Revisiting the multigene families: Plasmodium var and vir genes.
Malaria, one of the most widespread infectious diseases in humans is caused by the apicomplexan Plasmodium falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. Most severe form of malaria is caused by P. falciparum where the infected red blood cells (RBCs) have distinct antigenic properties generally with cytoadherent phenotypes (1). Plasmodium vivax is not fatal, though it is responsible for considerable morbidity in those populations where it is endemic through hypnozoites (the dormant parasite stages in liver) causing relapse within weeks to months after primary episode (2). The diverse Plasmodium genome poses a formidable challenge till date to the scientists community worldwide.
Diverse Plasmodium genome
The completion of P. falciparum and P. vivax genome project has revealed many contrasting features between the two genomes along with several similarities seen at the gene function level distributed among 14 chromosomes (3-4). The genome of P. vivax is 26.8 megabase (Mb) distinctly larger than P. falciparum genome of 23.3 Mb. Both the species are almost similar in terms of the number of genes where P. vivax has 5433 and P. falciparum has 5403 genes. The average gene length in P. vivax is 2164 bp whereas in P. falciparum the gene length is 2283 bp. The average intron length in P. vivax is 192 bp and in P. falciparum it is 179 bp though the average intergenic length between them is ~1994 and 1745 bp, respectively. The difference in the average intron and intergenic regions could be the reason for the larger genome size of P. vivax as the coding regions of both the species are considerably comparable. The major difference in the two genomes is the A+T nucleotide content found to be 57.7% in P. vivax and 80.6% in P. falciparum (4). The distribution of A+T rich regions varies in both the genomes by being restricted to the subtelomeric areas of the chromosomes in P. vivax and evenly distributed in P. falciparum similar to the multigene families encoding variant surface antigens (VSAs) following the same pattern of distribution in P. vivax and P. falciparum.
Antigenic variation in Plasmodium
Disease pathogenesis in malaria is related to the ability of the parasitized RBCs to escape immune response and establish chronic infections (5-6). The infection of RBCs by Plasmodium results in progressive and dramatic structural and biochemical modifications of the RBCs that can worsen into life-threatening complications of malaria (7). The phenomenon where parasite exhibits variable antigens on the surface of infected erythrocytes enables the parasite to endure and escape the host immune response known as antigenic variation. The symmetry of interactions between different antigenic variants can be explained by various mathematical models of antigenic variation in malaria (8).
The expression of VSAs has been linked to disease pathogenesis besides the survival of parasite by establishing long-lasting chronic infections (5). Most species of Plasmodium have several multicopy gene families situated at the subtelomeric ends of chromosomes coding for VSAs that are exported to the surface of the infected host erythrocyte to help the parasite evade the immune system (9). These multigene families are also highly diverged between species, and undergo high levels of recombination, generating further diversity.
Multigene families of Plasmodium
Several Plasmodium species contain multigene families on the telomeric and subtelomeric regions of their chromosomes which code for VSAs (10). The largest multigene family recognized so far is the Plasmodium interspersed repeats (pir) which includes repetitive interspersed family (rif) in P. falciparum, vir in P. vivax, kir in P. knowlesi and the cir/bir/yir family in three rodent malaria parasites P. chabaudi/P. berghei/P. yoelli, respectively (11). Since, the completion and annotation of the genome sequence of P. falciparum, three multigene families have been identified, i.e. the var genes encoding P. falciparum erythrocyte membrane protein 1 (PfEMP1), the rif encoding the RIFIN proteins and the subtelomeric variant open reading frame (stevor) genes coding for the STEVOR proteins (6). The multigene family in P. vivax is variant interspersed repeats (vir) which encodes for VIR proteins (5). These multigene families are responsible for the antigenic variation of the parasite in natural infections which enables it to escape the host immune response for its survival resulting in prolonged chronic infections. Theoretically, these genes can be considered as effective vaccine candidates which could have a great impact on malaria morbidity and mortality subsequently.
The var gene family: The best characterised multigene family in P. falciparum is the var gene family which encodes PfEMP1, a protein that is exported to the 'knob like' binding structures on the surface of infected erythrocytes with a key role in antigenic variation and cytoadherence (12). A total of 60 var genes are known to be present in single haploid genome of P. falciparum though only a single PfEMP1 type is expressed on the surface of the parasitized RBC stably inherited through successive cell cycles or a different gene can be expressed by switching during the course of infection (13). The completion of the genome project revealed 35 of the var genes in the subtelomeric regions and the remaining genes in clusters away from the ends of the chromosomes. Var gene repertoires have been extensively sequenced and worked on in 3D7 P. falciparum reference clone. The var genes are large (6-13 kb) and comprise of two exons where the first exon codes for the variable extracellular domain and transmembrane region, and the second exon for a highly conserved cytoplasmic or acidic terminal segment (ATS). The var genes present in the central regions of chromosomes can either be present singly or in groups which are arranged in tandem arrays with three to seven var genes. Each chromosome end contains one to three var genes followed by a group of rif, stevor and other gene families (Fig. 1). In the P. falciparum infection, cytoadhesion of the parasitized blood cells to the endothelial cells is due to the interactions between PfEMP1 encoded by the var gene family and defined host receptors on endothelial cells like cluster of differentiation-36 (CD36), intercelluar adhesion molecule-1 (ICAM-1), and chondroitin sulfate A (CSA). Multiple receptor-like domains, the duffy binding-like (DBL) domain and the cysteine rich inter domain region (CIDR) are present in the binding regions of PfEMP1. Although, there is a substantial variation in the sequence of the PfEMP1 proteins, the adhesion domains can be grouped on the basis of the sequence similarity and the domain design can offer insights in the binding function. There are many different DBL-[gamma] domains binding to CSA and several CIDR-[alpha] type domains which bind to CD36.
[FIGURE 1 OMITTED]
Var gene ancient sequence fragments termed homology blocks (HBs) recombine at very high rate and expression rates of some HBs are associated more strongly with the severe disease phenotypes than the expression rates of DBL-[alpha] types. More specifically, expression profiles of HB differ significantly for severe and mild disease and also for rosetting vs impaired consciousness associated severe disease (14).
The total number of functionally characterized PfEMP1 domains are still very limited and it is clear that the binding functionality of PfEMP1 can not be completely known by sequence analysis alone (15).
Based on sequence similarities the 5' promoter regions of the var genes are divided into five distinct groups, i.e. Upstream--UpsA, UpsB, UpsC, UpsD and UpsE. In the 3D7 genome, there are nine UpsA var genes, 22 UpsB var genes, 13 UpsC var genes, one UpsD var pseudogene and one UpsE var gene. The remaining 13 var genes comprise of UpsBC as their promoter sequences, i.e. they are phylogenetically between UpsB and UpsC (16). UpsD is grouped with UpsA and UpsC var genes located centrally in the chromosome, UpsB var genes are either central or subtelomeric and transcribed away from the telomere arranged in tandem arrays with other UpsB or UpsC var genes whereas UpsA and UpsE var genes are subtelomeric and transcribed towards the telomere in opposite direction to the UpsB genes (17). In the group, UpsA var genes are more closely related with each other and all encode for non-CD36-binding type CIDR domains whereas, UpsB and UpsC genes have CD36-binding CIDR domains. The UpsD and UpsE-linked var genes, viz. var1CSA and var2CSA and the UpsA-linked Type 3 var are exceptionally conserved in parasite isolates though the functional importance of the various promoters remains unclear (15, 18-19). Var gene transcription is tightly controlled by a special transcription mechanism that silences all the other var genes except the one that is being expressed per genome and this process could be controlled epigenetically (20). This frequent switching of the var genes ensures parasite survival against the host immune system and is one of the major causes of the severity of P. falciparum malaria indicating var genes as an important research area for vaccine development. Gene recombination between var paralogs is the major mechanism in generation of the extreme diversity in the variant antigen repertoire (21).
The vir gene family: The similar multigene superfamily in P. vivax is vir gene family, which like the var genes in P. falciparum might have a key role in antigenic variation. The annotation of the vir gene repertoire from P. vivax Sal-I genome, has revealed a total of 346 vir genes including fragments, and pseudogenes (5, 22). These genes range from 156-3434 bp in size and each gene has 1-5 exons where the first exon lacks the signal peptide sequences. The second exon is highly polymorphic containing the predicted transmembrane domain and conserved cysteine residues and the third exon is uniform in size encoding for the putative cytosolic domain (Fig. 2). The vir gene region between the second and the third exon is well-conserved. The vir gene family corresponds to 10% of the coding sequences comprising of 12 subfamilies christened from A to L varying in their extent of allele polymorphism and the remaining 82 genes could not be clustered. Unlike the var genes, the vir genes are not found in the internal regions of the chromosomes but are exclusively subtelomeric in location. VIR proteins encoded by the vir genes in natural infections are not known fully but it is speculated that they have a role to play in spleen-specific cytoadherence and in the chronicity of the disease (23). It has also been suggested that the vir genes may have different functions in immune evasion as not all the proteins are presented on the infected RBCs (24). Unlike the var genes of P. falciparum, vir genes are abundantly expressed at a given time and a number of subfamilies are transcribed by individual parasites (23).
[FIGURE 2 OMITTED]
Vir genes are the largest subtelomeric multigene family in P. vivax which might be responsible for bringing P. vivax malaria towards severity as P. vivax-infected erythrocytes also have some ability to cause cytoadherence (25). The vir genes are extensively more diverse than other Plasmodium pir families such as cir (P. chabaudi 135 members) and bir (P. berghei 245 members) though vir superfamily shares structural characteristics with Pfmc-2tm and surfin family found on the infected erythrocytes (5). Many VIR proteins lack Plasmodium export element (PEXEL) motifs showing that these proteins have subcellular localizations other than the surface membranes of infected reticulocytes, however, further investigations are needed to establish the role of VIR proteins as cytoadhesive ligands and the part they play in the severity of the disease in the changing paradigm of pathogenesis.
The complete annotation of the P. falciparum genome showed two other polymorphic multigene families, viz. rif and stevor to be associated with var in the genome (11). The rif gene family is located subtelomerically in the chromosomes, very close to the var genes (Fig. 1). It is not known how many RIFIN proteins are expressed on the surface of an RBC at a time but it is found that they are transcribed by immature trophozoites only for a short period of time (26). More than 200 rif genes are found per haploid P. falciparum genome which shows that the repertoire of rif genes is much larger than that of var genes (9). Nevertheless, evidence has been found that different RIFINs are being expressed on different parasite lines indicating that rif genes might have an additional role in antigenic variation and in immune evasion as well (26).
Located along the var and rif genes, stevor genes are more conserved in comparison but the hypervariable region of STEVOR has significant sequence diversity in different P. falciparum lines. While many var and rif genes are centrally located, the stevor genes are restricted to the chromosome ends (6). Stevor genes have 30-40 copies per haploid genome and have a two exon structure. STEVOR appears on the surface of infected RBCs (iRBCs) after both PfEMP1 and RIFIN demonstrating its significant role in the development of late stage parasites (9). It has been shown in the previous studies that STEVOR proteins are clonally variable on the surface of the RBC and are able to change the antigenic properties of the RBCs, thus playing a major role in the antigenic variation of the late asexual parasite stages (27). Similar to rif genes, the role of stevor genes in cytoadhesion is unknown.
The var gene repertoire is highly diverse in a single parasite and extensive diversity is also seen between isolates causing the prevailing immense global diversity in the var genes. Perhaps this existing diversity is responsible for host immune evasion in the parasite. The var genes encode PfEMP1 responsible for the cytoadhesive properties in P. falciparum, thus providing the selective advantage of preventing their clearance in the spleen (16). The PfEMP1 protein (200-400 kDa) remains the major target for naturally acquired antibodies and PfEMP1 variants expression is more often associated in children's plasma causing severe malaria than the non-severe disease (9). The chronic disease is closely associated with a shift in PfEMP1 expression and this kind of shift is responsible for expressing PfEMP1 molecules which are less optimal for adhesion (28). The PfEMP1 domain could serve as an ideal vaccine target though the extensive diversity present in PfEMP1 could be an obstacle but the domains which bind to CD36 and CSA are structurally conserved and could serve as potential vaccine targets aimed at cytoadhesion (29-30). It was observed that disruption of the var2CSA gene causes the parasite to lose its CSA-binding phenotype (31). There is ongoing research to evaluate var2CSA as a vaccine target against malaria (32). The expression of var genes and its correlation with the disease severity can reveal the role of different var genes in the pathogenesis of the disease. The recent understanding of antigenic variation after analyzing the var genes gives more insight into the mechanisms of immune evasion, hence promoting pathogenesis (33).
Studies indicate the vir genes relation with antigenic variation due to which the parasite survives elimination by the host. Recent sequence analysis of four vir genes from Indian populations revealed high diversity in them in natural infections both within and between the isolates (34). Adhesion of PfEMP1 to endothelial receptors has been associated with severe P. falciparum and now evidence shows in vitro cytoadherence of P. vivax-infected reticulocytes mediated by VIR proteins (24). Recently, it has been proved that VIR proteins are trafficked to different cellular compartments and can specifically cytoadhere to ICAM-1 endothelial receptor (24, 35). A detailed comparison between P. falciparum and P. vivax can be seen in the snapshot.
The detailed knowledge of genetic variability among the vir genes will provide an insight in the chronicity of the disease. The most challenging task for malaria researchers is to develop an efficient vaccine. Now that the vir gene sequences are known, DNA microarrays can be designed to look at how the expression of the genes changes. Such experiments will help identify the regulation mechanism of these genes and their functional role in the chronicity of the disease. Furthermore, it will also enable to identify the expression of the genes at different life-cycle stages of the parasite. The challenge to malariologists is to develop innovative ways to tackle this disease. The information about the vir genes should be used to test a suitable approach for developing a vir-based malaria vaccine since it is speculated to play a role in pathogenesis. It remains to be seen whether the emerging P. falciparum like characteristics of P. vivax associated with VIR proteins are responsible for P. vivax shifting from benign to severe. The var and the vir genes repertoire encompass a huge range of evolutionary strategies and constraints, representing an interesting model system to study in depth the host-pathogen evolution.
We would like to thank the Department of Biotechnology (DBT) and also like to extend thanks to Indian Council of Medical Research (ICMR), for providing us the grant required for carrying out all the research work during which the genesis of this paper took shape.
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Vineeta Singh , Purva Gupta  & Veena Pande 
 National Institute of Malaria Research (ICMR), Dwarka, New Delhi;  Department of Biotechnology, Kumaun University, Nainital, Uttarakhand, India
Correspondence to: Dr Vineeta Singh, Scientist 'C', National Institute of Malaria Research (ICMR), Sector-8, Dwarka, New Delhi-110 077, India.
Received: 8 July 2013 Accepted in revised form: 3 April 2014
Snapshot on similarities and dissimilarities between P. falciparum and P. vivax P. falciparum P. vivax Similarities Causes severe and complicated Though it is said to be benign, malaria situation seems to be changing and it is becoming severe Resistance to chloroquine well- Resistance to chloroquine proven established in several parts of the world (2,4) Plasmodium falciparum is known to Recently, P. vivax severity is cause cytoadherence which is one of attributed possibly to the prime reasons for severity of cytoadherent phenomenon (25) the disease (12) Has 5403 genes Has 5433 genes High conservation at functional level exists between two species. Eighty-two percent of the genes in P. falciparum with known functions are conserved in P. vivax (4). Has the ability to evade the host immunity by antigenic variation (1). P. falciparum P. vivax Dissimilarities Plasmodium falciparum has an Plasmodium vivax has origin in African origin and is more Asia and is more ancient (36). recent (36). Plasmodium falciparum is prevalent Plasmodium vivax is most in Africa and parts of Asia. commonly distributed in Asia and in south and central America. Invades all RBCs Preferentially invades reticulocytes. Enters host RBCs via multiple Requires the Duffy blood group pathways. as the receptor for entrance into reticulocytes (37). Gametocytes appear in peripheral Gametocytes appear in peripheral blood after clinical symptoms (38). blood before clinical symptoms (39). No dormant stages found. Dormant stages (hypnozoites) found. There are no clinical relapses. Hypnozoites cause clinical relapses. Avoids passage of mature asexual Passage of all asexual blood blood stages through the spleen stages through the spleen40. (19). Continuous in vitro culture for P. Continuous in vitro culture for falciparum available. P. vivax is not available although attempts are now being made. Isochores not seen. Isochores seen in genome with GC-content of 18 and 30%. A+T nucleotide content is 80.6% A+T nucleotide content is 57.7% A+T regions are restricted to the A+T regions are evenly subtelomeric areas of the distributed in the chromosome. chromosome. Contains multigene families like Contains multigene families like var, rif and stevor genes. vir genes. There are 60 var genes known to be There are 346 vir genes present present in P. falciparum along with in P. vivax (5). 200 members of rif and 28 members of stevor genes (27-28). At a time only one var gene is More than one vir genes are expressed (13). expressed at a given time (23). The var genes are clonally The vir genes are not expressed expressed in natural infections. clonally. The var genes have two exons. The vir genes have 1-5 exons. There is no grouping of var genes The vir genes are characterized into subfamilies. into 12 subfamilies ranging from A-L and 82 genes remain unclustered. Established role of var genes in Role of vir genes speculative in cytoadherence (12). pathogenesis and chronicity of the disease (5). The var genes are present in The vir genes are exclusively central as well as the subtelomeric present in the subtelomeric regions of the chromosomes. regions of the chromosomes.
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|Author:||Singh, Vineeta; Gupta, Purva; Pande, Veena|
|Publication:||Journal of Vector Borne Diseases|
|Date:||Jun 1, 2014|
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