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PERSPECTIVE
Are innate immune signaling pathways in plants and
animals conserved?
Frederick M Ausubel
Although adaptive immunity is unique to vertebrates, the
innate immune response seems to have ancient origins.
Common features of innate immunity in vertebrates,
invertebrate animals and plants include defined receptors for
microbe-associated molecules, conserved mitogen-associated
protein kinase signaling cascades and the production of
antimicrobial peptides. It is commonly reported that these
similarities in innate immunity represent a process of divergent
evolution from an ancient unicellular eukaryote that pre-dated
the divergence of the plant and animal kingdoms. However, at
present, data suggest that the seemingly analogous regulatory
modules used in plant and animal innate immunity are a
consequence of convergent evolution and reflect inherent
constraints on how an innate immune system can be
constructed.
Both plants and animals have complex innate mechanisms to recognize
and respond to attack by pathogenic microorganisms. Innate immunity relies on a defense strategy that involves a set of defined receptors
referred to as pathogen- or pattern-recognition receptors (PRRs) that
recognize microbe-associated molecules. There is a wealth of evidence
that the mammalian innate immune response has ancient origins in
arthropods1,2 and perhaps nematodes as well3–7. In vertebrates, the
innate immune response not only serves as a first line of defense in
the response to pathogenic microbes but also is key in the production
of costimulatory molecules involved in T cell activation and chemokines and cytokines. Protists, fungi and other unicellular eukaryotes
may also have evolved defensive mechanisms that confer resistance to
microbial pathogens. However, that is not addressed here and neither
is the involvement of highly conserved RNA interference–related antiviral defenses. Instead, the generally accepted view that PRRs, signal
transduction pathways and ‘downstream’ effectors are evolutionarily
conserved and are used by plants, insects and vertebrates is examined.
Pathogen-associated versus microbe-associated molecules
‘Pathogen-associated molecular pattern’ (PAMP) is the term generally used when referring to the molecules that elicit innate immune
responses. As classically defined, PAMPs are evolutionarily conserved
Frederick M. Ausubel is in the Department of Genetics, Harvard Medical School,
and Department of Molecular Biology, Massachusetts General Hospital, Boston,
Massachusetts 02114, USA.
e-mail: [email protected]
Published online 21 September 2005; doi:10.1038/ni1253
NATURE IMMUNOLOGY VOLUME 6 NUMBER 10 OCTOBER 2005
pathogen-derived molecules that distinguish hosts from pathogens.
PAMPs include lipopolysaccharide, peptidoglycan, bacterial flagellin
and mannans of yeast. However, because nonpathogens also synthesize
these molecules, the term ‘pathogen-associated’ is a misnomer and a
more precise term would seem to be ‘microbe-associated molecular
pattern’. Thus, it makes sense that hosts would also have defined receptors for molecules that are truly pathogen specific, but only in plants is
there definitive evidence for immune receptors that recognize pathogen-encoded virulence-related molecules such as type III effectors. To
avoid confusion here, the term ‘microbe-associated molecule(s)’ is used
instead of ‘PAMP’.
Toll-like receptors in insects and mammals
In insects and mammals, a family of conserved transmembrane Toll-like
receptors (TLRs) functions directly or indirectly as PRRs for microbeassociated molecules8–13. Study of conserved TLR signaling pathways
has served as a paradigm for insights that can be gained due to evolutionary conservation of innate immune signaling components14,15.
Initially, the Toll pathway was identified because of its involvement in
pattern formation in early drosophila embryo development16. Later,
the cytoplasmic domain of Toll (the Toll–interleukin 1 (IL-1) receptor (TIR) domain) was noted to have homology with the cytoplasmic
domain of human IL-1 (ref. 17), and analysis of the promoters of genes
encoding antimicrobial peptides in drosophila suggested that they were
regulated by NF-κB-like transcription factors that also function in the
Toll pathway18. This led to experiments demonstrating that drosophila Toll pathway mutants are immunocompromised19. Meanwhile, a
human homolog of Toll was shown to activate expression of NF-κBcontrolled genes20, and positional cloning of mouse Lps, which confers
resistance to lipopolysaccharide-induced endotoxin shock, identified
TLR4 as the lipopolysaccharide sensor21. Thus, a core component of the
mammalian innate immune system involved in mediating the cellular
response to lipopolysaccharide and the proinflammatory cytokine IL-1
was shown to have features in common with the signaling pathways of
the insect immune response.
TLRs are characterized by an extracellular leucine-rich repeat (LRR)
domain and an intracellular TIR protein-protein interaction domain.
LRRs are found in a variety of receptors in both plants and animals.
TLRs are coupled to signaling adaptors such as MyD88, which also have
TIR domains. Activation of the TLR signaling cascade results in the
nuclear translocation of NF-κB-like transcription factors, leading to
the production of antimicrobial peptides in both insects and vertebrates
and signaling molecules such as cytokines in vertebrates. In drosophila,
the TLR pathway responds to fungi and Gram-positive bacteria10,19,22,
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© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
PERSPECTIVE
a key component of the ‘inflammasome’, is
activated by the muramyl dipeptide component of peptidoglycan36. Muramyl dipeptide–
mediated activation of the ‘inflammasome’
leads in turn to activation of caspase 1 and
maturation of pro-IL-1b. It is not known
whether the peptidoglycan degradation products interact directly with the LRRs of Nod1,
Nod2 or NALP3 or whether there is a linker
protein involved. In any case, peptidoglycan
must translocate into the cytoplasm, and at
least some cell types such as macrophages
have intracellular hydrolyases that can digest
peptidoglycan36.
Plant response to microbial molecules
Like insects and vertebrates, plants have
Figure 1 Extracellular and intracellular PRRs in plants and animals. Animal TLRs and plant receptorreceptors for microbe-associated molecules
like kinases are similar in overall structure in that all are transmembrane receptors that have
and respond to many of the same molecules
C-terminal LRRs. However, the cytoplasmic domains are not conserved. In both plants and animals,
that animals respond to, including lipoextracellular receptors respond to highly conserved microbe-associated molecules such as bacterial
polysaccharide and flagellin (Fig. 1). Plants
flagellin. Like the extracellular receptors, the cytoplasmic animal CLR proteins and plant NBS-LRR
pathogen-resistance proteins have the same overall tripartite structure with C-terminal LRR and
also respond to a wide variety of molecules
central nucleotide-binding site (NBS) domains. As with TLRs and receptor-like kinases, however, the
associated with fungi or oomycetes, includN-terminal domains are not conserved between plants and animals. In animals, the N-terminal domain
ing cell wall components such as chitin and
can be, for example, one or two caspase activation and recruitment domains in Nod1 and Nod2,
ergosterol37. Has the comparison of innate
respectively, and pyrin and NACHT domains in NALP proteins. In plants, the N-terminal domains are
immune signaling pathways in plants and
usually TIR or coiled-coiled domains. Nod1, Nod2 and NALP3 respond to peptidoglycan degradation
animals led to new insights analogous to the
products, whereas the plant NBS-LRR proteins respond to pathogen-specific virulence factors.
Although the presence of the TIR domain in some NBS-LRR plant disease-resistance proteins suggests
comparison of TLR signaling in mammals
a common evolutionary origin of plant and animal PRRs, the downstream signaling pathways have
and flies?
nothing in common. The overall conservation of the tripartite structure of animal CLR and plant
The response of the reference plant
NBS-LRR proteins also suggests evolutionary conservation, but these proteins are not present in
Arabidopsis thaliana to eubacterial flagellin
nematodes or arthropods, suggesting independent evolutionary origins in plants and animals.
has been a focus of interest38–43. Arabidopsis
responds both to flagellin and to a highly conserved 22–amino acid fragment of the flagelwhereas a second immune signaling pathway, the immune-deficient lin protein called Flg22 (ref. 39). Flg22 activates a signal transduction
mutant (Imd) pathway, responds to Gram-negative bacteria via a pep- cascade that includes a transmembrane LRR receptor kinase (FLS2), a
tidoglycan-recognition protein23–25. Like the TLR pathway, the Imd MAP kinase cascade, so-called WRKY transcription factors and downpathway leads to the activation of NF-κB-like transcription factors. In stream effector proteins38,40,44 (Fig. 2). The structure of the FLS2 recepcomparing the drosophila and mammalian innate immune signaling tor is reminiscent of that of TLRs in that FLS2 has an extracellular LRR
pathways, the mammalian TLR pathway is made up of components domain. In addition, both the FLS2 and TLR signaling pathways involve
analogous to those found in the proximal and distal portions of the a conserved family of cytoplasmic serine-threonine kinases (cytoplasdrosophila TLR and Imd pathways, respectively26.
mic kinase domain of FLS2 and IRAK or PELLE kinases in mammals
and drosophila, respectively)45,46. However, the similarity between the
Mammalian CLR (Nod) receptors
FLS2 and the TLR signaling pathways does not extend beyond those
In addition to the transmembrane TLRs, mammals have a family of features. FLS2 corresponds functionally to TLR5 in mammals, which
cytosolic PRRs that belong to a family of proteins variously referred is also a flagellin receptor, but TLR5 and FLS2 respond to different
to as CATERPILLER (CLR) or Nod proteins that are involved in apop- epitopes in the flagellin protein47. The LRR domains of FLS2 and TLR5
totic and inflammatory responses13,27–31. CLR (Nod) proteins, here- are very divergent. The FLS2 receptor does not have an intracellular
after referred to CLR proteins, are characterized by a tripartite domain TIR domain like the TLRs, and no downstream signaling components
architecture consisting of a variable N-terminal domain, a central have been identified in plants homologous to the MyD88 family of TIR
nucleotide-binding domain and C-terminal LRRs and are structur- domain–containing adaptor proteins. If a functional flagellin receptor
ally similar to the TIR-NBS-LRR and CC-NBS-LRR pathogen-resis- had evolved in an ancestral eukaryote, it is difficult to explain why both
tance proteins in plants (discussed below) that function in the plant the flagellin ligand specificity and the intracellular signaling domain are
immune response (Fig. 1). CLR proteins include NALPs, Nods and different in the plant and animal receptors. Finally, plants do not have
NAIPs. The two Nod proteins Nod1 and Nod2 mediate intracellular transcription factors homologous to the Rel-like family of transcription
responsiveness to peptidoglycan degradation products, leading to factors that includes Dif and NF-κB in flies and mammals, respectively,
the activation of NF-κB. Nod1 responds to γ-D-iso-glutamyl diami- and the WRKY family of transcription factors activated downstream of
nopimelic acid, and Nod2 responds to muramyl dipeptide32–34. The FLS2 in arabidopsis is not found in animals.
Thus, although the overall structure of microbe-associated molecule
two Nod proteins differ mainly in that Nod1 has one and Nod2 has
two N-terminal caspase activation and recruitment domains. There signaling pathways in plants and animals is similar in that both involve
are 14 NALP proteins in humans31,35. Like Nod2, NALP3, which is transmembrane LRR receptors, mitogen-associated protein kinase
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VOLUME 6 NUMBER 10 OCTOBER 2005 NATURE IMMUNOLOGY
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
PERSPECTIVE
(MAPK) signaling cascades, production of active oxygen and nitrogen species, calcium fluxes, activation of transcription factors and the
inducible expression of immune effectors, there is little evidence that
this overall similarity reflects evolutionary conservation of an ancient
signaling pathway. Indeed, the apparent conservation that is typically
cited seems to be equally well explained as being a reflection of the
overall conservation of the components of canonical MAPK signaling
cascades that form a bridge between diverse signal sensors and/or receptors and target genes in eukaryotes. These MAPK signaling pathways,
which often include transmembrane receptors, MAPKKKs, MAPKKs,
MAPKs and downstream transcription factors, are present in yeast,
plants, invertebrates and vertebrates and presumably appeared very
early in evolution before the emergence of multicellularity.
caspase-dependent apoptosis is restricted to animals. Thus, although the
conserved structure of CLR proteins and the fact that the CLR receptors activate programmed cell death in both plants and animals seem
to provide evidence for an ancient origin for innate immune signaling
pathways, it is not possible to distinguish a common evolutionary origin
from convergent evolution. One line of evidence that may favor the convergent evolution model is that CLR proteins as a class do not seem to be
encoded in the Caenorhabditis elegans and drosophila genomes and that
the vertebrate CLR family did not evolve until the teleost lineage31. Thus,
it seems likely that the plant NBS-LRR and vertebrate CLR proteins have
evolved independently as immune signaling components.
In mammals, both the extracellular TLRs and intracellular CLR PRRs
can lead to NF-κB activation. Analogously in plants, both transmembrane LRR-containing receptors and intracellular NBS-LRR receptors
can activate defense responses involving programmed cell death of
infected cells. It is not known whether any intracellular plant NBS-LRR
proteins respond to highly conserved microbe-associated molecules
and activate a relatively weak response like the FLS2 flagellin receptor.
It is also not known whether any CLR proteins in mammals function as
receptors for microbe-associated molecules in addition to peptidoglycan or for pathogen-specific virulence factors as they do in plants.
Intracellular CLR receptors in plants
The best-characterized plant immune receptors are a large class of intracellular receptors referred to as NBS-LRR pathogen-resistance proteins,
which have an overall tripartite structure similar to that of the mammalian CLR proteins48,49 (Fig. 1). In general, plants have large families
of these NBS-LRR proteins; arabidopsis has 140 (ref. 50) and rice has
over 500 (ref. 51). Most of the NBS-LRR pathogen-resistance proteins
have either a TIR or a coiled-coil N-terminal domain. In contrast to
the Nod1, Nod2 and NALP3 proteins, which respond to peptidoglycan Evolutionary conservation of TIR domain receptors
degradation products, the plant NBS-LRR pathogen-resistance proteins The presence of a TIR domain in some of the plant NBS-LRR pathogenthat have been studied respond to pathogen-specific signals, includ- resistance proteins has fueled speculation about a common evolutioning pathogen-encoded virulence-related factors. In the best-studied ary origin between the plant and animal innate immunity systems.
cases, NBS-LRR proteins function indirectly
as receptors for bacterial effector proteins that
are translocated directly into host cells by the
type III secretion system, in that they recognize the host cell proteins targeted by the type
III effector proteins48,49. These targets include
components of the host defense response,
including innate immune response pathways
or other critical cellular processes52–58. If a
plant host can recognize a particular effector protein directly, or indirectly by virtue of
the action of the effector protein on a target,
a rapid and potent defense response ensues
that often involves localized programmed cell
death of infected cells. An important issue
that has not been fully resolved is whether the
defense responses activated downstream of
NBS-LRR pathogen-resistance proteins are
qualitatively or quantitatively different from
those activated downstream of receptors such
as FLS2 that respond to generic highly conserved microbe-associated molecules. Some
data (S. Ferrari, C. Denoux, J. Dewdney, G. de
Lorenzo and F.M.A., unpublished data and Figure 2 Signaling pathways downstream of PRRs in mammals, insects, nematodes and plants.
ref. 43), however, suggest that Flg22 rapidly In insects and mammals, a family of TLRs mediates the recognition of highly conserved microbeassociated molecules, and there is considerable correspondence between the downstream signaling
activates a set of genes independently of the components. The C. elegans genome encodes a single Toll-like protein that does not seem to function
signaling pathways known to be involved in in immune signaling and does not encode Rel-like transcription factors such as mammalian NF-κB
NBS-LRR signaling.
or drosophila Dif and Relish. However, C. elegans, drosophila and mammals share a conserved p38
Notably, activation of programmed cell MAPK signaling module. Moreover, C. elegans has a TIR domain–containing protein, TIR-1, that
death is a feature shared by both plant NBS- functions in innate immune signaling upstream of p38 (refs. 61,64), controls the expression of
LRR proteins and at least some animal CLR antimicrobial peptides (D. Kim and F.M.A., unpublished data; N. Pujol and J. Ewbank, personal
communication) and is homologous to the mammalian SARM protein. Plants have a family of receptorproteins. But there is no evidence that the like kinases such as the flagellin receptor FLS2. Although the overall structure of the FLS2 signaling
programmed cell death signaling pathways pathway seems similar to that of the PRR signaling pathways in animals, there is no conservation of
downstream of the plant and animal CLR pro- any individual components and the similarity most likely reflects the ubiquity of eukaryotic MAPK
teins share any common components, in that stress-response cassettes that respond to environmental signals.
NATURE IMMUNOLOGY VOLUME 6 NUMBER 10 OCTOBER 2005
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© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
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In animals, TIR domains are found only in immune-related proteins,
but this does not seem to be the case in plants. Moreover, there are no
similarities in the signaling pathways downstream of TLRs in animals
and TIR-NBS-LRR pathogen-resistance proteins in plants, obscuring
any potential evolutionary relationship.
Investigation of innate immune signaling pathways in C. elegans
has supported the conclusion that the presence of TIR domains in
plant NBS-LRR pathogen-resistance proteins and in animal TLRs
and TIR domain adaptor proteins is not indicative of evolutionary
conservation. Like plants, the nematode C. elegans does not have Rellike transcription factors, and although a single TLR-like protein is
encoded in the C. elegans genome, mutation of this TLR does not
confer an immunocompromised phenotype59. Nevertheless, transcriptional profiling analysis has shown that C. elegans respond to bacterial pathogens by activating a variety of genes, homologs of which
are involved in antimicrobial responses in insects and mammals60,61.
Moreover, other results have demonstrated a key requirement for an
ancient, highly conserved p38 MAPK signaling cassette in C. elegans
immunity62,63 that also is an important in insect and mammalian
immunity. Despite the apparent lack of involvement of TLR signaling
in C. elegans immunity, a TIR domain protein has been identified that
functions upstream of p38 MAPK61,64 that is highly homologous to the
human protein SARM. Although a clear function for human SARM in
innate immune signaling has not been established, it is not likely that
SARM functions upstream of NF-κB64. It can argued from these data
that the C. elegans TIR-1–(p38) MAPK pathway may be an ancient
conserved immune pathway and that the evolutionary recruitment
of TLRs and NF-κB into innate immune signaling pathways occurred
after the divergence of insects and nematodes4,64. Work in mammalian
cells and with ‘knockout’ mice has also suggested that the p38 MAPK
pathway is a more ancient component of innate immune signaling
than is NF-κB65,66.
Additional plant immune response pathways
Another reason to think that plant and animal immune signaling pathways have distinct evolutionary origins is that there is essentially no
overlap between a large set of immune signaling components identified in plants and those found in animals. For example, a variety of
arabidopsis genes involved in innate immune signaling have been
identified, and a large body of genetic, physiological and biochemical
work has shown that these immunity-related genes are important in
conferring pathogen resistance67. Confirming a variety of biochemical studies, this collective mutant analysis has also shown that several
low-molecular-weight signaling molecules, including salicylic acid, jasmonic acid, ethylene and nitric oxide, are key in the regulation of plant
innate immune pathways and that the plant innate immune response is
complex, involving several parallel defense response signaling pathways
that interact or intersect at key regulatory steps56,68–70. However, either
the genes identified in these signaling pathways have no mammalian
homologs or there is no evidence that the mammalian homologs are
involved in innate immune responses.
Although the innate immune signaling pathways seem to have little
in common in plants and animals, some of the defense reactions that
are directly involved in attacking invading pathogens may indeed have
very ancient origins. Both plants and animals, for example, synthesize a wide range of small antimicrobial peptides and both produce an
oxidative burst via conserved gp91phox NADPH oxidases. Arabidopsis
mutants that contain disruptions of both AtrbohD and AtrbohF, which
encode gp91phox–like NADPH oxidases, fail to generate a full oxidative
burst in response to infection by bacterial and fungal pathogens71–73.
However, plant gp91phox NADPH oxidases also function in a variety
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of developmental and physiological processes, including root development and stomatal closure. Thus, the multiple functions of gp91phox
NADPH oxidases may reflect the reuse of a highly evolved process for
diverse functions. Thus, it seems just as likely that the recruitment of
NADPH oxidases for immune response pathways may have occurred
independently in the plant and animal kingdoms.
Why do plants have species-specific PRRs?
An important distinction between the plant and animal innate
immune systems is that plants seem to encode a much larger array
of PRRs than do animals, including receptors for pathogen-specific
virulence factors. The TLRs in flies and mammals, the Imd system in
flies and the CLR proteins in mammals respond only to highly conserved microbe-associated molecules. For vertebrates, the evolution
of the adaptive immune system and concomitant ability to somatically
generate a vast array of pathogen-specific receptors may have obviated the need for the expansion of defined PRRs to include pathogen-specific ones or may have allowed their disappearance. From this
perspective, the presence of pathogen-specific receptors in plants such
as the NBS-LRR pathogen-resistance proteins suggests that they may
function analogously to the adaptive immune system in mammals in
providing pathogen-specific immunity. If it is true that plants have
many more innate immune receptors than do invertebrate animals,
this may be a consequence of the fact that plants are sessile and have
relatively long lives compared with those of many invertebrate animals
and they do not have any mobile cells that can become specialized in
pathogen defense. Cells in plants are fixed in place by their cell walls
and every cell in a plant is therefore both responsible for and capable
of its own defense.
As discussed above, plants have at least two categories of PRRs.
The arabidopsis FLS2 flagellin receptor is an example of a plant PRR
that functions analogously to the animal PRRs, responding to generic
microbe-associated molecules. FLS2 is a member of a large family
of receptor-like kinases in plants that have a domain configuration
resembling that of transmembrane receptors45,46. Other members
of the family function in defense responses, and it seems likely that
many receptor-like kinases function as receptors for microbe-associated molecules. The NBS-LRR pathogen-resistance proteins are a
second class of PRRs in plants, responding to strain-specific pathogen-encoded virulence factors. A third potential class of plant PRRs is
the rice Xa21 resistance protein74. Xa21 is a receptor-like kinase that
is highly homologous to FLS2, but it seems to respond to a speciesspecific secreted molecule from Xanthomonas oryzae rather than to
a broadly conserved microbe-associated molecule like lipopolysaccharide75–77. Despite its structural similarity to FLS2, Xa21 functions
similarly to NBS-LRR pathogen-resistance proteins in that it elicits
a strong defense response that confers resistance to X. oryzae strains
expressing the corresponding AvrXa21 elicitor. Because Xa21 responds
to an extracellular signal that may not be a virulence factor itself, it
blurs the distinction between receptor-like kinases that recognize
microbe-associated molecules and NBS-LRR proteins that recognize
pathogen-encoded virulence factors.
How do the various categories of plant PRRs function together to
provide a coordinated defense response? One possibility is that the
different types of receptors mutually reinforce the immune response,
thereby constituting a ‘two-hit’ requirement to reduce the wasteful
production of a full-blown response to nonpathogenic microbes.
Extracellular non–species-specific receptors such as FLS2 may serve
as early warning sentinels to alert the plant to the presence of a potential pathogen, activating local transient responses and/or priming
the plant defense response such that a more vigorous and systemic
VOLUME 6 NUMBER 10 OCTOBER 2005 NATURE IMMUNOLOGY
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
PERSPECTIVE
long-lasting response is mounted when a second cytosolic signal is
detected by an NBS-LRR receptor. Alternatively, having receptors for
both highly conserved microbe-associated molecules and pathogenspecific virulence factors may allow plants to directly distinguish pathogens from saprophytic and commensal microbes.
In a long-term evolutionary process of pathogen-host warfare, it is
possible to envisage that pathogens evolved type III effectors to abrogate
the plant response pathways to microbe-associated molecules56 and
that plants in turn evolved receptors for the type III effectors. Because
there are an almost unlimited number of potential type III effectors
that plants would have to recognize, the NBS-LRR receptors evolved
to ‘guard’ the targets of the type III effectors rather than functioning
as receptors for the type III effectors themselves78. These targets may
be individual signaling components or so-called ‘functional modules’,
collections of proteins that carry out signal transduction or the synthesis of complex secondary products. Published data have provided
compelling evidence for the latter scenario and have explained how
plants can potentially recognize a diverse set of pathogens and pathogen-specific molecules using a relatively limited number of pathogenreceptors56,79–81. Thus, the evolutionary solution in plants to identify
pathogens involves self surveillance, whereas the evolutionary solution
in the adaptive immune response in vertebrates for the same problem
involves detection of foreign antigens.
Conclusions
Although it seems to be generally accepted that the innate immune
responses of plants and animals share at least some common evolutionary origins, examination of the available data fails to support
that conclusion, despite similarities in the overall ‘logic’ of the innate
immune response in diverse multicellular eukaryotes (Fig. 2). It is
notable that different transcription factor families are used in plant
and animal innate immune responses. Indeed, the WKRY family
of transcription factors used in plants is absent from animals, the
NF-κB family used in insects and vertebrates is not present in plants,
and C. elegans does not use either family. Moreover, even though
individual components of the plant and animal innate immune signaling pathways share some common protein motifs, including TIR,
NBS and LRR domains, it seems just as likely that these motifs have
been recruited independently in different evolutionary lineages to
function in immune signaling as it is that they evolved from common
ancestral innate immune signaling proteins. Phylogentic studies of
gene families involved in innate immunity support that conclusion,
suggesting that other components of innate immune signaling in
insects and vertebrates, including TLRs and NF-κB, represent highly
conserved generalized signaling proteins that were ‘co-opted’ independently to function in innate immune signaling82,83. This is not
necessarily unexpected. LRRs, for example, are used as receptors for a
variety of ligands in many different eukaryotic proteins. The idea of a
process of convergent evolution is also supported by the recombinatorial immune system in lampreys (a jawless vertebrate), which involves
highly diverse LRRs instead of the immunoglobulin gene segments
found in jawed vertebrates84. Although the conclusion that convergent evolution best explains the similarities in the plant and animal
immune response pathways is expressed in some reviews37,85, it is
generally not stated explicitly. Similar conclusions have been reached
about the evolution of multicellularity and developmental processes
in plants and animals. Although the underlying logic of multicellular
development in plants and animals is unexpectedly similar, it seems
that multicellularity evolved independently in plants and animals and
that the basic molecular mechanisms specifying pattern formation
were independently derived86.
NATURE IMMUNOLOGY VOLUME 6 NUMBER 10 OCTOBER 2005
Given the compelling case for convergent evolution of innate immune
pathways, an important issue is why evolution has chosen a limited
number of apparently analogous regulatory modules in disparate evolutionary lineages. Does this reflect inherent biochemical constraints
that result from a similar overall ‘logic’ of how an effective immune system can be constructed? For example, TIR domain–containing proteins
are involved in three apparently disparate innate immune signaling
pathways: TIR-NBS-LRR proteins in plants, TIR–(p38) MAPK signaling in nematodes (and possibly other animal phyla) and TLR-mediated
signaling in insects and vertebrates. Moreover, at least for animals, TIR
domain proteins seem to be used exclusively in immune signaling pathways. It is conceivable that TIR domains, as well other domains such
as LRRs and pelle-receptor-like kinases commonly found in immune
pathways, have intrinsic biochemical properties that are particularly
well suited for these pathways or are particularly resistant to disruption
by pathogen-encoded counter-defense mechanisms. Assuming that the
last common ancestor of plants and animals was a primitive unicellular eukaryote, it would be informative to determine how many of the
components of innate immune signaling pathways are present in and
have immune functions in these organisms.
Despite many similarities, plants and animals do have one main
strategic difference in responding to pathogen attack in that plants
elaborate a variety of pathogen-specific PRRs, whereas PRRs in animals
seem to be limited to the recognition of very highly conserved microbeassociated molecules. Although it can be argued that this difference in
strategy may be an evolutionary consequence of plant architecture, this
line of reasoning is not fully explanatory and raises the possibility that
both invertebrate and vertebrate animals also have pathogen-specific
receptors that have yet to be identified. Indeed, it has been suggested
that mammals may express pathogen-specific factors that confer resistance to particular pathogens. Specific alleles of mouse Naip5 (also
known as Birc1e), which encodes a member of the CLR protein family,
is associated with resistance to Legionella pneumophila87,88. In work that
illuminates the molecular basis of the resistance of Old World monkeys
to infection with human immunodeficiency virus, it was shown that
such infection is blocked more efficiently in cells expressing rhesus
monkey TRIM5α, a RING finger protein, than in those expressing
human TRIM5α89. In a final example, a mouse gene, Ipr1, has been
identified that confers resistance to Mycobacterium tuberculosis and
Listeria monocytogenes when expressed in macrophages90; however,
because Ipr1 confers resistance to two very different pathogens, this
suggests that it may function analogously to a plant NBS-LRR guard
protein rather than a PRR. Although preliminary, these examples may
illustrate yet another common feature of the overall logic of the innate
immune response in plants and animals.
ACKNOWLEDGEMENTS
I thank C. Dardick, W. Dietrich, J. Dangl, J. Ewbank, J. Jones, T. Nurnberger,
P. Ronald, P. Schulze-Lefert and J. Sheen for comments.
COMPETING INTERESTS STATEMENT
The author declares that he has no competing financial interests.
Published online at http://www.nature.com/natureimmunology/
Reprints and permissions information is available online at http://npg.nature.com/
reprintsandpermissions/
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