemia and sickle-cell disease. The gene mutations that cause these blood disorders offer significant protection against malaria in heterozygotes, and so through Darwinian selection they have become highly prevalent in populations that live or have lived in malaria-endemic regions. The search is continuing for more genes that can make a difference: that is to say, for any gene that—once a person is infected—will delay or hinder death from malaria. Two main approaches have been used. First is a geographical approach—ie, seeking a positive correlation between the frequency of an allele and malaria endemicity.1Haldane JBS Disease and evolution.Ric Sci. 1949; 19: 68-76Google Scholar, 2Montalenti G Discussion of J B S Haldane.Ric Sci. 1949; 19: 333-334Google Scholar, 3Allison AC Protection afforded by the sickle-cell trait against subtertian malarial infection.BMJ. 1954; 1: 290-294Crossref PubMed Scopus (711) Google Scholar Second is the clinical approach—seeking a negative correlation between the frequency of an allele and forms of severe malaria that are immediately life-threatening. In The Lancet Haematology, Carolyne Ndila and colleagues4Ndila CM Uyoga S Macharia AW et al.Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.Lancet Haematol. 2018; (published online July 19.)http://dx.doi.org/10.1016/S2352-3026(18)30107-8Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar used the second approach: they report findings of an association study in which they analysed data from 2244 children with severe malaria and controls from the community in Kilifi, Kenya. Among 70 genes previously identified as candidates, the authors pinpointed 15 alleles that were significantly lower in frequency among children with severe malaria than among controls, suggesting that they hinder the transition from uncomplicated malaria to severe malaria.5WHOGuidelines for the treatment of malaria.2nd edn. World Health Organisation, Geneva2010Google Scholar The most common clinical syndromes that define severe malaria fall into three main categories: severe anaemia, cerebral malaria, and acidosis with respiratory distress. These can occur separately or in combination. For haematologists, the severe anaemia form of severe malaria might seem straightforward, since large numbers of red cells are physically destroyed through the schizogenic cycle of P falciparum. However, non-parasitised red cells make up a large proportion of those that are haemolysed; evidence also indicates impaired erythropoiesis.6Menendez C Fleming AF Alonso PL Malaria-related anaemia.Parasitol Today. 2000; 16: 469-476Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar In a review,7White NJ Turner GD Day NP Dondorp AM Lethal malaria: Marchiafava and Bignami were right.J Infect Dis. 2013; 208: 192-198Crossref PubMed Scopus (95) Google Scholar the century-old idea of parasite sequestration causing microvascular obstruction emerged as fundamental to the pathogenesis of cerebral malaria if it happens in the brain, and of acidosis with respiratory distress if it happens in other organs. The mechanisms by which uncomplicated malaria evolves to severe malaria are understood only in part.8Cunnington AJ Walther M Riley EM Piecing together the puzzle of severe malaria.Sci Transl Med. 2013; 5: 211ps18Crossref PubMed Scopus (34) Google Scholar It is unknown why, in one individual, uncomplicated malaria progresses to severe anaemia, in another to cerebral malaria, and in another to acidosis with respiratory distress. Although this progression might occur as a stochastic process, it is tempting to surmise that host factors can affect the direction taken by the disease (figure). Ndila and colleagues may have had this notion in mind when they investigated whether an individual gene can protect specifically against one or the other syndrome of severe malaria, but no discrete pattern has emerged. Answering this question might require even more individuals, but another explanation is that most of the protective effect is upstream of the differentiation of severe malaria types. Patients with acidosis with respiratory distress had the highest levels of parasitaemia,4Ndila CM Uyoga S Macharia AW et al.Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.Lancet Haematol. 2018; (published online July 19.)http://dx.doi.org/10.1016/S2352-3026(18)30107-8Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar but parasitaemia is not proportional to parasite biomass,9Dondorp AM Desakorn V Pongtavornpinyo W et al.Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.PLoS Med. 2005; 2: e204Crossref PubMed Scopus (328) Google Scholar which probably best reflects how far a protective gene is able to affect the sum total of parasite proliferation, parasite survival, and efficiency of reinfection of new red blood cells by the parasite. In keeping with this notion, most of the 15 genes discussed by Ndila and colleagues are expressed in red cells, and others might be related to parasite removal. For example, among polymorphisms they highlight, an ATP2B4 allele—through calcium extrusion—could affect parasite metabolism; and a FREM3 allele is almost certainly a marker for a closely linked glycophorin variant that might affect red-cell invasion by the parasite. Three aspects of Ndila and colleagues' study deserve further consideration. First, when only heterozygotes are protected, selection produces a balanced polymorphism and the frequency of the protective allele reaches a plateau; by contrast, if homozygotes are also protected,4Ndila CM Uyoga S Macharia AW et al.Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.Lancet Haematol. 2018; (published online July 19.)http://dx.doi.org/10.1016/S2352-3026(18)30107-8Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar the frequency of the selected allele might reach fixation. Second, the sickle-cell gene (at the HBB locus) offers far more protection than any other gene4Ndila CM Uyoga S Macharia AW et al.Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.Lancet Haematol. 2018; (published online July 19.)http://dx.doi.org/10.1016/S2352-3026(18)30107-8Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar (and possibly than all the others taken together). However, any gene that offers even a little protection provides insight into the biology of malarial infection. It has been hoped for a long time10Luzzatto L Genetics of red cells and susceptibility to malaria.Blood. 1979; 54: 961-976PubMed Google Scholar that insights learnt from individuals who have some genetic resistance to P falciparum can be applied to protect others from malaria. In this respect, the sickle-cell gene is probably not a good candidate, because it would not seem a good idea to develop a drug that will make red cells sickle. A gene that is less protective but that does not cause a disease could offer more possibilities. For example, an appropriately targeted drug capable of reducing calcium availability to the parasite—similar to some ATP2B4 alleles—might not be toxic and could be worth investigating. Third, the extensive genomic analysis in Ndila and colleagues' work,4Ndila CM Uyoga S Macharia AW et al.Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.Lancet Haematol. 2018; (published online July 19.)http://dx.doi.org/10.1016/S2352-3026(18)30107-8Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar and in other reports, accounts for only 5–7% of the variance between having severe malaria and being a control. For an acquired disease like malaria, it is unsurprising that environmental factors—primarily exposure and the resultant immune response—still retain the lion's share in terms of acquiring the disease and, therefore, in terms of the patient's ultimate outcome. Thus, prevention remains of primary public health importance. I declare no competing interests. I thank Nick White for thoughtful comments and Paola Caboara and Luciana Gargiulo for assistance with the figure. Laboratory work on malaria in our institution receives financial support from Medicines for Malaria Venture and from the MAGI Foundation. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association studyBoth ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Full-Text PDF Open Access