Serine Repeat Antigen (SERA5) Is Predominantly Expressed among the SERA Multigene Family of Plasmodium falciparum, and the Acquired Antibody Titers Correlate with Serum Inhibition of the Parasite Growth

Abstract

The Plasmodium falciparum serine repeat antigen (SERA) is one of the blood stage malaria vaccine candidates. The malaria genome project has revealed that SERA is a member of the SERA multigene family consisting of eight SERA homologues clustered on chromosome 2 and one SERA homologue on chromosome 9. Northern blotting and real time quantitative reverse transcription-PCR with five independent parasite strains, including three allelic representative forms of the SERA gene, have shown that all of the SERA homologues are transcribed most actively at trophozoite and schizont stages and that SERA5 (SERA/SERP) is transcribed predominantly among the family. Polyclonal antibodies were raised against recombinant proteins representing the Nterminal portions of four significantly transcribed SERA homologues (SERA3 to -6) in the center of the cluster on chromosome 2. Using these antibodies, indirect immunofluorescence microscopy detected the expression of SE-RA3 to -6, with similar localization, in all trophozoite-and schizont-infected erythrocytes. We have examined 40 sera from Ugandan adults for their antibody reactivity and found that enzyme-linked immunosorbent assay titer against SERA5 N-terminal domain, but not against other SERA proteins, is positively correlated with the inhibition of in vitro parasite growth by individual sera. Our data confirm the usefulness of the N-terminal domain of SERA5 as a promising malaria candidate vaccine.

Clues to Evolution of the SERA Multigene Family in the Genus Plasmodium

“…During blood stage growth, all SERA gene family member of P. falciparum are transcribed most actively at trophozoite and schizont stages. SERA5 is the most abundantly expressed gene family member, with expression levels estimated to be approximately 0.5-1.5% of the whole mRNA at schizont stage (Aoki et al, 2002). However, sero-positivity rate against the Nterminal domain of P. falciparum SERA5 was observed to be relatively low (Fig.…”

“…In addition, a gene family member in P. falciparum, SERA5, is a vaccine candidate now on phase Ib clinical trial (Horii et al, 2010). Two observations promise SERA5 as a vaccine candidate: (1) SERA genes are not differently expressed like other antigen encoding gene families such as var and rifin that show antigenic variation to evade host immune response (Aoki et al, 2002;Miller et al, 2002;Palacpac et al, 2006;Schmidt-Christensen et al, 2008;Putrianti et al, 2010;Arisue et al, 2011); and (2) P. falciparum SERA5 is less polymorphic (Fox et al, 1997: Morimatsu et al, 1997Liu et al, 2000) than other vaccine candidate genes such as merozoite surface protein 1 (McBride et al, 1985) and apical membrane protein 1 (Polley et al, 2003;Cortés et al, 2003). These characteristics are indeed appealing and show the unique biological features of Plasmodium SERA.…”

“…The complete genome sequence of P. falciparum revealed that SERA belongs to a multigene family (Gardner et al, 1998). The originally described SERA gene was renamed SERA5 according to the gene arrangement order in P. falciparum (Aoki et al, 2002;Miller et al, 2002). It is interesting to note that SERA5 is the only member with repeated serine residues among nine gene members.…”

“…P. falciparum SERA5 is a vaccine candidate molecule now on clinical trial in Uganda (Horii et al, 2010). Serum antibodies against the N-terminal domain of P. falciparum SERA5 in individuals living in malaria endemic area protect infants from clinical malaria and inhibit in vitro parasite growth (Okech et al, 2001(Okech et al, , 2006Aoki et al, 2002;Horii et al, 2010). During blood stage growth, all SERA gene family member of P. falciparum are transcribed most actively at trophozoite and schizont stages.…”

“…Transcription profile of the SERA gene family was analyzed first by Aoki et al (2002) in P. falciparum. Genes were most actively transcribed at the late trophozoite to schizont stages of the parasite with SERA5 predominantly transcribed among the family (Fig.…”