Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant conflicts of interest.
Ferreira A, Marguti I, Bechmann I, et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell. 2011;145:398-409.
Allison in 19541 was among the first to propose that the sickle cell trait protected against Plasmodium Falciparum. This conclusion was in part based on the observations that the prevalence of the HbS gene was greatest in malaria endemic areas and, furthermore, that infected children with the trait had lower parasitemia. The cellular and molecular bases of the antimalarial actions of HbS trait include faster sickling of parasitized RBCs, enhanced splenic recognition and clearance of infected RBCs, retarded growth of the malaria parasite in RBCs possibly due to toxic heme/iron-catalyzed oxidants, and altered adhesion of infected RBCs to vascular endothelium.2 Ferreira et al. in the laboratory of Miguel Soares at the Instituto Gulbenkian de Ciência in Portugal provide new insights into the mechanism by which HbS trait protects against malaria and thus possibly define new therapeutic tools.
Using C57BL/6 normal and transgenic mice that express human HbS, the investigators found that infection with a rodent parasite, P. berghei, killed all of the normal mice in six to 12 days, but only 20 percent of the sickle mice. Experimental cerebral malaria (ECM) was evident in normal mice but not sickle mice. Cerebral edema was marked with an inflammatory infiltrate of CD8 T cells in the normal mice but not in the sickle mice. However, parasitemia and the mean number of infected RBCs were similar in both, suggesting that HbS confers tolerance to P. berghei infection. Heme oxygenase-1 (HO-1), the primary heme-degrading enzyme, has been shown to be protective against severe forms of malaria in mice.3 Partial deletion of Hmox1 in transgenic sickle mice or treatment with an HO-1 inhibitor caused lethality in response to P. berghei in sickle mice. Induction of HO-1 by sickle Hb inhibited chemokine production involved in the pathogenesis of ECM. Sickle Hb inhibited the activation of CD8+ T cells recognizing antigens expressed by P. berghei. Likewise, HbS conferred tolerance to malaria via a mechanism involving carbon monoxide (CO) production through heme catabolism by HO-1. It is hypothesized that HbS inhibits free heme accumulation in the infected mice via the production of CO by modulating Hb oxidation and free heme release.
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The authors speculate that the protective effect of sickle Hb against ECM may be due to released heme from Hb, which can induce HO-1 via Nrf-2. Heme catabolism by HO-1 can produce CO, which may prevent heme release during infection, suppressing ECM. HbS may have an immunoregulatory effect on T cells as well as antigen presenting cells (APCs) (Figure).
The studies are provocative, but several limitations must be noted. First, mouse malaria is not the same as human malaria. In symptomatic human malaria, individuals with sickle trait have less parasitemia, while in these studies HbS protected against ECM in infected mice, but parasitemia was not affected. Mouse models of sickle cell disease do not fully represent the process in humans, especially the sickle trait. Regardless, these investigations may provide new therapeutic targets for the control and therapy of malaria.
- Allison AC. Protection afforded by sickle cell trait against subtertian malarial infection. Br Med J. 1954;1:290-294.
- Eaton JW. “Malaria and the selection of the sickle gene.” In Sickle Cell Disease: Basic Principles and Clinical Practice; Embury SH, Hebbel RP, Mohandas N, and Steinberg MH. Eds.; Raven Press, Ltd.: New York, 1994;13-18.
- Pamplona A, Ferreira A, Balla J et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 2007;13:703-710.
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