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Biochemical Society Transactions (2011) Volume 39, part 4
An expanded family of proteins with
BPI/LBP/PLUNC-like domains in trypanosome
parasites: an association with pathogenicity?
Eva Gluenz1 , Amy R. Barker and Keith Gull
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K.
Abstract
Trypanosomatids are protozoan parasites that cause human and animal disease. Trypanosoma brucei
telomeric ESs (expression sites) contain genes that are critical for parasite survival in the bloodstream,
including the VSG (variant surface glycoprotein) genes, used for antigenic variation, and the SRA (serumresistance-associated) gene, which confers resistance to lysis by human serum. In addition, ESs contain
ESAGs (expression-site-associated genes), whose functions, with few exceptions, have remained elusive.
A bioinformatic analysis of the ESAG5 gene of T. brucei showed that it encodes a protein with two
BPI (bactericidal/permeability-increasing protein)/LBP (lipopolysaccharide-binding protein)/PLUNC (palate,
lung and nasal epithelium clone)-like domains and that it belongs to a multigene family termed (GR)ESAG5
(gene related to ESAG5). Members of this family are found with various copy number in different members of
the Trypanosomatidae family. T. brucei has an expanded repertoire, with multiple ESAG5 copies and at least
five GRESAG5 genes. In contrast, the parasites of the genus Leishmania, which are intracellular parasites,
have only a single GRESAG5 gene. Although the amino acid sequence identity between the (GR)ESAG5 gene
products between species is as low as 15–25%, the BPI/LBP/PLUNC-like domain organization and the length
of the proteins are highly conserved, and the proteins are predicted to be membrane-anchored or secreted.
Current work focuses on the elucidation of possible roles for this gene family in infection. This is likely to
provide novel insights into the evolution of the BPI/LBP/PLUNC-like domains.
Introduction
Protists of the family Trypanosomatidae represent one of
the most divergent groups of eukaryotes [1] and include
several clinically relevant pathogens transmitted by insect
vectors. Trypanosoma brucei (Figure 1A) causes the cattle
disease nagana and the subspecies T. b. gambiense and
T. b. rhodesiense cause HAT (human African trypanosomiasis) (also known as sleeping sickness [2]) in geographically distinct regions of sub-Saharan Africa. Trypanosomatid genomes encode a family of proteins with BPI
(bactericidal/permeability-increasing protein)/LBP [LPS
(lipopolysaccharide)-binding protein]/PLUNC (palate, lung
and nasal epithelium clone)-like domains. This gene family
was termed (GR)ESAG5 [gene related to ESAG5 (expressionsite-associated gene 5)] [3]. To date, the only functionally
characterized proteins with BPI/LBP/PLUNC-like domains
are from metazoans, where they play important and
diverse roles in lipid transfer and immune defence [4–6].
Protein sequences with homology with BPI/LBP/PLUNClike domains are, however, present in a broader range
of eukaryotic taxa ([7] and E. Gluenz, A.R. Barker and
K. Gull, unpublished work). Elucidating the function of
the (GR)ESAG5 proteins in trypanosomes is of interest
for two reasons: (i) information about the biochemistry
of these proteins in this protist may provide insights
into the ancestral functions of the BPI/LBP/PLUNC-like
domain and the evolution of the superfamily; and (ii) the
founding member of the (GR)ESAG5 family, ESAG5, is
located in tightly regulated polycistronic transcription units
at telomeric ESs (expression sites) associated with immune
evasion mechanisms. In the present review, we discuss recent
progress in the characterization of the (GR)ESAG5 family in
the context of the biology of the bloodstream-form parasite
and its interactions with its host environment.
Key words: BPI/LBP/PLUNC-like domain, expression site-associated gene (ESAG), pathogenicity,
serum-resistance-associated gene (SRA gene), Trypanosoma brucei, variant surface glycoprotein
(VSG).
Abbreviations used: APOA1, apolipoprotein A1; APOL1, apolipoprotein L1; BPI,
bactericidal/permeability-increasing protein; ES, expression site; ESAG, expression-siteassociated gene; GRESAG5, gene related to ESAG5; HDL, high-density lipoprotein; LBP,
lipopolysaccharide-binding protein; LDL, low-density lipoprotein; LPS, lipopolysaccharide; PLTP,
plasma lipid-transfer protein; PLUNC, palate, lung and nasal epithelium clone; Pol I, polymerase
I; SRA, serum-resistance-associated; TAR, transformation-associated recombination; TbHpHbR,
Trypanosoma brucei haptoglobin–haemoglobin receptor; TLF, trypanolytic factor; VSG, variant
surface glycoprotein.
To whom correspondence should be addressed (email [email protected]).
1
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Authors Journal compilation Telomere-associated contingency genes
in African trypanosomes
In the human bloodstream, trypanosomes encounter potentially destructive serum proteins, most importantly
immunoglobulins and the trypanolytic factor (discussed
below). A number of important contingency genes located
Biochem. Soc. Trans. (2011) 39, 966–970; doi:10.1042/BST0390966
Proteins with a BPI/LBP/PLUNC-Like Domain: Revisiting the Old and Characterizing the New
Figure 1 ESAG5 is located in T. brucei telomeric ESs
(A) Scanning electron micrograph of a T. brucei bloodstream form (arrow) surrounded by mouse red blood cells. Scale
bar, 2 μm. (B) T. brucei telomeric ESs are polycistronic transcription units containing several ESAGs (white boxes) and one
telomere-proximal VSG gene (grey). Hatched boxes indicate ESAG pseudogenes. Open arrow, Pol I promoter; black triangles,
hexanucleotide repeat region; black bars, 70-bp repeat region. Figure based on data taken from [23]. (C) The R-ES of T. b.
rhodesiense [20].
at telomeres [8] provide the parasite with mechanisms of
escaping these host defence mechanisms.
African trypanosomes evade the adaptive antibodymediated immune response by a mechanism of antigenic
variation of their surface coat (reviewed recently in [9]). The
surface of the T. brucei bloodstream-form parasite is fully
covered in a coat of 5×106 dimers of a single VSG (variant
surface glycoprotein). There are at least 1500 VSG genes in
the genome [10] and periodic switching at a rate of between
10 − 2 and 10 − 7 per cell per generation [11] to a different VSG
allows a small proportion of parasites to escape detection
by the antibody response mounted against the predominant
VSG type in the population. Multiple levels of regulation,
including nuclear positioning [12] and epigenetic factors
[13], control monoallelic expression of only one VSG from
a single ES. Successive expansions of parasite populations
carrying a different VSG type on their surface give rise to
the characteristic waves of parasitaemia first described in
a human patient a century ago [14]. If untreated, African
sleeping sickness is fatal.
Humans and some non-human primates are resistant
to T. b. brucei infections because their serum contains a
potent TLF (trypanolytic factor) (reviewed in [15,16]). TLF
is associated with the densest subfraction of HDL (highdensity lipoprotein) particles (HDL3) containing APOA1
(apolipoprotein A1), APOL1 (apolipoprotein L1) and HPR
(haptoglobin-related protein). These HDL particles are
taken up by the trypanosome through receptor-mediated
endocytosis, via the haptoglobin–haemoglobin receptor,
TbHpHbR [17]. Within the acidic environment of the
lysosome, the HDL particle dissociates and a conformational
change in APOL1 causes its N-terminal domain to form an
anion-selective channel in the lysosome membrane, leading
to swelling of the lysosome and eventual trypanosome
lysis [18,19]. Expression of the SRA (serum-resistance-
associated) protein renders the human-infective subspecies
T. b. rhodesiense resistant to TLF lysis [20]; SRA binds to
APOL1 within the lysosome, thereby preventing its insertion
into the membrane [18,19].
Active VSG genes and the SRA gene (which is thought
to have evolved from a VSG gene [21]) are exclusively
expressed from telomeric ESs (Figure 1B). At least 14 ESs
have been fully sequenced in the most widely used laboratory
strain of T. brucei (Lister 427) [22,23]. Each ES contains one
telomere-proximal VSG and several ESAGs, which form a
polycistronic transcription unit of 40–70 kb [22] transcribed
from an RNA Pol I (polymerase I) promoter. ESAG5 is
one of 12 distinct ESAGs that have been identified to
date. Most of the different ESs in T. b. brucei 427 contain
polymorphic variants of most of the known ESAGs in a
largely conserved order [22,23]. Most ESAGs are predicted
to encode membrane-associated or secreted proteins with
possible roles in host–parasite interactions, but their specific
functions have remained frustratingly elusive [9,24]. The bestcharacterized ESAGs are ESAG6 and ESAG7, which encode
the two subunits of a heterodimeric transferrin receptor
[25]. Limited information is available about the function of
most of the other ESAGs: ESAG4 encodes a receptor-type
adenylate cyclase [26,27], ESAG8 encodes a nucleolar protein
[28], ESAG9 encodes an N-glycosylated secreted protein upregulated in the short stumpy bloodstream form [29], and
ESAG10 encodes a protein homologous with the Leishmania
biopterin transporter BT1 [30].
(GR)ESAG5s belong to a superfamily of
proteins with LBP/BPI/PLUNC-like domains
Bioinformatic characterization of ESAG5 showed that it
belongs to a large and diverse multigene family termed
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Authors Journal compilation 967
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Biochemical Society Transactions (2011) Volume 39, part 4
(GR)ESAG5, comprising a set of genes from different
trypanosomatid species [3]. All of the predicted (GR)ESAG5
proteins are of similar length (∼480 amino acids) with
a predicted N-terminal signal peptide. Classification of
(GR)ESAGs as BPI/LBP/PLUNC-like domain proteins was
based on sequence homology, established through sensitive
iterative BLAST searches and hidden Markov models [3].
This was independently confirmed in a cluster analysis of a
wide range of BPI/LBP/PLUNC-like domain homologues
[7]. Prediction of two-dimensional (GR)ESAG5 structures
showed high similarity to human BPI, and homology
modelling using the BPI crystal structure [31] showed that
ESAG5 could adopt a similar three-dimensional structure, the
characteristic quasi-symmetric fold consisting of two barrels
linked by a β-sheet [3].
The (GR)ESAG5 family in trypanosomatids
With recent advances in the sequencing of trypanosomatid
genomes and addition of the important and previously
underrepresented telomeric sequences of T. brucei [23], we
can begin to build a fuller picture of the complexities of
the (GR)ESAG5 family, which comprises the following three
groups of genes.
(i) ESAG5 genes
ESAG5 genes are found in ESs of T. brucei and closely related
species of African trypanosomes. TAR (transformationassociated recombination) cloning of T. b. brucei, T. b.
gambiense and T. equiperdum ESs allowed for the first time
a characterization of their full repertoire of ESAG sequences
[22], yielding at least 13 ESAG5 genes in T. b. brucei 427
[23], 23 in T. b. brucei EATRO 2340, 14 in T. b. gambiense
and 13 in T. equiperdum [32]. In phylogenetic analyses of
(GR)ESAG5 sequences, the ESAG5s form a distinct clade
with two main groups [3,32]. At the level of protein sequence,
ESAG5 sequences are >80 % identical. Estimation of rates of
non-synonymous and synonymous substitutions provided
evidence for adaptive evolution of ESAG5 genes, and 34
positively selected codons were found distributed across the
protein [32]. The C-terminal domains tend to exhibit slightly
more variability than the N-terminal domains, but variations
of single amino acid residues were found throughout primary
sequences of ESAG5 [3].
The reason for the location of ESAGs in ESs has
remained a mystery. ES location might be expected to confer
bloodstream-stage-specific expression and these sites are
subject to frequent recombination; whether these factors are
important for the function of ESAGs is unknown. ESAG5
transcripts were detected in both procyclic and bloodstreamform parasites in a recent large-scale microarray-based
analysis of gene expression across developmental stages of
T. brucei [33]. The functional significance of this is not
known, and it remains to be shown whether ESAG5 protein
expression is stage-specific. The attractive hypothesis that
a large and diverse ESAG repertoire may be adaptive to a
large host range [24] has remained controversial, and recent
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Authors Journal compilation comparisons between T. b. brucei, T. b. gambiense and T.
equiperdum did not show a positive correlation between host
range and ESAG sequence diversity [32]. The R-ES of T.
b. rhodesiense, which contains the SRA gene that enables
survival in human serum, is the only known example where
adaptation to a specific host is evident. Compared with the
canonical T. b. brucei ES, the T. b. rhodesiense R-ES is
truncated, containing, in addition to the SRA and VSG genes,
only ESAG5, ESAG6 and ESAG7 (Figure 1C) [20]. In the
study of T. brucei 427 ESs, ESAG5, ESAG6 and ESAG7 were
shown to belong to one of three linkage blocks of ESAGs that
have only infrequently been split by recombination [23], and
the linkage of ESAG5 to SRA is conserved in T. b. rhodesiense
isolates from geographically distinct locations [34].
(ii) GRESAG5 genes in chromosome-internal
positions in the T. brucei genome
Several genes related to ESAG5 were identified outside
ESs, in chromosome-internal positions (genes Tb927.2.1920,
Tb927.4.810, Tb927.5.340, Tb927.7.6860, Tb09.244.2120,
Tb09.v4.0016 and Tb09.v4.0016). Transcripts for these T.
brucei GRESAG5 genes were detected by RT (reverse
transcription)–PCR in procyclic (insect-stage) and bloodstream forms (A.R. Barker, E. Gluenz and K. Gull, unpublished work). Quantitative mRNA expression profiling studies showed modest (no more than 2-fold) down-regulation
of Tb927.2.1920 and Tb927.4.810 during the differentiation
from bloodstream to procyclic forms, whereas Tb927.5.340
showed the reverse pattern [33,35,36]. Trypanosomatids
control gene expression post-transcriptionally, and therefore
developmental regulation of the GRESAG5 genes needs to
be verified by measurement of protein levels.
(iii) GRESAG5 genes in chromosome-internal
positions in other trypanosomatids
GRESAG5 genes have now been identified in every
trypanosomatid genome that has been sequenced to date. This
includes T. brucei, two other species of African trypanosomes,
T. congolense and T. vivax, the American trypanosome
T. cruzi and the Leishmania species L. major, L. infantum,
L. mexicana and L. braziliensis. African trypanosomes have
the largest repertoire of (GR)ESAG5 genes. Leishmania
species and T. cruzi have only a single GRESAG5 gene
per haploid genome (genes Tc00.1047053508257.220 and
LmjF34.3930). There is considerable conservation of synteny
between the genomes of T. brucei, T. cruzi and L. major and
the T. cruzi and Leishmania GRESAG5 genes are in a genomic
location syntenic with Tb927.4.810 [3].
Is ESAG5 required for parasite survival
in the human bloodstream?
The conservation of ESAG5 in the R-ES of T. b. rhodesiense
and its homology with proteins known to interact with
human HDL and LDL (low-density lipoprotein) particles
makes this the most interesting gene within the (GR)ESAG5
Proteins with a BPI/LBP/PLUNC-Like Domain: Revisiting the Old and Characterizing the New
family. Does ESAG5 support parasite survival in the human
bloodstream, and, if so, by what mechanism? Insight into the
biochemical properties of ESAG5 may come from application
of methods that defined the functions of well-characterized
homologues. Mammalian CETP (cholesteryl ester-transfer
protein) is a key component of reverse cholesterol transport
mediating bidirectional transfer of cholesteryl esters and
triacylglycerols among plasma lipoproteins [6,37], whereas
PLTP (plasma lipid-transfer protein) mediates phospholipid
transfer and HDL conversion [38]. Lipid-binding activity
has also been demonstrated for mammalian BPI and
LBP, which function in antimicrobial defence and immune
regulation. BPI is produced by myeloid precursors of
polymorphonuclear leucocytes and has strong binding
affinity for the lipid A portion of LPS. It exhibits selective
toxicity for Gram-negative bacteria, neutralizes endotoxic
activity and has opsonizing activity [4]. LBP is an acute-phase
plasma protein, produced by hepatocytes, which mediates
transfer of LPS to MD2-CD14 [39] and binds to a variety
of amphiphilic bacterial compounds in addition to LPS
(summarized in [40]). On the basis of sequence homology
with these lipid-transfer proteins, one would predict a lipidbinding or -transfer function for the (GR)ESAG5s, yet
what specific biological functions might be being served and
whether putative ligands are of host or parasite origin are
entirely open questions.
Lipid metabolism in trypanosomatids has been studied
extensively, and the experimental evidence combined with
genome analysis show that all major phospholipid classes
are present in trypanosomes, as is the capability for de
novo synthesis of all phospholipids and glycolipids required
(reviewed in [41]). Lipids scavenged from the environment
provide components for de novo lipid biosynthesis, and
serum lipoproteins are essential for growth of T. brucei
bloodstream forms in axenic culture [42]. Uptake of
plasma proteins in T. brucei bloodstream forms occurs via
receptor-mediated endocytosis. Bloodstream forms acquire
cholesterol from LDL particles, and a candidate LDL
receptor has been characterized biochemically [43,44].
Biochemical studies also suggest the existence of another
lipoprotein receptor that mediates uptake of HDL, LDL
and TLF [45], but the genes encoding these receptors have
not been identified. HDLs are taken up via the TbHpHbR,
which was shown to mediate delivery of the trypanolytic
APOL1 protein into the trypanosome [17]. It is noteworthy
that human PLTP, a regulator of phospholipid transfer
and HDL conversion, was recently isolated in a complex
with 28 proteins implicated in immunity and inflammation,
including APOA1 and APOL1 [46]. Future biochemical
studies combined with genetic manipulation of trypanosomes
will reveal whether (GR)ESAG5 proteins are surface-exposed
or secreted proteins, as predicted by protein sequence
analysis, and whether ESAG5 plays a role in the survival of
T. b. rhodesiense in the human bloodstream. We raise the
idea that (GR)ESAG5 proteins may be intimately linked
in to the mechanism of serum component recognition,
uptake and (in some species) resistance in trypanosomes.
The new telomere sequence data obtained by TAR cloning
[22,23] will greatly facilitate the design and interpretation
of relevant experiments. Testing whether ESAG5 or any of
the GRESAG5 proteins could interact with host lipoprotein
particles in a manner similar to PLTP might be a first step
towards establishing whether they play any role in lipid
scavenging, intracellular lipid metabolism or modulation of
host innate immunity.
In many organisms with BPI/LBP/PLUNC-like domain
proteins, their functional studies are complicated by the
presence of multiple copies of a gene or paralogues that
may compensate for the loss of function of a single gene.
Investigation of ESAG5 function faces a similar challenge.
However, studying the function of the related GRESAG5
proteins in organisms with a single family member, such as
Leishmania, might provide new insights into the function of
ESAG5 in T. brucei. Finally, dissection of the evolutionary
relationships between proteins with a BPI/LBP/PLUNClike domain and measurement of biochemical activities of
hitherto uncharacterized family members will no doubt
contribute to a deeper understanding of their biology from
trypanosomes to humans.
Acknowledgements
We thank Samantha Griffiths for the image in Figure 1(A) and Athina
Paterou for comments on the paper.
Funding
Work in K.G.’s laboratory is supported by the Wellcome Trust and EP
Abraham Trust. A.R.B. was the recipient of a studentship from the
Biotechnology and Biological Sciences Research Council.
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Received 12 January 2011
doi:10.1042/BST0390966