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• W1979285251 abstract "Sickle cell hemoglobin conveys resistance to malaria. In this issue of Cell Host & Microbe, LaMonte et al., 2012LaMonte G. Philip N. Reardon J. Lacsina J.R. Majoros W. Chapman L. Telen M.J. Ohler U. Nicchitta C.V. Haystead T. Chi J.-T. Cell Host Microbe. 2012; 12 (this issue): 187-199Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar demonstrate a surprising mechanism for this innate immunity. A microRNA enriched in sickle red blood cells is translocated into the parasite, incorporated covalently into P. falciparum mRNAs and inhibits parasite growth. Sickle cell hemoglobin conveys resistance to malaria. In this issue of Cell Host & Microbe, LaMonte et al., 2012LaMonte G. Philip N. Reardon J. Lacsina J.R. Majoros W. Chapman L. Telen M.J. Ohler U. Nicchitta C.V. Haystead T. Chi J.-T. Cell Host Microbe. 2012; 12 (this issue): 187-199Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar demonstrate a surprising mechanism for this innate immunity. A microRNA enriched in sickle red blood cells is translocated into the parasite, incorporated covalently into P. falciparum mRNAs and inhibits parasite growth. Haldane was the first to suggest that individuals with the red blood cell disorder β-thalassemia are more frequent in malaria endemic regions because the mutation confers resistance to the parasite (Haldane, 1949Haldane J.B.S. Proc. VIII Int. Cong. Genet. Hereditas. 1949; 35: 267-273Google Scholar). Several other red blood cell disorders are associated with malaria resistance, including G6PD deficiency, pyruvate kinase deficiency, and α-thalassemia. Most strikingly the variant of the β-globin gene that causes sickle cell disease, HbS, protects against clinical malaria caused by infection with the most virulent species, Plasmodium falciparum (Hill et al., 1991Hill A.V.S. Allsopp C.E.M. Kwiatkowski D. Anstey N.M. Twumasi P. Rowe P.A. Bennett S. Brewster D. McMichael A.J. Greenwood B.M. Nature. 1991; 352: 595-600Crossref PubMed Scopus (1220) Google Scholar). Our current understanding of the molecular mechanism for this protection rests on several observations. First, under conditions of low O2 tension, both homozygous HbSS sickle cells and heterozygous HbAS sickle cell trait cells do not support growth of P. falciparum, in contrast to wild-type HbAA red blood cells (Pasvol et al., 1978Pasvol G. Weatherall D.J. Wilson R.J. Nature. 1978; 274: 701-703Crossref PubMed Scopus (226) Google Scholar). This was attributed to the enhanced propensity of HbSS to polymerize, creating an environment not conducive to parasite growth. A second mechanism posits that HbSS erythrocytes have an enhanced ability to elicit immunity, resulting in a more rapid clearance of parasitized erythrocytes (Ayi et al., 2004Ayi K. Turrini F. Piga A. Arese P. Blood. 2004; 104: 3364-3371Crossref PubMed Scopus (259) Google Scholar). It has also been suggested that presentation of the major virulence protein, PfEMP1, on the surface of parasite-infected erythrocytes is impaired in HbSS and HbCC red blood cells (Fairhurst et al., 2005Fairhurst R.M. Baruch D.I. Brittain N.J. Ostera G.R. Wallach J.S. Hoang H.L. Hayton K. Guindo A. Makobongo M.O. Schwartz O.M. et al.Nature. 2005; 435: 1117-1121Crossref PubMed Scopus (150) Google Scholar). Recently, a molecular mechanism for this altered presentation has been suggested to result from an aberrant actin remodeling in HbSS and HbCC red blood cells (Cyrklaff et al., 2011Cyrklaff M. Sanchez C.P. Kilian N. Bisseye C. Simpore J. Frischknecht F. Lanzer M. Science. 2011; 334: 1283-1286Crossref PubMed Scopus (168) Google Scholar). LaMonte et al., 2012LaMonte G. Philip N. Reardon J. Lacsina J.R. Majoros W. Chapman L. Telen M.J. Ohler U. Nicchitta C.V. Haystead T. Chi J.-T. Cell Host Microbe. 2012; 12 (this issue): 187-199Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar now add a further layer of complexity to the interactions between the host erythrocyte and the P. falciparum parasite (Figure 1). They find that at least two human microRNAs (miRNAs), miR-451 and miR-233, are more abundant in both sickle cells and in the epidemiologically relevant sickle cell trait cells compared to normal red blood cells. In tightly controlled experiments, they show that miR-451 is translocated into the parasite, where it is incorporated covalently into P. falciparum mRNAs, leading to an inhibition of mRNA translation and a modest but significant reduction in parasite growth. When overexpressed in normal erythrocytes, miR-451 and miR-223 reduced parasite growth; conversely, blocking the erythrocyte to parasite translocation of miR-451 and miR-223, using 2′-O-methyl antisense oligonucleotides, diminished malaria resistance in both sickle cells and sickle cell trait cells. miRNAs are a recently discovered class of small noncoding eukaryotic RNAs 18–24 nucleotides long that downregulate target genes at a posttranscriptional level. The majority of miRNA genes are transcribed by RNA polymerase II into long primary (pri) miRNA transcripts, processed by the nuclear nuclease Drosha into ∼60 bp hairpins termed precursor (pre) miRNAs, and further cleaved in the cytosol by the Dicer nuclease into mature miRNAs. Mature miRNAs are then incorporated into the multiprotein RNA-induced silencing complex (RISC), exerting posttranscriptional repression of target mRNAs, either by inducing mRNA degradation or blocking mRNA translation. Why any miRNAs are present in mature erythrocytes is a mystery, since there is no ongoing protein synthesis. Red blood cell miRNAs like miR-451 and miR-223 are generated during erythroblast proliferation and differentiation, prior to enucleation. miR-451 is induced during red blood cell development and is important for formation of erythrocytes (Dore et al., 2008Dore L.C. Amigo J.D. Dos Santos C.O. Zhang Z. Gai X. Tobias J.W. Yu D. Klein A.M. Dorman C. Wu W. et al.Proc. Natl. Acad. Sci. USA. 2008; 105: 3333-3338Crossref PubMed Scopus (277) Google Scholar), but it is unclear why it is retained in mature erythrocytes or why its level is higher in sickle than normal red blood cells. Experimentally, miRNAs can be introduced into mature erythrocytes, so exogenous miR-223 or miR-451 could possibly be used therapeutically in treating malaria. How miRNAs are incorporated into intracellular malaria parasites is also unknown. Plasmodium parasites are contained within a parasitophorous vacuolar membrane, and thus the miRNA would have to cross from the red blood cell cytosol through both this membrane and the parasite’s plasma membrane. Direct visualization of mir-451 in the parasitophorous vacuolar membrane will need to be reconciled with its activity within the parasite. There is a precedent for this, however, as one can use preloaded erythrocytes to introduce plasmid DNA into the parasite (Deitsch et al., 2001Deitsch K. Driskill C. Wellems T. Nucleic Acids Res. 2001; 29: 850-853Crossref PubMed Scopus (237) Google Scholar), although the efficiency of this process is very low at ∼1 in 106 cells. It will be of great interest to elucidate the mechanism of miRNA translocation, as this may form the basis for more efficient genetic manipulation of this Plasmodium species. Plasmodium parasites do not contain Dicer or any Argonaute homologs that comprise the RISC complex. RNA interference, including conventional functions of miRNAs, is not functional in these organisms. Thus, it was a huge surprise that the translocated miRNAs became covalently linked to certain Plasmodium mRNAs, forming chimeric RNAs. Indeed, several transcripts in a Plasmodium EST database contain miR-451 at their 5′ ends, and this linkage was subsequently confirmed by both real-time PCR and northern blots on parasite material. Covalent linkage requires a trans-splicing event, but in unicellular eukaryotes this has only been observed in kinetoplastid organisms, where a leader sequence is spliced onto the 5′ end of all RNA transcripts during processing and maturation (Sutton and Boothroyd, 1986Sutton R.E. Boothroyd J.C. Cell. 1986; 47: 527-535Abstract Full Text PDF PubMed Scopus (325) Google Scholar). In P. falciparum, miRNA tagging occurs to a minority of transcripts, including genes such as PKA-R, PEAMT, and the 28S and 18S rRNAs. We do not know what determines the specific enrichment of certain miRNAs or the incorporation of these miRNAs to specifc parasite mRNAs. This study raises many other questions. Has increased miRNA-451 or miR-223 expression in red blood cells been selected for as a malaria resistance factor, similar to the selection for other red blood cell disorders? Why does a reduction in PKA-R result in reduced parasite proliferation and increased conversion to sexual stage parasites? What, if any, are the functional consequences of the other miRNAs differentially regulated between HbSS and HbAA? Is there conservation of this mechanism in protection against other Plasmodium species? What is the relative contribution of miRNA-based inhibition of parasite growth in HbSS erythrocytes compared to other postulated mechanisms of protection, particularly under low oxygen tension when inhibition of parasite growth is most marked (Pasvol et al., 1978Pasvol G. Weatherall D.J. Wilson R.J. Nature. 1978; 274: 701-703Crossref PubMed Scopus (226) Google Scholar)? Clearly, Lamonte and colleagues have revealed a startling and unique mechanism of cross species trans-splicing in P. falciparum-infected erythrocytes where the effector molecule of parasitic inhibition is the miRNA itself. Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria ResistanceLaMonte et al.Cell Host & MicrobeAugust 16, 2012In BriefErythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite. Full-Text PDF Open Archive" @default.
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