A Subset of Plasmodium falciparum SERA Genes Are Expressed and Appear to Play an Important Role in the Erythrocytic Cycle

Abstract

The Plasmodium falciparum serine repeat antigen (SERA) has shown considerable promise as a blood stage vaccine for the control of malaria. A related protein, SERPH, has also been described in P. falciparum. Whereas their biological role remains unknown, both proteins possess papain-like protease domains that may provide attractive targets for therapeutic intervention. Genomic sequencing has recently shown that SERA and SERPH are the fifth and sixth genes, respectively, in a cluster of eight SERA homologues present on chromosome 2. In this paper, the expression and functional relevance of these eight genes and of a ninth SERA homologue found on chromosome 9 were examined in blood stage parasites. Using reverse transcriptase-PCR and microarray approaches, we demonstrate that whereas mRNA to all nine SERA genes is synthesized late in the erythrocytic cycle, it is those genes in the central region of the chromosome 2 cluster that are substantially up-regulated at this time. Using antibodies specific to each SERA, it was apparent that SERA4 to -6, and possibly also SERA9, are synthesized in blood stage parasites. The reactivity of antibodies from malaria-immune individuals with the SERA recombinant proteins suggested that SERA2 and SERA3 are also expressed at least in some parasite populations. To examine whether SERA genes are essential to blood stage growth, each of the eight chromosome 2 SERA genes was targeted for disruption. Whereas genes at the periphery of the cluster were mostly dispensable (SERA2 and -3 and SERA7 and -8), those in the central region (SERA4 to -6) could not be disrupted. The inability to disrupt SERA4, -5, and -6 is consistent with their apparent dominant expression and implies an important role for these genes in maintenance of the erythrocytic cycle.

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

“…Mz egress is preceded by a sharp rise of intracellular Ca 2 þ that triggers the discharge of the exoneme content in the PV 25 , including an active form of SUB1. Subsequently, SUB1 matures the serine-rich repeat antigens (SERAs) 11 , a serine and papain-like family of proteases that participates in the rupture of the PV and infected RBC membranes 26 . In addition, SUB1 processes several parasite surface proteins, priming Mz for subsequent invasion of new erythrocytes 14,15,27 .…”

A Key Role for Plasmodium Subtilisin-like SUB1 Protease in Egress of Malaria Parasites from Host Hepatocytes

“…In P. falciparum, two of the nine sera genes, Pfsera5 and Pfsera6, cannot be inactivated in blood stages. In contrast, Pfsera4-null parasites complete the blood cycle normally, whereas overexpressing Pfsera5 (20,44). P. berghei produces five PbSERAs.…”

“…Although SUB1 has so far only been reported as being expressed in erythrocytic stages, the SERAs are expressed in both erythrocytic and liver stages. The P. falciparum genome contains nine SERA-encoding genes, all transcribed during the parasite erythrocytic cycle (20). The genome of the rodent malaria parasite Plasmodium berghei encodes five SERAs (24), and four of these are known to be expressed in liver stages (25,26).…”

Signalling in malaria parasites – The MALSIG consortium

“…As long as merozoites are viable and maintain a low Ca 2+ concentration in the host cell cytoplasm, infected cells will not be recognized by macrophages expressing PS receptors. It has previously been speculated that putative parasite cysteine proteases of the SERA family are critically involved in the process of PVM destruction in infected erythrocytes (Miller et al, 2002) (Sturm et al, 2006). At the end of the liver stage, Plasmodium merosomes can be detected in liver sinusoids.…”