REVIEWS

The evolutionary conundrum of

pathogen mimicry
Nels C. Elde and Harmit S. Malik
Abstract | Evolutionary conflicts involving mimicry are found throughout nature. Diverse
pathogens produce a range of ‘mimics’ that resemble host components in both form and
function. Such mimics subvert crucial cellular processes, including the cell cycle, apoptosis,
cytoskeletal dynamics and immunity. Here, we review the mounting evidence that mimicry
of host processes is a highly successful strategy for pathogens. Discriminating mimics can
be crucial for host survival, and host factors exist that effectively counteract mimics, using
strategies that combine rapid evolution and an unexpected degree of flexibility in
protein–protein interactions. Even in these instances, mimicry may alter the evolutionary
course of fundamental cellular processes in host organisms.

Divergent evolution
The appearance of increasing
differences in features between
different lineages.
Convergent evolution
Independent acquisition of
similar features in different
lineages.
Perfect mimic
A pathogen factor that takes
on the exact characteristics of
a host factor and confers an
advantage to the pathogen
from the resemblance.
Fitness
The replicative or reproductive
success of an entity.
Imperfect mimic
A pathogen factor with some
characteristics of a host factor
but also one or more distinct
functions that confer additional
advantages to the pathogen.
Division of Basic Sciences,
Fred Hutchinson Cancer
Research Center, Seattle,
Washington 98109, USA.
Correspondence to N.C.E.
e-mail: nelde@fhcrc.org
doi:10.1038/nrmicro2222
Published online
6 October 2009
Pathogens often take on features of their hosts to gain evo-
lutionary advantages, and diverse strategies of molecular
mimicry are increasingly being recognized. For example,
over time the genomes of some RNA viruses can come to
resemble genomic features of host populations. As influ-
enza viruses adapt to humans, the frequencies of CpG
dinucleotides in their genomes are reduced to levels con-
sistent with those of human genomes1. In this case, mim-
icry of host genome composition may confer an advantage,
because these viruses are less likely to activate the host
immune responses that would be triggered by the recog-
nition of foreign nucleic acids. Conversely, some viruses
take on characteristics of a host specifically to trigger host
responses. For instance, when poxvirus particles are pack-
aged they become covered in host phospholipids, thereby
taking on the appearance of apoptotic cellular fragments;
these fragments are engulfed by neighbouring cells,
therefore this mimicry might facilitate viral spread2.
Here, we consider the evolutionary dynamics between
pathogen-encoded protein ‘mimics’ and the host factors
that they imitate. We define mimics as pathogen-encoded
factors that resemble host factors in order to co-opt or dis-
rupt host functions to the pathogen’s advantage. Pathogen
mimics can evolve by two mechanisms. Divergent evolution
of the mimic after horizontal gene transfer from a host
genome3,4 (FIG. 1) might be detected by sequence similarity
to the model, although many cases are obscured by the
rapid evolution of pathogens or their long co-evolutionary
histories with hosts, which leave little or no trace of the
common origins of the genes in question. Alternatively,
mimics can arise by convergent evolution, which occurs
when non-homologous factors encoded by pathogens
independently evolve features of host components5,6
(FIG. 1). Such mimicry is generally harder to detect, as it is
made evident only by more detailed analyses that reveal
functions of pathogenic factors that are similar to those
of host factors, despite the different protein structures7.
Regardless of whether mimics arise through diver-
gent or convergent evolution, most mimics bear only
a faint resemblance to the factors that they imitate (see
Supplementary information S1 (table)).
When defining mimicry, it is useful to consider two
additional categories to describe these factors more pre-
cisely. Perfect mimics co-opt host functions to favour patho-
gen fitness. Imperfect mimics resemble host components but
perform functions that are distinct from those of the host
factors that they model and that are for the benefit of the
pathogen. The same terminology is often used to describe
mimicry at the level of ecosystems8 (BOX 1). Extended to the
molecular level, these definitions are roughly analogous
but include biochemical functions in addition to mim-
icry based strictly on physical appearances. Distinguishing
between types of mimicry is important, because the evo-
lutionary potential of hosts to counteract mimicry can
hinge on the types of mimics that they face. Differing lev-
els of conservation among mimics is also an important
aspect of the evolutionary dynamics of mimicry. In some
cases it may seem that exactly mimicking a host factor
would be the most advantageous option for a pathogen.
Virus-encoded proteins that mimic host proteins could
potentially work to a pathogen’s advantage, even as car-
bon copies. However, the high degree of divergence of
imperfect mimics reflects the fact that viruses often gain
greater advantages when these factors diverge. At least a

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REVIEWS

a Divergent evolution

Host
Host gene eIF2α
(e.g. eIF2α) Horizontal gene transfer

Pathogen
Pathogen gene Mimic K3L

eIF2α 9('99091956,$(0*$<96//(<11,(*0,//6(/6555,56,1./,5,*51(&999,59'.(.*<,'/6.55963((
K3L $*'9,.*59<(.'<$/<,</)'<3+)($,/$(69.0+0'5<9(<5'./9*.79.9.9,59'<7.*<,'91<.50&5+4

RhoGAP

b Convergent evolution
Host Arg85
Host gene
(e.g. RhoGAP)

ExoS

Pathogen Arg146
Pathogen gene Mimic
(unknown)

Figure 1 | The evolutionary origins of mimics encoded by pathogens. The diagrams show simple phylogenetic
relationships between host factors and their mimics that are derived by either divergent or convergent evolution.
Nature Reviews Purple
| Microbiology
segments represent the accumulation of mutations as the genes diverge or converge. Green segments represent regions
with sequence or structural similarity between host and pathogen genes, as a result of convergent evolution. a | In the
case of divergent evolution, mimics often arise from horizontal gene transfer events. For example, K3L is a
poxvirus-encoded mimic of eukaryotic translation initiation factor 2 subunit-α (eIF2α; see main text for details). Ribbon
representations of K3L and eIF2α, based on crystal structures (Protein Data Bank entries 1LUZ and 2A1A)79,80 show similar
arrangements of β-strands (orange) in mimic and model. A sequence alignment shows that eIF2α and K3L also share
sequence homology, reflecting a common origin before their divergence; orange arrows indicate sequences that form
β-strands. Pathogens that are less constrained for genome size, such as bacteria and double-stranded DNA viruses, are
more likely to retain horizontally transferred genes and therefore have a higher likelihood of gaining mimics by this
evolutionary route. b | Mimics that arise by convergent evolution independently gain features or functions that resemble
those of hosts. Rho GTPase-activating protein (RhoGAP) is mimicked by a range of pathogens107 and even parasites108.
These mimics seem to converge on host functions, because there is no trace of shared sequences or notable structural
features. Ribbon representations show the Pseudomonas aeruginosa-encoded factor ExoS, a mimic of RhoGAP (Protein
Data Bank entries 1TX4 and 1HE1)107,109. The structures show similarly positioned, functionally important arginine residues
that are shared between the mimic and the host factor, but there are no other signs of notable similarity.

Adaptation
A feature that becomes
prevalent in a population
because of a selective
advantage that it conveys.
Natural selection
The differential survival or
reproduction of classes of
entities that differ by one or
more characteristics.
partial explanation for such adaptations in mimics is that
host factors commonly fall under the regulation of cel-
lular processes that control their activity, whereas avoid-
ing cellular regulation can be key to effective mimicry for
pathogens. Imperfect mimicry is therefore generally more
advantageous to pathogens, because effective mimics do
not just mirror host functions but also subvert cellular
processes to favour pathogen fitness.
Although imperfect mimicry can strongly favour a
pathogen, the differences between mimics and the factors
that they model can also give hosts an immunological or
evolutionary foothold for discriminating mimics. From an
evolutionary perspective, host factor adaptations that dis-
favour mimics or reinforce host functions will be highly
advantageous and favoured by natural selection. However,
rapid evolution of pathogens can lead to the emergence of
new variants of mimics that can re-establish an activity or
interaction that again favours the pathogen. In this man-
ner, mimics and host factors can dynamically evolve in
genetic conflicts resembling ‘arms races’ (BOX 2), with each
side gaining only temporary advantages. That said, many
highly conserved host factors that are targeted by mimics
have a restricted potential to adapt, because they carry out
essential functions and are subject to tight evolutionary

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Box 1 | Mimicry: from ecosystems to molecules

There are some fundamental similarities between the strategies used in mimicry that has been long recognized in
ecological settings and pathogen mimicry that is operating in the context of infections. In the nineteenth century Henry
Bates first articulated the argument that mimicry constitutes a selective advantage, using the example of edible Brazilian
forest butterflies that adapt in appearance to imitate unpalatable butterflies. In this manner, butterfly mimics deceive
their predators, which avoid them as meals. Mimicry therefore serves an essential role in the survival of these edible
butterflies. But it also imposes a cost on the inedible ‘model’ species of butterflies: as the frequency of mimics increases,
the warning associated with their particular physical appearance fades and both they and the models are more likely to be
sampled as potential meals. Thus, the benefit to the mimic imposes costs on both the model and the predator and forms
the basis of an evolutionary conflict. Mimicry pervades predator–prey interactions, with numerous types of visual,
behavioural and even acoustic mimicry playing parts in these life-or-death encounters97,98.
Examining pathogen mimicry through this lens of antagonistic evolution is a perspective that is useful for gaining a
deeper understanding of the dynamics of these crucial host–pathogen interactions. Costs, benefits and trade-offs are
important considerations in all types of mimicry. Taking an even broader view, mimics across nature exemplify Voltaire’s
observation, “A good imitation is the most perfect originality.”

constraints. This poses an evolutionary conundrum
for hosts, to maintain crucial activities while not being
exploited by pathogenic mimics that are honed to divert
host functions.
Pathogens also face an evolutionary conundrum due
to mimicry. In cases in which host factors are acquired by
horizontal gene transfer, these genes are often exact copies
of host-encoded factors before they then adapt to become
mimics. Such genes can be a burden on the streamlined
genomes of pathogens and are therefore frequently lost,
except in rare cases when an adaptation arises that pro-
vides a useful function to the pathogen and so increases
its fitness. Thus, it is common for host factors that are
acquired by pathogens to adapt to look less like their mod-
els rather than resembling them exactly. The dynamics
of imperfect or inaccurate mimicry is a topic that is also
actively considered in ecology 8,9.
Hosts also pay a price for contending with pathogens,
because expressing immunity-related factors can impose
substantial fitness costs10–12. For hosts, the cost of dealing
with mimicry or other types of pathogen challenges must
be evolutionarily weighed against the cost of mounting
adaptive responses. Similar considerations may dictate
the retention and use of viral mimics. These types of
trade-offs associated with pathogen mimicry are impor-
tant considerations for understanding the dynamics of
host–pathogen interactions involving mimicry.
The evolutionary study of host–mimic interactions
is not just historically informative but also provides an
important perspective for understanding host–pathogen
relationships more generally. For example, the ecologi-
cal concept of mimicry rings, in which unrelated species
acquire common features that confer an advantage, is
directly analogous to mimicry by unrelated pathogens that
target common cellular factors or functions13. The cellular
factors that are modelled by multiple independent mim-
ics therefore represent common cellular weak spots that
are vulnerable to mimicry. under these circumstances,
mimicry is not ‘the sincerest form of flattery’ but is rather
a strategy of evolutionary deception that impinges on
the survival of host species. In this Review, we survey
how pathogenic strategies of mimicry interfere with
all major cellular processes, including cell growth and
survival, cytoskeletal dynamics, membrane traffic
and immune-related functions.
Control of apoptosis and the cell cycle
A common cellular response to pathogenic challenge is to
undergo cell death to limit infection. The ability to block
apoptosis is a potentially crucial advantage for pathogens,
allowing them to promote robust and persistent replica-
tion. Indeed, some viruses use mimicry to counteract
apoptosis (FIG. 2). A common example is viral mimicry
of b-cell chronic lymphocytic leukaemia/lymphoma 2
(bcl-2), a pro-survival host factor that prevents cell
death14. DNA viruses, such as poxviruses and herpes-
viruses, acquired bcl-2 from host transcripts by horizontal
gene transfer 15. These virus-encoded, divergent vari-
ants of bcl-2, called v-bcl-2s, can directly interfere with
apoptotic signalling to promote cellular survival during
infections16–18. Some v-bcl-2s sequester bcl-2 homology 3
(bH3) domain proteins, which would otherwise trigger
the caspase-driven cascades that promote apoptosis19,20.
other pathogen-encoded bcl-2 mimics carry out distinct
functions, such as interfering with innate immune signal-
ling to promote infectivity 21,22. Therefore, it would seem
that general characteristics of the bcl-2-like structure are
useful to a range of pathogens. Not all v-bcl-2s are easily
recognizable as bcl-2 mimics from their sequence alone.
Homology between bcl-2s and v-bcl-2s can be as high
as 30% identity, but some viruses encode anti-apoptotic
factors that have limited or no detectable sequence homol-
ogy to bcl-2. In these cases, structural or functional analy-
ses were required to reveal that they also act like bcl-2
mimics23,24.
In contrast to v-bcl-2s, a viral mimic of the host Golgi
anti-apoptotic protein (GAAP; also known as trans-
membrane bAX inhibitor motif-containing protein 4),
designated v-GAAP, which blocks apoptosis, is nearly
70% identical to the host factor that it models. v-GAAP
counteracts apoptosis for a subset of poxviruses, including
camelpox virus and some strains of vaccinia virus25. little
is currently known about the functional mechanism of
GAAP, and its potentially important role in cellular regu-
lation was initially inferred from the fact that it is mim-
icked by poxviruses. The high conservation of v-GAAP
may reflect its recent introduction into poxviral genomes.
Alternatively, a limited distribution in viral strains may
reflect a cost that is associated with using this mimic, such
that it might have been lost in other viral lineages despite
an older, common origin.

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Box 2 | Genetic conflicts lead to evolutionary arms races
Many conflicts in nature lead to evolutionary scenarios
resembling arms races. Ongoing antagonistic evolution
has been described by the ‘Red Queen hypothesis’ (REF. 99),
a reference to the Red Queen’s statement in Lewis Carroll’s
Through the Looking Glass: “It takes all the running you can
do, to stay in the same place.” Evolutionary arms races are
common to a range of genetic conflicts, including
host–pathogen interactions (see the figure, part a). For
example, if a host immunity factor recognizes some
feature of a pathogenic protein (step 1), variants of the
pathogen factor can arise that are not recognized by
the host factor (step 2). Variants of the host factor that
re-establish the interaction with the pathogenic factor will
then be favoured (step 3), completing a single cycle of this
molecular arms race. When genetic conflicts involve
protein–protein interactions, arms races can occur in a form of rapid evolution called positiveNature
positive selection include elevated rates of non-synonymous changes (N) in gene codon sequences compared with rates
of synonymous (silent) changes (S), as measured by the dN/dS ratio; ratios exceeding 1 are often consistent with positive
selection. Mimicry of host factors by pathogens adds a substantial challenge for hosts in these arms races. Hosts must
avoid mimicry but still recognize mimicked factors in order to stay effective (see the figure, part b).
Another host–pathogen battleground is mimicry for
control of the cell cycle (FIG. 2). Quiescent cells in the G0
phase of the cell cycle may be less conducive to virus pro-
duction than actively dividing cells. Therefore, mimicking
cyclin activity seems to be a viral strategy for promoting
passage through the cell cycle26. Herpesviruses encode sev-
eral types of mimics to disrupt cellular processes and pro-
mote infection27. Some of these viruses are oncogenic and
encode v-cyclins that mimic D-type cyclins, which are cel-
lular factors that promote cell cycle progression. Examples
of such viruses include Kaposi’s sarcoma-associated
herpesvirus (KSHV; also known as human herpesvirus 8)
and murine gammaherpesvirus 68, which are associated
with lymphoma in mice28. like D-type cyclins, v-cyclins
bind and activate cell-cycle-promoting kinases, which
phosphorylate retinoblastoma-associated protein (Rb)
and other factors to facilitate entry into the cell cycle.
v-Cyclins seem to recognize a larger set of substrates
than do host cyclins, potentially giving viruses even more
influence over the cell cycle29,30. Importantly, v-cyclins
also avoid inhibition by cyclin-dependent kinase inhibi-
tors (CKIs) that would otherwise promote quiescence31.
v-Cyclins provide yet another example of pathogen mim-
ics, including perfect mimics, that have evolved to avoid
the cellular regulation that governs host components.
The context in which mimics act is also an important
consideration. For example, in contrast to other v-cyclins
that promote cell cycle progression, KSHV-encoded v-cyclin
can lead to activation of DNA damage checkpoints and
senescence32. Therefore, pathogenic mimics may cause
opposite outcomes depending on when and where they
are deployed. This may reflect the fact that different viruses
gain benefits by altering the cell cycle in opposite ways at
different stages or states in their life cycle.
other herpesviruses, which may be oncogenic33, have
additional factors that influence the cell cycle to their
advantage. Cytomegalovirus protein ul97 mimics the
activity of cyclin-dependent kinases (CDKs) to directly
phosphorylate Rb and promote cell cycle progression34.
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a b
Antiviral Virus protein
protein
Host protein 2
1
Host
protein 1
3 2
Mimic
Reviews
selection. | Microbiology
Signatures of
ul97 acts as a functional mimic of CDK activity and can
even rescue yeast cell cycle progression in a CDK mutant.
like v-cyclins, ul97 avoids regulation by CKIs. This type
of mimicry seems to be widespread, as variants of ul97
are encoded by a large range of herpesviruses35. mimicry
of CDK1 activity by ul97 also promotes nuclear lamin
disassembly, facilitating virus entry into the nucleus36.
Increasingly, other mimics of cell cycle factors are being
recognized from a range of viruses. For example, the
poxvirus orf virus encodes a potential mimic of anaphase
promoting complex subunit 11 (APC11; m. mo and
A.A. mercer, personal communication). This mimic,
called b5l, seems to interfere with the interaction
between APC11 and the rest of the anaphase promoting
complex, disrupting cell cycle regulation to somehow
favour the virus.
Although v-bcl-2s and v-cyclins can, in some cases,
be recognized by their unambiguous homology to host
factors, similar mimics are less commonly observed in the
genomes of pathogenic bacteria, making the identification
of mimics by sequence alone more challenging in bacteria
than in viruses. Such mimics from bacteria may be more
diverged from their host models than mimics from con-
temporary viruses, owing to longer co-evolutionary his-
tories between these bacterial pathogens and their hosts.
However, some bacteria, including Chlamydia trachomatis,
do inhibit apoptosis by targeting bcl-2 family pro-
teins37. Whether bacterial counteraction of apoptosis
involves mimicry, as viral counteraction often does,
remains to be elucidated.
Cytoskeleton and membrane trafficking
one of the most spectacular examples of pathogen mim-
icry is the actin-filament-based propulsion of bacteria
such as Listeria monocytogenes38 (FIG. 2). L. monocytogenes
encodes actin-assembly-inducing protein (ActA),
which contains motifs that mimic the functions of sev-
eral regulatory host proteins, such as WASP (Wiskott-
Aldrich syndrome protein). These host proteins recruit
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a Cytoskeletal dynamics c Cell cycle

E.coli
EspFU
S. Typhimurium

Cyclin
CKI
SptP

CDK v-Cyclin
GTPase p78/83
OFF ON
cycle
UL97 Rb
SopE ER

Baculovirus
RickA d Apoptosis
ActA
R. conorii v-GAAP
Nucleus
L. monocytogenes

b Membrane traffic
L. pneumophila GAAP
C. trachomatis Golgi
GTPase ON stacks
OFF
cycle
Bcl-2
DrrA and LepB
v-Bcl2
Inclusion IncA BH3 proteins

E3 RIDα
Adenovirus

Mitochondria

Host receptors

Figure 2 | Mimics commandeer the cell. Schematic of a cell showing mimics disrupting host processes. a | Pathogens
benefit from controlling the host cytoskeleton, making it a common target of mimicry. TheNature
assembly of actin
Reviews filaments
| Microbiology
to produce cellular features such as filopodia and lamellipodia is commonly hijacked by pathogens. Escherichia coli
and Salmonella enterica subsp. enterica serovar Typhimurium use distinct strategies of mimicry to promote actin
nucleation. SptP and SopE regulate GTPase signalling by cell division control protein 42 (CDC42) and RAC1 to cause
membrane ‘ruffling’ that promotes cellular entry. Mimicry by EspFU (also known Tccp) recruits actin filaments to create
structures at the cell membrane called pedestals, which support extracellular E. coli. Unrelated pathogenic bacteria
and viruses such as Rickettsia conorii, Listeria monocytogenes and baculoviruses independently mimic the actin
nucleation promoting factor WASP (Wiskott-Aldrich syndrome protein) to facilitate their propulsion through the
cytoplasm by filamentous actin structures resembling comet tails. b | Mimics also disrupt membrane trafficking
pathways. Examples include pathogen-encoded factors resembling components that regulate membrane-bound
compartments. Inclusion membrane protein A (IncA), a mimic from Chlamydia trachomatis, has regions resembling
SNARE proteins that are involved in membrane fusion. This mimic is involved in the formation of the inclusion
compartment where C. trachomatis accumulates in cells. Legionella pneumophila encodes DrrA and LepB, mimics that
subvert the RAB1 GTPase cycle to promote the formation of an endoplasmic reticulum (ER)-derived compartment
that is conducive to L. pneumophila replication. Adenoviruses use mimicry of RAB7A by E3 RIDa to alter membrane
traffic to late endosomes in order to downregulate membrane proteins that are involved in immune signalling.
c | Virus-encoded mimics impinge on the cell cycle. D-type cyclins are mimicked by v-cyclins that promote cell cycle
progression but avoid regulation by other cell cycle regulators, such as cyclin-dependent kinase (CDK) inhibitors
(CKIs). UL97 mimics the activity of CDKs to promote the phosphorylation of retinoblastoma-associated protein (Rb)
and other substrates in order to promote cell cycle progression. UL97 also causes the breakdown of the nuclear
lamina to promote herpesvirus replication. d | v-Bcl-2s and viral Golgi anti-apoptotic proteins (v-GAAPs) are
viral proteins that mimic the functions of host Bcl-2 and GAAP, respectively, to inhibit apoptosis and promote viral
replication. Most, but not all, v-Bcl-2s mimic the function of Bcl-2 by counteracting pro-apoptotic, Bcl-2 homology 3
(BH3) domain proteins such as Bcl2 antagonist of cell death (BAD) and BAX. Although Bcl-2 is itself regulated by BH3
proteins, some v-Bcl-2s avoid this form of cellular regulation. The mimic v-GAAP shares the anti-apoptotic function of
its model, in a potential example of perfect mimicry.

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REVIEWS
a Ecological mimicry ring
Model Mimics
Vespula vulgaris Syrphus ribesii Clytus arietis Sesia apiformis
(common wasp) (hoverfly) (wasp beetle) (hornet moth)
b Molecular mimicry ring
Model
Eukaryotic host (WASP) WH1 B GBD PP W C A
Mimics
Rickettsia conorii (RickA) PP W C A
Baculoviruses (p78/83) PP W PP W C A
Listeria monocytogenes (ActA) SS A W C PP PP PP PP
Figure 3 | Mimicry rings in ecological and molecular settings. A comparison
of mimicry rings from an ecosystem and from host cytoplasm. Nature
a | Reviews | Microbiology
Assemblages of
species of varied relatedness but that share common features or patterns are often
observed in nature. The images show a ring of such mimics, each modelling the
common wasp to various degrees. Here, mimicry is thought to deter predation.
b | A mimicry ring of factors from unrelated pathogens that model Wiskott-Aldrich
syndrome protein (WASP). The pathogenic factors show varied degrees of mimicry
according to the subset and arrangement of domains that they share with WASP. In
each instance, pathogens have independently mimicked the WASP protein,
highlighting both its central role in regulating the cytoskeleton and its susceptibility
to pathogen mimicry. A, acidic region; ActA, actin-assembly-inducing protein;
B, basic domain; C, central region; GBD, GTPase-binding domain; PP, polyproline
domain; SS, signal sequence; W, WASP homology 2 region; WH1, WASP homology 1
region. Wasp and mimic images courtesy of P. Wilkins, Peregrine Productions, UK.
actin-nucleating factors, such as the actin-related pro-
tein complex 2/3 (Arp2/3). ActA contains a domain with
limited homology to the WASP homology 2 domain in
WASP as well as seemingly scrambled central and acidic
regions (FIG. 3). The middle region of ActA contains pro-
line-rich motifs with sequence similarity to those of the
host cytoskeletal proteins zyxin, vinculin and palladin.
unlike the v-bcl-2s described above, which are products
of single gene acquisition events, ActA may be the prod-
uct of multiple gene transfers and acquired distinct func-
tions that tailor its actin-nucleating activity by imperfect
mimicry. In this sense, ActA might also be considered
a ‘chimeric mimic’, cobbling together segments from
different host proteins for optimal subversion of the
cytoskeleton. by targeting ActA to the bacterial surface
in a polarized manner, L. monocytogenes drives actin
polymerization to promote its movement through the
cytoplasm, which facilitates bacterial spread. Rickettsia
conorii, which is distantly related to L. monocytogenes,
produces RickA, a factor that also mimics WASP to
nucleate actin polymerization and propulsion39,40. RickA
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© 2009 Macmillan Publishers Limited. All rights reserved
was acquired independently from ActA and has a more
canonical, WASP-like WCA domain (which consists of
a central and an acidic region and a WASP homology 2
domain) (FIG. 3).
In contrast to these bacteria, enteropathogenic
Escherichia coli cultivates an extracellular lifestyle, but
it uses mimicry to hijack actin polymerization to its
advantage nonetheless41,42 (FIG. 2). In this case, the bac-
teria inject the protein EspFu (also known as TccP) into
host cells through a type III secretion system. EspFu
consists of several repeated motifs that mimic an auto-
inhibitory interaction of WASP to promote its activation.
This mechanism evolved completely independently from
those of ActA and RickA and may have arisen through
convergent evolution, given the complete lack of sequence
similarity with WASP. Actin polymerization promoted
by EspFu leads to the formation of structures on epi-
thelial cells called pedestals, which promote survival
of pathogenic E. coli in the intestine.
Pathogens can also mimic other host regula-
tory functions to modulate cytoskeletal activity and
gain distinct evolutionary advantages (FIG. 2). These
include Salmonella enterica subsp. enterica serovar
Typhimurium, which also uses a type III secre-
tion system to translocate pathogenic proteins into
the host cytoplasm. one such factor, SptP, modulates the
GTPases cell division control protein 42 (CDC42) and
RAC1 by mimicking GTPase-activating protein activity.
At the same time, SptP acts as a tyrosine phosphatase to
further mimic host signalling 43. The phosphatase func-
tion of SptP was acquired by horizontal gene transfer,
whereas its role in GTPase modulation arose conver-
gently 7. Therefore, different functions of a single patho-
gen mimic can arise by different means. Interestingly,
SptP seems to counterbalance the guanine nucleotide
exchange factor activity of other mimics encoded by
S. Typhimurium, including SopE44. Together, SptP and
SopE finely manipulate host signalling by complex
means in order to influence cytoskeletal dynamics and
promote bacterial internalization into the cell.
An additional family of bacterial effectors contain-
ing WXXXE motifs mimic GTPases or their regulators
and can include targeting motifs that resemble those
found in the host factors45,46. For example, SifA is a
WXXXE-containing factor from S. enterica that may
use mimicry to influence the GTPase RHoA, a regula-
tor of actin assembly. SifA contributes to the tubulation
of phagosomes containing bacteria47,48, which produces
compartments (known as Salmonella-induced filaments)
that are important for pathogenesis.
using mimicry to control the cytoskeleton is not
limited to bacteria49. Poxviruses encode F11l, a factor
that interacts with RHoA through a region mimicking
the interface with Rho-associated kinase50. F11l is an
essential factor for vaccinia viruses, promoting host cell
motility and possibly also facilitating viral motility by
affecting both actin and microtubule dynamics in the
cell51,52. Herpesviruses also interfere with Rho-related
signalling to alter cytoskeletal dynamics at several
stages of the viral cycle53. In addition, baculoviruses
encode the factor p78/83, which mimics domains of
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IL
IFN
D7L
B18R
Toll-like receptors
IFN receptor IL receptor
A46R TcpB
E3L
K3L TcpC TIpA
dsRNA PKR elF2α
P P
Poxvirus B. melitensis
E. coli
S. Typhimurium
Figure 4 | Mimics interfere with immunity factors. Vaccinia viruses
Nature and |other
Reviews Microbiology
poxviruses encode a range of mimics to disrupt immune functions. These include B18R
and D7L, factors that mimic interferon and interleukin receptors, respectively. By
secreting soluble mimics of receptors, poxviruses disrupt immune signalling. Poxviruses
also encode E3L and K3L, which are mimics that interfere with important components of
innate immunity, including the antiviral protein kinase R (PKR). Escherichia coli,
Salmonella enterica subsp. enterica serovar Typhimurium and Brucella melitensis produce
mimics of Toll-like receptor domains to subvert another component of innate immune
signalling. Poxviruses also target the same Toll-like receptor domain with mimics110,
forming part of another mimicry ring.
WASP to recruit Arp2/3, promoting actin assembly in
the insect host cells54. It is striking, from an evolutionary
perspective, that pathogens as diverse as Gram-negative
and Gram-positive bacteria as well as viruses independ-
ently mimic WASP proteins to modulate actin assembly.
In this regard, mimics from unrelated pathogens resem-
ble the mimicry rings that are observed in ecosystems, in
particular in populations of butterflies and other insects
(FIG. 3). Thus, diverse pathogens, exposed to the same host
cytoplasm, independently arrived at related strategies
of mimicry to favour their dissemination.
Pathogens also mimic factors that are involved in reg-
ulating the transport and identity of membrane-bound
compartments (FIG. 2). Inclusion membrane protein A
(IncA) is a factor encoded by C. trachomatis that mim-
ics motifs in SNARE proteins, which have crucial roles
in membrane fusion events55. IncA recruits a subset of
host SNAREs, vesicle-associated membrane protein 3
(VAmP3), VAmP7 and VAmP8, to a membrane-bound
compartment called the inclusion, where C. trachomatis
multiplies, although the biological advantage gained
from this recruitment is currently unclear. Interestingly,
a small fraction of clinical C. trachomatis isolates lack
fully functional IncA and form less fusogenic inclu-
sions56. other bacteria also use mimicry to tailor the
composition of pathogen-derived compartments. DrrA
and lepb from Legionella pneumophila mimic the activity
of proteins that regulate the GTPase RAb1 (REFS 57,58).
Rabs act as switches to regulate membranes and vesicu-
lar transport, by recruiting effectors that promote mem-
SNARE protein brane fusion and related activities59. The recruitment and
Soluble NSF
(N-ethylmaleimide-sensitive
misregulation of RAb1 by DrrA and lepb promotes the
factor) attachment protein formation of an endoplasmic-reticulum-related compart-
(SNAP) receptor protein. ment that is produced by L. pneumophila to support its
NATuRE REVIEWS | Microbiology
© 2009 Macmillan Publishers Limited. All rights reserved
REVIEWS
own replication. In this case, subversion of RAb1 blocks
the maturation of phagosomes containing L. pneumophila
into degradative lysosomal compartments60. The remod-
elling of this compartment also provides L. pneumophila
with endoplasmic-reticulum-associated host factors that
facilitate its replication.
As with other cellular processes, viruses also use mim-
icry to co-opt intracellular compartments. Adenovirus-
encoded E3 RIDα alters the maturation of endosomes by
mimicking the function of the GTPase RAb7A61. This
activity downregulates the expression of cell surface
receptors that would otherwise contribute to immune
responses in infected cells. like mimicry rings target-
ing factors that nucleate actin assembly (FIG. 3), diverse
pathogens are known to use mimicry to target various
GTPases regulating a range of cellular processes62.
Subversion of signalling and immunity
Pathogenic subversion of host functions also involves
direct targeting of immunity factors and related cellu-
lar signalling processes (FIG. 4). Just as viruses encode
v-bcl-2s and v-cyclins, they also encode viro-ceptors and
viro-kines that mimic cellular receptors, chemokines
and cytokines63,64. Examples of viro-ceptors and viro-
kines include mimics of proteins that are involved in
innate immunity, such as interferon (IFN) and inter-
leukin (Il) signalling components. In many cases viruses
encode soluble variants of host receptors to sequester
ligands that would otherwise promote pro-immune
responses. Poxviruses are especially adept at countering
a range of immunity functions with mimicry. Vaccinia
virus strains encode soluble IFNa and IFNβ receptors
that dampen the antiviral effects of IFN65. Poxviruses
also encode mimics that bind Il-18 (REF. 66) and imi-
tate CD47 to downregulate macrophage activation67.
Additional mimics from poxviruses interfere with
signalling by certain chemokines68 or masquerade as
other related immunity factors69. Interestingly, not all
mimics function like the proteins that they may have
originally modelled. m135R is a poxviral mimic from
myxoma virus that has clear homology to an IFN recep-
tor, but it does not recognize IFN; instead, it acquired
an important but currently unknown function for pro-
moting infections70. This striking example of imper-
fect mimicry illustrates an important consideration. In
the time between horizontal gene transfer events and
fully fledged mimicry, pathogenic factors can undergo
numerous adaptations and acquire new functions,
sometimes even acquiring multiple functions. Not
surprisingly, pathogenic bacteria also use mimicry to
counteract immunity. E. coli, Brucella melitensis and
S. Typhimurium, for example, encode factors resembling
Toll-like receptors that interfere with innate immune
signalling 71,72.
Pathogens also produce mimics to short-circuit innate
immunity factors downstream of signalling. For exam-
ple, the 2′-5′-oligoadenylyl synthetase (oAS)–RNase l
and protein kinase R (PKR) antiviral pathways respond
to double-stranded RNA (dsRNA) from pathogens to
trigger immune responses that shut down cells as poten-
tial pathogen factories. PKR imposes a robust block on
VolumE 7 | NoVEmbER 2009 | 793
REVIEWS

a Poxvirus protein translation in infected cells, by phosphorylat-

ing eukaryotic translation initiation factor 2 subunit-α
(eIF2α) (FIGS 4,5a), whereas RNase l degrades cellular
dsRNA RNA on activation. The E3l protein encoded by pox-
viruses contains Z-DNA- and dsRNA-binding domains
K3L
PKR with some homology to those found in host factors like
dsRNA-specific adenosine deaminase (DRADA; also
known as ADAR1) (REFS 73–76). by sequestering dsRNA
eIF2α Ribosome and binding host factors, E3l dampens the activation
of oAS–RNase l and PKR pathways during infections.
P K3l, another poxviral mimic, specifically targets the
PKR pathway. K3l is a mimic of eIF2α that acts as a
b
competitive inhibitor of substrate binding to prevent
eIF2α phosphorylation by PKR77–80. Deploying mimics
of eIF2α seems to be a common evolutionary strategy
for DNA viruses, because a range of iridoviruses, which
primarily infect amphibians and fish, also encode K3l-
K3L like factors81. As a remarkable illustration of mimicry
αD P honing in on the same biological process, baculovi-
αG ruses encode PK2, which is a mimic of a PKR-related
αE kinase domain (instead of eIF2α) that seems to act as a
dominant-negative allele82.

PKR kinase domain Host evolution

Positive selection
Selection for an allele that
increases fitness.
eIF2α
c eIF2α kinase not
targeted by mimicry
Affinity for substrate
Maximal
discrimination
PKR against mimics
Adaptive landscape
Figure 5 | PKr versus K3l: evolution of a host
Nature Reviews factor to
| Microbiology
defeat a mimic. a | Schematic showing the antiviral
response of protein kinase R (PKR) that can be blocked by
K3L. PKR is inactive until it dimerizes on binding
double-stranded RNA from viruses. Once active, PKR
phosphorylates eukaryotic translation initiation factor 2
subunit-a (eIF2α), resulting in a strong block on protein
translation. K3L, a mimic of eIF2α, acts as a competitive
inhibitor of PKR to restore translation and virus
replication. b | An evolutionary and functional study of
potentially adaptive changes at multiple surfaces of the
kinase domain of PKR (including the helices αG, αE and
possibly αD) reveals how PKR may effectively compete
against rapidly evolving mimics like K3L83. Ribbon
representations of K3L and eIF2α79,80 highlight β-strands in
the two proteins that share sequence and structural
homology (orange). Because changes on different surfaces
allow PKR to discriminate against K3L, variants of PKR
resisting mimicry are more likely to arise. c | The ‘adaptive
landscape’ of eIF2α kinases. Evolutionary analysis of those
eIF2α kinases that are not challenged by mimicry (in blue)
suggests that they are optimized for substrate
recognition83. However, adaptive changes in PKR might
come at some cost to maximal substrate affinity. Variants of
PKR (in red) may tolerate temporary reductions in substrate
affinity to gain discrimination against substrate mimics.
The preceding sections illustrate the many biologi-
cal processes that are subverted by pathogen mimicry.
Pathogens generally hold substantial advantages in
these genetic conflicts involving mimicry. Such advan-
tages include higher mutation rates and larger popula-
tion sizes than hosts, highlighting the importance of the
rapid and flexible responses that are afforded by proc-
esses such as adaptive immunity. mimicry places the
added challenge of self-discrimination onto hosts. Host
components being mimicked (and the host factors that
interact with such components) might adapt to disfa-
vour effective mimicry (BOX 2). However, the spectrum of
potentially useful adaptations that would facilitate host
escape from mimicry is limited by the need to maintain
host–host interactions and functions. Therefore, hosts
face a daunting conundrum when challenged by mim-
icry. They must maintain functions that are being co-
opted and disrupted by pathogenic mimics that resemble
host factors themselves.
What then are the evolutionary prospects for hosts
to counteract mimics? An example of the evolutionary
dynamics between host factors and mimics has been
examined in detail. The poxvirus protein K3l mim-
ics eIF2α, the highly conserved substrate of the innate
immunity kinase PKR (FIG. 5). This substrate is essentially
unchanged among primates, making it a vulnerable tar-
get for mimics like K3l. Although K3l may have been
originally co-opted by an ancestral poxvirus as a result
of horizontal gene transfer of eIF2α, it no longer acts as
a substrate for PKR. Instead, it has evolved to become
an imperfect mimic as a competitive inhibitor of PKR.
In this context, an evolutionary conflict ensues, as host-
encoded PKR must discriminate against mimics like K3l
while still recognizing eIF2α in order to remain effec-
tive. An important clue about how PKR counteracts K3l
comes from the fact that it is under strong positive selection
in primates and many other mammalian lineages83,84,

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 REVIEWS

Box 3 | Reverse mimicry: when hosts imitate pathogens

Although not as common as mimicry by pathogens, hosts can turn the tables and mimic pathogen factors to their
advantage. For example, Friend virus susceptibility protein 1 (Fv1) and Fv4 are host-encoded virus restriction
factors in mice that confer resistance to retroviruses100. Fv4 is a mimic of a retroviral envelope gene that was
originally identified in Japanese wild mice. In infected mice, Fv4 is incorporated into virus particles and blocks
virus entry by interfering with cell surface receptor recognition. Fv1 also mimics a retroviral factor, in this case
the gag gene product. Fv1 targets virus capsids to impede virus replication by a currently unknown mechanism.
Interestingly, Fv1 is under positive selection, indicating that this mimic–pathogen interaction may be locked in a
molecular arms race101. In both cases, hosts have acquired virus factors and use mimicry to interfere with virus
production. Similarly, it is evident that the recent incorporation of sheep retroviruses into host genomes (also
known as ‘endogenization’) provides a protective benefit to the host against subsequent infections102. A similar
benefit to host genomes has been suggested to explain the selective retention of a retroviral envelope gene in
fruit flies103.
Hosts also use co-opted virus factors for functions other than reverse mimicry. For instance, syncytins are
retrovirus-derived envelope genes used by mammals for cellular fusion events that are required in placental
development104. Perhaps one of the most elaborate examples of hosts usurping viral factors is the case of polydnaviruses,
which challenge the definition of what it means to be a virus105. Polydnavirus particles are derived from parasitic wasps
that encode genes for the structural components of nudivirus-like insect viruses106. These particles are packaged with host
genes for replication instead of viral genes. When these wasps lay their eggs in lepidopteran hosts, such as caterpillars,
they also deposit polydnaviruses. These virus-like particles deliver host genes that suppress host immune responses
against the wasps’ eggs, which would otherwise impede the parasitic larvae. Although these are not strictly examples
of mimicry, syncytins and polydnaviruses show how usurping pathogen factors and using their functions can provide
substantial advantages to hosts. Host genomes seem to follow the same evolutionary adage as pathogens: why invent
when you can steal?

Duplication
Production of another copy of
a gene (or other sequence),
which is incorporated into the
genome and inherited.
Neofunctionalization
Divergence of duplicate genes
such that one copy acquires a
new function.
even at residues that are thought to be crucial for the
PKR–eIF2α interaction. These signals of adaptive evo-
lution are consistent with an arms race scenario, similar
to those seen for other immunity factors that are locked
in conflict with pathogenic mimics (BOX 2). However,
positive selection on one surface alone does not explain
how PKR evades mimicry by K3l, which evolves rapidly
relative to PKR.
Repeated adaptation on multiple surfaces of the
kinase domain of PKR allows it to compete more effec-
tively against mimics like K3l than it would with changes
on a single surface alone83 (FIG. 5b). Were PKR limited to
adaptations at only one interface, it would be unlikely
to escape mimicry. making changes at only a single surface
might also compromise binding to eIF2α. However, vari-
ation in residues at an additional interface with K3l can
compensate and provide resistance to mimics, allowing
PKR to explore mutations that may not have otherwise
been viable. The ability to toggle resistance between sur-
faces helps to improve the odds for PKR to defeat mim-
icry. Adaptation on multiple surfaces also forces mimics
to evolve against more than one interface. In addition,
although certain substitutions in PKR may sacrifice
some affinity for its substrate, such reductions might still
be selectively advantageous, because they increase PKR’s
ability to escape mimicry (FIG. 5c). Therefore, although
PKR evolves at a slower rate than the pathogens chal-
lenging it, variants of PKR that confer resistance against
mimicry are more likely to arise given the extraordinary
level of evolutionary flexibility of this antiviral kinase.
Do all host factors targeted by mimics rapidly evolve
in arms races against pathogens? The evolutionary flex-
ibility of PKR reflects the fact that it can tolerate substan-
tial variation but still recognize its substrate. However,
many of the essential cellular factors that are targeted
by mimicry, including many of those considered here,
may operate under more rigid evolutionary constraints
to carry out crucial cellular functions. Some widely
mimicked host factors, like WASP, may be successfully
targeted by pathogens owing in part to the strong evo-
lutionary constraints on such factors and their inability
to respond to mimicry. In addition, such factors may be
more likely to be targeted by perfect mimicry. Taking
on a host function increases the challenge of mimicry,
because these perfect mimics are less likely to be coun-
tered by host adaptations, as there are few discrimina-
tory features to differentiate host proteins from perfect
mimics. Whether highly constrained factors adapt in
the face of perfect mimicry is an interesting and largely
unexplored question.
Evolution to defeat pathogen mimicry may confer
additional costs on hosts. Factors that evolve against
mimics may be compromised in overall function. For
example, mildly deleterious alleles of WASP85,86 may
have arisen and been selected for because they confer
some resistance to pathogens. Such alleles may actu-
ally be partially compromised for WASP function and
therefore associated with pathogen-independent dis-
ease. This may explain the prevalence of some disease-
causing alleles in human populations. A much better
established and somewhat analogous scenario, albeit one
with higher prevalence, is at play with sickle cell disease
and the trade-offs that are associated with resistance
against malaria87.
The evolutionary history of cellular factors that are
mimicked by pathogens has not been elucidated for the
vast majority of cases described so far. Although many of
these factors are not under the strong positive selection
seen for PKR, adaptive changes and other evolutionary
innovations such as duplication and neofunctionalization
are likely to provide avenues for counteracting mim-
icry 88. In some cases, hosts use the strategy of mimicry

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REVIEWS

themselves to counteract pathogens (BOX 3). At the same
time, large-scale analyses of genomes for positive selec-
tion89–92 suggest that numerous genes — including some
that are known to be mimicked by pathogens — are sub-
ject to arms race-like conflicts with pathogen-encoded
factors. more tests to clarify the functional consequences
of positive selection acting on these genes will provide
an enormous degree of insight into the evolution and
counteraction of this prevalent form of deception by
pathogens.
Concluding remarks
Host–pathogen interactions that determine the results
of potentially deadly infections can play out in hours,
minutes or even seconds in an organism. However, the
outcomes of such interactions are also interwoven with
the long evolutionary histories of these interacting fac-
tors, because they influence the survival of species. These
histories leave hosts or pathogens either susceptible or
resistant in contemporary cellular conflicts93. As sur-
veyed here, pathogens use the strategy of mimicry to
disrupt immunity and usurp a wide range of host proc-
esses to their advantage. As evolutionary analyses are
increasingly coupled with functional assays to investi-
gate these interactions83,94, it is becoming clear how the
evolution of such factors impinges on outcomes at cur-
rent host–pathogen interfaces. Such analyses provide
an emerging picture of how even closely related species
have different fates in genetic conflicts with identical
pathogens. For example, some primate species resist HIV
more strongly than humans, owing in part to extensive
variation in restriction factors95,96. Evolutionary studies
provide a means for uncovering adaptations that are cru-
cial for aiding hosts with pathogen evasion. Similarly,
elucidating the evolutionary dynamics of host–mimic
interactions will provide important insights into these
widespread genetic conflicts that can hold the fates of
entire species in the balance.

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Acknowledgements
We thank E. Goley, J. Kerns and A. Mercer for comments and
suggestions and P. Wilkins for providing the images of insect
mimics. We are supported by a Burroughs Wellcome
Investigator in Pathogenesis Award and a National Science
Foundation CAREER grant (H.S.M.), as well as an Ellison
Medical Foundation Fellowship of the Life Sciences Research
Foundation (N.C.E.). H.S.M. is a Howard Hughes Medical
Institute early career scientist.
DATABASES
Entrez Genome: http://www.ncbi.nlm.nih.gov/sites/
entrez?db=genome
camelpox virus | Kaposi’s sarcoma-associated herpesvirus |
murine gammaherpesvirus 68 | orf virus | vaccinia virus
Entrez Genome Project: http://www.ncbi.nlm.nih.gov/sites/
entrez?db=genomeprj
Brucella melitensis | Chlamydia trachomatis | Escherichia coli |
Legionella pneumophila | Listeria monocytogenes |
Pseudomonas aeruginosa | Rickettsia conorii | Salmonella
enterica subsp. enterica serovar Typhimurium
Protein Databank: http://www.rcsb.org/pdb/home/home.do
1HE1 | 1LUZ | 1TX4 | 2A1A
UniProtKB: http://www.uniprot.org
ActA | Bcl-2 | E3L | E3 RIDa | eIF2a | IncA | K3L | LepB | RickA |
SifA | SopE | SptP | UL97 | v-GAAP | WASP
FURTHER INFORMATION
Nels C. Elde’s homepage: http://cellvolution.org
SUPPLEMENTARY INFORMATION
See online article: S1 (table)
All linKs Are AcTive in The online Pdf
VolumE 7 | NoVEmbER 2009 | 797