As noted in my last post, the selective advantage of heterozygosity for the sickle allele at the beta-globin locus has been known since Allison’s report in 1954 (Lancet).  Nevertheless, a plausible and detailed mechanism to account for the protective effect of an allele that is typically highly deleterious when homozygous has not been forthcoming until now.

In order to appreciate the studies discussed below it is important to know that the most serious consequences of infection by Plasmodium falciparum, which is the most clinically consequential form of human malaria, involve the tendency of parasitized erythrocytes to adhere to microvascular endothelial cells.  This cytoadherence phenomenon is mediated by the malarial protein P. falciparum –erythrocyte membrane protein-1 (PfEMP1) which is found on the surfaces of parasitized erythrocytes in structures referred to as “knobs.”  Additional parasite-induced changes in erythrocyte shape and deformability, in conjunction with the increased tendency to adhere to endothelial cells, causes sequestration of the infected erythrocytes in capillaries and post-capillary venules of the brain and other organs.  This sequestration and subsequent release of parasite-encoded molecules elicits secretion of cytokines (molecules that deliver signals to cells) such as tumor necrosis factor-alpha and causes impairment of blood flow leading to inadequate delivery of oxygen and ischemic tissue damage.

Also of relevance in placing the new results in perspective is that homozygosity or heterozygosity for hemoglobin C (HbC) as well as heterozygosity for hemoglobin S (HbS, the sickle allele) can be protective against malaria caused by P. falciparum.  HbC results from a mutation, from glutamic acid to lysine, at the sixth position (from the amino-terminal end of the polypeptide) in the beta-globin chain whereas HbS results from mutation of the sixth amino acid from glutamic acid to valine.

Cyrklaff et al. (Science, 2011) build on previous work by Fairhurst et al. (Nature, 2005) and Cholera et al. (PNAS, 2008).  The earlier reports by these two groups of authors provided strong evidence for altered or decreased surface expression of the malarial protein PfEMP1 on infected erythrocytes from individuals heterozygous for either HbC or HbS, respectively.  Furthermore, the decrease in surface expression of PfEMP1 was associated with less erythrocyte adherence to microvascular endothelial cells (or monocytes in the case of HbS).  They tested the hypothesis that HbS and HbC interfere with the processes, established by the malarial parasite after infection of the red cell, whereby pathogen-encoded proteins, such as PfEMP1, are transported to the cell surface.

Cyrklaff and colleagues compared parasitized erythrocytes from wild-type (HbAA; i.e., homozygous  for HbA) individuals and parasitized erythrocytes from individuals heterozygous for both HbA and HbC (HbSC) or homozygous for HbC (HbCC).  They demonstrated that the presence of either HbS or HbC is associated with aberrant Maurer’s clefts, parasite-derived structures that are involved in trafficking of parasite proteins to the red cell surface, and an altered actin cytoskeleton.  Based on the increased tendencies, relative to HbA, of both HbS and HbC to become oxidized, Cyrklaff et al. then examine the hypothesis that the increased oxidation of HbS and HbC affects actin cytoskeleton formation, thereby reducing delivery of PfEMP1 to the erythrocyte surface.  They show that in in vitro assays of actin polymerization in the presence of total protein extracts from erythrocytes of different genotypes, the actin filaments are shorter if the red cell extracts are from HbSC or HbCC versus HbAA individuals.  Furthermore, a modified form of Hb, known as ferryl Hb and which is spontaneously generated in human HbS and HbC erythrocytes under conditions of oxidative stress, is known to oxidize actin and interfere with actin polymerization.  Ferryl Hb is shown to duplicate the effects of red cell extracts containing either HbSC or HbCC on actin dynamics.

Certainly it is curious, if Cyrklaff et al. are on the right track, that HbS when homozygous causes changes in erythrocyte attributes, such as shape and deformability, that lead to microvascular obstruction and tissue damage and HbS when heterozygous prevents changes in attributes, such as shape and deformability, of parasitized erythrocytes (that are caused by the infecting malarial parasite) that would lead to microvascular obstruction and tissue damage.  Thus, this arguably most paradigmatic case of the connection between evolution and clinical medicine also informs us as to the potentially intimate relationships between basic cell biology and both evolution and medicine.


Allison, AC. Protection afforded by sickle-cell trait against subtertian malarial infection. Br. Med. J. i:290-294, 1954.

Cyrklaff M, Sanchez CP, Kilian N, Bisseye C, Simpore J, Frischknecht F, Lanzer M. Hemoglobins S and C Interfere with Actin Remodeling in Plasmodium falciparum-Infected Erythrocytes. Science 2011 Nov 10. [Epub ahead of print] PubMed PMID: 22075726.

Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL, Hayton  K, Guindo A, Makobongo MO, Schwartz OM, Tounkara A, Doumbo OK, Diallo DA, Fujioka H, Ho M, Wellems TE. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature. 2005 Jun 23;435(7045):1117-21. PubMed PMID: 15973412.

Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakité SA, Arie T, Krause MA, Guindo A, Tubman A, Fujioka H, Diallo DA, Doumbo OK, Ho M, Wellems TE, Fairhurst RM. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):991-6. Epub 2008 Jan 11. PubMed PMID: 18192399; PubMed Central PMCID: PMC2242681.