Abstract
PfEMP1 are variant parasite antigens that are inserted on the surface of Plasmodium falciparum infected erythrocytes (IE). Through interactions with various host molecules, PfEMP1 mediate IE sequestration in tissues and play a key role in the pathology of severe malaria. PfEMP1 is encoded by a diverse multi-gene family called var. Previous studies have shown that that expression of specific subsets of var genes are associated with low levels of host immunity and severe malaria. However, in most clinical studies to date, full-length var gene sequences were unavailable and various approaches have been used to make comparisons between var gene expression profiles in different parasite isolates using limited information. Several studies have relied on the classification of a 300 - 500 base-pair "DBLα tag" region in the DBLα domain located at the 5' end of most var genes. We assessed the relationship between various DBLα tag classification methods, and sequence features that are only fully assessable through full-length var gene sequences. We compared these different sequence features in full-length var gene from six fully sequenced laboratory isolates. These comparisons show that despite a long history of recombination, DBLα sequence tag classification can provide functional information on important features of full-length var genes. Notably, a specific subset of DBLα tags previously defined as "group A-like" is associated with CIDRα1 domains proposed to bind to endothelial protein C receptor. This analysis helps to bring together different sources of data that have been used to assess var gene expression in clinical parasite isolates.
Highlights
PfEMP1 is an important target of naturally acquired immunity to malaria (Chan et al, 2012) and plays a central role in malaria pathology through interaction with host endothelial receptors such as ICAM-1 (Berendt et al, 1989), CD36 (Barnwell et al, 1989), CR1 (Rowe et al, 1997) and endothelial protein-C receptor (EPCR) (Turner et al, 2013)
Previous studies have shown that that expression of specific subsets of var genes are associated with low levels of host immunity and severe malaria
In an attempt to bring together information from the DBLα tag with information available from the full length var gene, we examined associations between full length var gene classifications available from a recent study (Rask et al, 2010) and var tag classifications used in previous studies of clinical parasite isolates (Bull et al, 2005b; Bull et al, 2007; Kirchgatter & Portillo, 2002; Kyriacou et al, 2006; Warimwe et al, 2009)
Summary
PfEMP1 is an important target of naturally acquired immunity to malaria (Chan et al, 2012) and plays a central role in malaria pathology through interaction with host endothelial receptors such as ICAM-1 (Berendt et al, 1989), CD36 (Barnwell et al, 1989), CR1 (Rowe et al, 1997) and endothelial protein-C receptor (EPCR) (Turner et al, 2013). PfEMP1 molecules contain a combination of two to nine domains (Rask et al, 2010; Smith et al, 2000a) organized in a modular architecture comprising an N-terminal segment, Duffy binding-like (DBL), cysteine inter-domain region (CIDR) and acidic terminal segment domains. Understanding the relationships between specific PfEMP1 variants and clinical malaria is not straightforward, since 1) due to recombination between var genes on non-homologous chromosomes, the overall architecture of PfEMP1 encoded by different parasites genotypes is extremely diverse and sequences are mosaics of many semi-conserved sequence blocks, and 2) multiple var genes are expressed simultaneously within the infecting parasite population. The range of var genes expressed at any one time in the infecting parasite population varies according to the antibodies and other in vivo selection pressures. 3) Analysis is further complicated by the high diversity of each domain subclass and lack of clear associations between specific adhesion phenotypes and classes of domains
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
