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Infection and Immunity, December 2007, p. 5565-5574, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00405-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evidence for a Common Role for the Serine-Type Plasmodium falciparum Serine Repeat Antigen Proteases: Implications for Vaccine and Drug Design{triangledown} ,{dagger}

Joanne E. McCoubrie,1,2,{ddagger} Susanne K. Miller,1,2,{ddagger} Tobias Sargeant,1,2 Robert T. Good,1 Anthony N. Hodder,1 Terence P. Speed,1 Tania F. de Koning-Ward,1 and Brendan S. Crabb1*

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia,1 Department of Medical Biology, University of Melbourne, Melbourne, Australia2

Received 18 March 2007/ Returned for modification 14 May 2007/ Accepted 4 September 2007

Serine repeat antigens (SERAs) are a family of secreted "cysteine-like" proteases of Plasmodium parasites. Several SERAs possess an atypical active-site serine residue in place of the canonical cysteine. The human malaria parasite Plasmodium falciparum possesses six "serine-type" (SERA1 to SERA5 and SERA9) and three "cysteine-type" (SERA6 to SERA8) SERAs. Here, we investigate the importance of the serine-type SERAs to blood-stage parasite development and examine the extent of functional redundancy among this group. We attempted to knock out the four P. falciparum serine-type SERA genes that have not been disrupted previously. SERA1, SERA4, and SERA9 knockout lines were generated, while only SERA5, the most strongly expressed member of the SERA family, remained refractory to genetic deletion. Interestingly, we discovered that while SERA4-null parasites completed the blood-stage cycle normally, they exhibited a twofold increase in the level of SERA5 mRNA. The inability to disrupt SERA5 and the apparent compensatory increase in SERA5 expression in response to the deletion of SERA4 provides evidence for an important blood-stage function for the serine-type SERAs and supports the notion of functional redundancy among this group. Such redundancy is consistent with our phylogenetic analysis, which reveals a monophyletic grouping of the serine-type SERAs across the genus Plasmodium and a predominance of postspeciation expansion. While SERA5 is to some extent further validated as a target for vaccine and drug development, our data suggest that the expression level of other serine-type SERAs is the only barrier to escape from anti-SERA5-specific interventions.

* Corresponding author. Mailing address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Phone: 61 3 9345 2469. Fax: 61 3 9347 0852. E-mail: crabb{at}wehi.edu.au

{triangledown} Published ahead of print on 24 September 2007.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. F. Urban, Jr.

{ddagger} J.E.M. and S.K.M. contributed equally to this work.

Infection and Immunity, December 2007, p. 5565-5574, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00405-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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