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From the Several pathogenic microorganisms, ranging from viruses to
protozoa, evade the mammalian immune response by periodically changing
the molecular constituents on their surface, a phenomenon called
antigenic variation(1) . Two pathogens particularly adept at
using this strategy are Borrelia hermsii, a prokaryotic
spirochete that causes relapsing fever in the western United States and
Canada(2) , and African trypanosomes, eukaryotic protozoan
parasites that cause sleeping sickness in Africa(3) . B.
hermsii is transmitted by ticks and African trypanosomes by tsetse
flies. Both of these organisms circulate extracellularly in the
bloodstreams of their mammalian hosts and keep one step ahead of their
hosts' immune systems by periodically switching the major protein
on their surface. Recent studies demonstrate that the molecular
mechanisms responsible for antigenic variation in these two pathogens
share many features. The first two sections of this review compare
these features, and the third section illustrates that their mechanisms
of immune evasion resemble in some ways the mechanisms utilized by the
immune system to attack them.
Antigenic Variation in B. hermsii Spirochetes constitute a separate phylum of eubacteria
distinguished by their helical shape and the presence of multiple
flagella that lie in the periplasmic region between the inner and outer
membranes, rather than beyond the outer
membrane(4, 5) . The most extensively characterized
spirochetes are B. hermsii and Borrelia burgdorferi,
the agent responsible for Lyme disease. These species of Borrelia have a linear DNA molecule of about 1 million bp, ( At least 40 antigenically distinct serotypes can arise from a single
cell of B. hermsii, each of which appears to be due to the
expression of a different surface Vmp(12) . New serotypes occur
spontaneously within the bacterial population at a frequency of
10 The vmps studied to date are located on linear plasmids of
28-32 kb(12, 16) . In a given bacterium all vmps are transcriptionally silent except for one, which can be
activated by at least two different mechanisms. In one activation
mechanism, typified by the switch from B. hermsii serotype 7
to serotype 21, the silent vmp21 on one linear plasmid is
duplicated, and the duplicated copy is transposed downstream of a
promoter at a telomere-linked expression site on another linear
plasmid(12, 16) . The vmp7 originally in this
expression site is displaced by the incoming vmp21 and
disappears from the genome. The genetic information of vmp7 is
not eliminated from the genome by the displacement, however, because it
was itself duplicated from a silent vmp7 donor gene located on
another plasmid. The boundaries of the duplicated regions usually are a
short common sequence just upstream of the start codons of silent and
expressed genes and a 200-bp conserved sequence located downstream of
their stop codons(16, 17) . This duplicative
translocation is equivalent to a gene conversion event involving the
unidirectional, nonreciprocal transfer of nucleotide sequences to a new
site from a donor gene that remains unchanged after the
transfer(18) . A second activation mechanism is associated
with a frequently detected switch from serotype 7 to serotype
26(15) . In this case, a pseudogene version of vmp26,
called
Figure 1:
Diagrams of
the expression sites for the vmp genes of B. hermsii (A) and the vsg genes of African trypanosomes (B). In both panels rectangles represent genes, blackcircles are telomeres, redflags are promoters, and redhorizontalarrows are RNAs. A, in this example, taken from (19) ,
the expression of B. hermsii vmp7 is initiated by a joint
duplication of vmp7 and the downstream pseudogene
Variants of the Vmp26 amino acid sequence can be
generated by post-switch mutations of the expressed vmp26 within its expression site via a mechanism thought to introduce
mutations into other expressed vmp genes as well(19) .
This additional Vmp diversity appears to be caused by partial gene
conversions that are templated from Vmp pseudogenes located directly
upstream of the expression site and oriented in both directions (Fig. 1A). Sequence determinations of seven different
expressed vmp26 gene sequences present in Vmp26 relapse
populations following infections of mice with single cells of serotype
7 revealed that specific nucleotides within vmp26 were
replaced with nucleotides within 10-20-bp blocks that appeared to
be derived from the upstream pseudogenes(19) . Furthermore, the
experimental evidence suggested that the mutations occurred after vmp26 was placed in the expression site and that they appeared
as early as 2-3 days after the switch. It is not known whether
these mutations continue to accumulate asymptotically to the point
where few if any bacteria contain an expressed vmp26 unchanged
in sequence, but the rate of new mutations did appear to decline later
in the infection. Remarkably, the mutated vmp26 genes occurred
in Vmp26 populations succeeding serotype 7 but not in Vmp26 populations
following serotype 17, indicating that the mutation phenomenon might be
specific for the intramolecular deletion that accompanied the switch
from expression of vmp7 to vmp26. A similar deletion
is not associated with the switch from expression of vmp17 to vmp26; rather, that switch is accompanied by a duplicative
transposition. Thus, the two known mechanisms by which B.
hermsii can activate a silent vmp are a gene conversion
between linear plasmids and a gene deletion within a linear plasmid.
Imposed on top of these two mechanisms is a third mechanism by which
the diversity of a rearranged vmp can be increased via
post-switch mutations templated from pseudo-vmps located on
the same linear plasmid as the expression site.
Antigenic Variation in African Trypanosomes Several African trypanosome species have been shown to evade
their hosts' immune responses by undergoing antigenic
variation(3) , although most of the studies have been conducted
on the Trpanosoma brucei subspecies or on Trpanosoma
equiperdum. In the bloodstream of their mammalian hosts each
trypanosome is coated with about 10 Mature VSGs possess
about 450 amino acids after the removal of a signal peptide of
20-30 amino acids and a C-terminal hydrophobic tail of about 20
amino acids. The last 50 amino acids of mature VSGs are rich in
cysteines and display some sequence similarities that permit VSGs to be
classified into two or three groups(3) . The C terminus itself
is linked to a phosphatidylinositol anchor so these C-terminal 50 amino
acids are likely to be in close contact with the membrane and not
exposed on the surface. The three-dimensional structures of the
N-terminal variable domains (about 380 amino acids) of two
antigenically distinct VSGs have been determined by x-ray
crystallography and found to be strikingly similar despite very little
sequence similarity(25) . This finding suggests that all VSGs
may possess similar three-dimensional structures, an unexpected result
given the variability in VSG sequences but perhaps not too surprising
since all VSGs must pack tightly together on the surface. It is not
known how many antigenically distinct VSGs potentially can be produced
from a single trypanosome, but more than 100 serotypes have been
detected in a single infection(26) . The estimate of 1000 vsgs in the genome and demonstrations that new genes can be
created (see below) suggest the maximum number is much higher. The
frequency at which a new VSG coat arises ranges from 10 The activation of a new vsg and formation of a
new serotype often are associated with one of three types of gene
rearrangements(3, 32, 33) . The best studied
rearrangement is the duplicative transposition of a silent, donor vsg from either an interior chromosomal location or a
telomeric location to a telomere-linked expression site, displacing the vsg already at that site (34) (Fig. 1B). This gene conversion can be
either an inter- or intrachromosomal event. In many cases it is
mediated on the 5` side by homologous recombination between a few
copies of a 76-bp repeat upstream of the donor gene and hundreds of
copies of this same repeat in the expression site. On the 3` side of
the duplication, homologous recombination often occurs between the
segments of sequence similarities in the C-terminal coding regions or
in the 3`-untranslated regions(35, 36) . A variation
on this gene conversion mechanism is a telomere conversion whereby one
entire telomeric region including its expressed vsg is
replaced with a duplicated copy of another telomeric region and its
silent vsg, followed by activation of the duplicated silent
gene(37, 38, 39) . The third kind of
rearrangement is telomere exchange in which two telomeres and their
associated vsgs undergo a reciprocal exchange, activating one
gene and inactivating the other(40) . In addition to these DNA
rearrangement events, still other vsgs that are already
telomere-linked can be activated in situ without apparent DNA
rearrangement via an unknown mechanism. Thus, to be expressed it is
necessary, but not sufficient, for a vsg to be located near a
telomere. Furthermore, since with very few exceptions (41, 42, 43) one and only one telomere-linked vsg is expressed at a time, other events that are not
understood must activate one telomere-linked expression site and
silence all of the others. It has been suggested for both B.
hermsii(19) and African trypanosomes (45) that
nucleotide modifications might be involved in regulating the expression
of the vmp or vsg once it has reached its respective
telomere-linked expression site. B. hermsii has a dam methylation system (44) that possibly could methylate
silent vmp genes(19) , whereas trypanosomes have an
unusual glycosylated hydroxymethyluracil at some positions within
silent telomere-linked vsgs but not at the corresponding
positions within actively transcribed telomere-linked vsgs(45) . Proof that these modifications in either B. hermsii or trypanosomes regulate gene expression remains to
be provided. A dramatic outcome of some vsg gene
conversions in trypanosomes is the formation of mosaic, or composite, vsgs that are derived from two or more donor vsgs(46, 47, 48) . In some cases the
newly created vsg is generated during the duplication event
via multiple crossovers among related donor pseudogenes containing
internal termination codons, resulting in a functional mosaic vsg with an open translation reading frame in the expression
site(47, 48) . In other cases, the newly duplicated vsg in the expression site contains internal sequences derived
from unknown regions of the genome(46) . In still other
examples, the newly duplicated vsg clearly is derived from a
single specific donor gene, but it has point mutations distributed
primarily across the middle one-half of the coding region at a
frequency of 1-3% of the base pairs(36, 49) . In
contrast to the templated vmp mutations of B. hermsii described above, these point changes do not appear to be templated
from elsewhere in the genome. One trypanosome example has been reported
in which the newly duplicated vsg is a mosaic of three closely
related donor genes and also has three point changes that are not
derived from the donor genes(48) . A general feature of
Trypanosomatids is that many of their genes are transcribed into large
polycistronic precursor RNAs, which are processed into individual mRNAs
by internal cleavages followed by addition of a 39-nucleotide spliced
leader to the 5` ends and polyadenylation at the 3` ends(32) .
This unusual property is exemplified by transcription of at least some
telomere-linked vsg expression sites (Fig. 1B). The promoters for two specific vsg expression sites have been found to occur 60 and 45 kb,
respectively, upstream of the vsg(50, 51, 52) . Between the
promoter and the vsg in each case is a series of expression
site-associated genes (ESAGs) that are co-transcribed with the vsg and that are members of as many as seven different gene families.
All vsg expression sites examined carefully contain at least
one ESAG. None of the ESAGs encode other VSGs, although pseudogenes or
partial genes for VSGs occasionally have been detected in the vicinity
of an expression site(53) . The steady state levels of the
mRNAs for the ESAG products and the VSG differ by as much as
100-fold(54) , indicating that expression of these
co-transcribed genes is regulated at least in part by
post-transcriptional events such as pre-mRNA processing and/or mRNA
stability.
Similarities with the Mammalian and Avian Immune Systems Many reviews have summarized the gene rearrangements
associated with the creation of vertebrate
immunoglobulins(55, 56) . Briefly, in mammals
individual genes responsible for the primary antibody repertoire are
assembled by intrachromosomal DNA rearrangements that juxtapose a
member of the variable region (V) genes adjacent to a member of the
diversity (D) and/or joining (J) elements and a representative of the
constant region gene family. The diversity of this repertoire is
enhanced by the multiplicity of V genes and the D and J elements
(combinatorial diversity), and imprecision in the duplex DNA joining
process (junctional diversity). Several features of these general DNA
rearrangements leading to antibody diversity are similar to those
discussed above for B. hermsii and African trypanosomes. For
example, the intrachromosomal deletion of sequences that often
accompanies the juxtaposition of a V gene and a D or J element to
create an open translation reading frame across their junction is
reminiscent of the vmp7 and However, the most striking similarity of these three
gene systems (two responsible for antigen variability in a pathogen and
one for antibody diversity in the host) is the fact that in each case
there are built-in mechanisms to introduce point mutations that
increase the number of their potential gene products to a virtually
infinite number. In the case of immunoglobulin genes, these somatic
mutations in the rearranged V gene, coupled with antigen selection,
often drive maturation of the immune response to the production of
antibodies with an improved affinity for the antigen(56) .
Nevertheless, as many as 75% of these mutations appear to have no
effect on affinity, suggesting that they simply are part of an
intrinsic mutational process(57, 58) . One way to
distinguish between somatic mutations selected for their increased
antigen affinity and those that merely are carried along by
``hitchhiking'' is to examine mutations in associated
passenger transgenes that have not been selected for their improved
antigen binding(56) . Another way is to analyze mutations in
the flanking regions of antigen-selected V genes where the nucleotide
changes are not expected to be selected for increased antigen
binding(59, 60, 61) . Both approaches have
been used and generated rather similar results (70). In B. hermsii and trypanosomes there is no evidence that the mutations are
selected for an improved property of their corresponding surface
proteins. Table 1compares 71 somatic mutations detected in a
passenger transgene within the immunoglobulin gene system (56, 57) and 74 non-templated mutations detected in
three separate trypanosome vsg duplications from the same
donor MVAT5 vsg gene(36) . This comparison shows that
in both antibody genes and trypanosome vsgs, the mutational
process exhibits a strong bias in the coding strand for transitions
over transversions and favors purine transitions over pyrimidine
transitions. In addition, in both systems thymines in the coding strand
have the least likelihood of undergoing a mutation (only 10% of the
mutations for antibody genes and 5% for vsg genes). This
strand-specific bias of the mutations almost surely provides a clue
about the molecular mechanism responsible for the mutations, but
unfortunately despite substantial effort, it is not clear what that
mechanism is. Nevertheless, for both systems several models come to
mind, including the possibilities that the mutations are (i) associated
with the strand-specific process of
transcription(62, 63) , (ii) initiated by nicks at one
end of the mutated region followed by subsequent error-prone 5` to 3`
DNA repair (36, 56) , or (iii) generated by the
presence of nucleotide modifications(45) .
An indication
that the molecular mechanisms of the antibody and trypanosome vsg mutational systems are not completely identical is the distinctive
difference in the mutations that occur from cytosine in the coding
strand (redbox in Table 1). In the antibody
system most detected cytosine mutations are transitions to thymines
(80%), whereas only one of the 22 cytosine mutations in the vsg system is a transition to a thymine. The remaining 21
substitutions are transversions to adenines (68%) or guanines (27%).
Thus, in the antibody system cytosine to thymine transitions are
clearly favored, whereas in the vsg system they are not
preferred. Another slightly less dramatic difference in the two systems
is the adenine mutations. In the antibody system 6 of the 24 adenine
mutations (25%) are transversions to thymine, whereas in the vsg system, none of the 18 mutated adenines convert to a thymine.
Although the total number of mutations available for analysis in both
systems is not large (71 and 74 for the antibody and vsg systems, respectively), the fact that in the antibody system the
mutational proportions shown in Table 1compare favorably with a
compilation of more than 1000 naturally occurring base substitutions
detected in rearranged V genes (56) suggests that these
differences in the two systems indeed do reflect a difference in at
least part of the molecular mechanism responsible for them. As
described above and in contrast to the non-templated base substitutions
in the duplicated trypanosome MVAT5 vsg gene, the mutations in vmp26 of B. hermsii appear to be derived from
upstream pseudo-vmps(19) . Interestingly, an analogy
to this situation exists in, not the mammalian immune system, but the
immune system of birds(64, 65) . In avian B cells a
single V gene for the light chain immunoglobulin is activated by an
intrachromosomal deletion that positions it beside a J element
preceding a constant region gene. Upstream of this V gene lies a group
of pseudo-V genes, oriented in either direction, that donate
homologous, but non-identical, segments of 10-100 bp as
replacements within the activated V gene, thereby diversifying the
amino acid sequence of the encoded antibody. Thus, both B. hermsii and the avian immune system increase diversity by small partial
gene conversions templated from upstream pseudogenes, whereas African
trypanosomes and the mammalian immune system increase the diversity via
non-templated mutations.
Volume 270,
Number 14,
Issue of April 7, 1995 pp. 7783-7786
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
INTRODUCTION
Antigenic Variation in B. hermsii
Antigenic Variation in African Trypanosomes
Similarities with the Mammalian and Avian Immune Systems
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)as
well as circular plasmid-like DNAs and several small linear DNA
molecules of 10-200 kb that are called linear plasmids or
minichromosomes(4) . Furthermore, these organisms are polyploid
with each cell containing between 10 and 20 copies of the large
chromosome and each of the linear plasmids(6) . The extreme
ends, or telomeres, of both the large linear chromosomal DNA molecule
and the linear plasmids are covalently closed
hairpins(7, 8) . The linear plasmids contain genes
encoding the outer membrane lipoproteins, called the variable major
protein (Vmp) in the case of B. hermsii and the outer surface
protein (Osp) for B.
burgdorferi(9, 10, 11) . In B.
burgdorferi, circular plasmids also can encode Osps, and as many
as four different osp genes can be expressed simultaneously.
In B. hermsii only one vmp at a time has been found
to be active(12) . Since antigenic variation is much better
understood in B. hermsii than in B. burgdorferi, the vmps of B. hermsii will be the focus of this review. 
-10
per generation time
of about 6 h (13) . The different Vmps whose genes
have been sequenced fall into two size categories, one group of Vmps
that have 360-370 amino acids and another group containing about
210 amino acids (14) . No functional differences between these
two groups have been reported. As a group, the genes for the smaller
Vmps display 70-80% identity, with the most similarity occurring
in the N and C termini coding regions and the least similarity within
the middle region(15) . Collectively, the small Vmp genes and
the large Vmp genes have 40-50% identity over the length that
they can be compared. Presumably, the unique antigenicities of the
different Vmps are conferred by the segments exposed on the outer
surface of the bacterium that differs in sequence and structure.
vmp26, is located immediately downstream of vmp7, both in the telomere-linked expression site of one
linear plasmid (Fig. 1A), and in another linear plasmid
containing the correspondingly linked donor genes. The silent version
of vmp26 lacks the first two codons of the expressed vmp26 but has at this position the same 20 nucleotides that
follow the first two codons of vmp7. In the switch from vmp7 to vmp26 the 20 nucleotides common to the two
adjacent genes serve as sites for a homologous recombination event
within the expression site that deletes the expressed vmp7 as
a transient circular DNA segment and positions the first two codons of vmp7 in front of vmp26, creating a functional vmp26 in the same expression site. Thus, an intramolecular
deletion juxtaposes coding regions derived from two genes, generating a
functional composite gene, an event reminiscent of DNA rearrangements
leading to functional antibody genes in the vertebrate immune system
(see below).
vmp26 from one linear plasmid to the indicated
expression site near the telomere of another linear plasmid. RNA
synthesis of vmp7 extends from the promoter to a transcription
termination site between vmp7 and vmp26. The
subsequent intramolecular deletion of most of vmp7 places its
first two codons in front of, and in frame with, the coding sequence of vmp26 and creates a functional vmp26 in the
expression site. With time, templated point changes are donated to vmp26 from a cluster of other pseudo-vmps located
upstream of the promoter for the expression site. B, VSG
switching in African trypanosomes often is caused by the duplicative
transposition of a vsg to a telomere-linked expression site
and the concomitant deletion of the previous vsg at that site.
The boundaries of the duplicated segment in the expression site are
within several hundred 76-bp repeats located upstream and within the
conserved C-terminal coding or 3`-untranslated regions located
downstream. Sometimes the gene duplication is accompanied by the
formation of a mosaic vsg and/or non-templated point changes
in the VSG coding region. Transcription of the expression site is
initiated at a promoter located 45-60 kb upstream of the vsg and extends through a cluster of expression site-associated genes
(ESAG cluster) that are members of as many as seven different gene
families. Two ESAG families encode transferrin binding proteins and
adenylate cyclases (66, 67, 68) . The
functions of the other ESAGs are not known. The polycistronic pre-mRNA
is processed by 5` spliced leader addition and 3` polyadenylation to
generate individual mRNAs for the ESAG products and the
VSG.
molecules of a
glycolipid-anchored glycoprotein called the variant surface
glycoprotein or VSG. Antigenic variation of VSGs has several of the
features described above for the B. hermsii Vmps but with an
apparent increase in complexity. At 3.7 
10 bp, the
African trypanosome haploid genome is 30-40 times larger than
that of B. hermsii(20) . The diploid organisms contain
about 20 chromosomes, whose DNAs range from several hundred to several
thousand kb, and 100 or more linear minichromosomes, whose DNAs are
50-150 kb (21) . Within the trypanosome genome are as
many as 1,000 different vsgs(22) , some of which are
closely related isogenes but only one of which is usually expressed at
a time. The transcriptionally silent vsgs are scattered about
all of the chromosomes, including the minichromosomes which appear to
be repositories for unexpressed vsgs(23) . As many as
20 different potential expression sites for these vsgs may
exist, all of which are situated near a telomere(24) . These
potential expression sites appear to be located on most, if not all, of
the chromosomes except the minichromosomes.
to 10
per cell doubling time of 5-6 h in
the blood(27) . The appearance of new VSGs normally does not
follow a preprogrammed order, although some VSGs do tend to appear
early in an infection whereas others usually occur
later(28, 29, 30, 31) . There is no
evidence that the immune system of the host induces the VSG switches,
but it does contribute to an environment in which new, and temporarily
unrecognized, serotypes can prosper, giving rise to a new wave of
parasitemia.
vmp26 fusion
described above for B. hermsii. Likewise, the creation of
functional mosaic vsgs in trypanosomes from two or more donor vsgs is similar to the multi-segmental nature of functional
antibody genes.
)
I thank A. G. Barbour, A. D. Klion, and L. V.
Kirchhoff for reading the manuscript.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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