The acute transcriptional response of the coral Acropora millepora to immune challenge: expression of GiMAP/IAN genes links the innate immune responses of corals with those of mammals and plants
- Yvonne Weiss†1, 2,
- Sylvain Forêt†1, 3Email author,
- David C Hayward3,
- Tracy Ainsworth1, 2,
- Rob King4,
- Eldon E Ball3 and
- David J Miller1, 2Email author
© Weiss et al.; licensee BioMed Central Ltd. 2013
Received: 23 December 2012
Accepted: 24 May 2013
Published: 14 June 2013
As a step towards understanding coral immunity we present the first whole transcriptome analysis of the acute responses of Acropora millepora to challenge with the bacterial cell wall derivative MDP and the viral mimic poly I:C, defined immunogens provoking distinct but well characterised responses in higher animals.
These experiments reveal similarities with the responses both of arthropods and mammals, as well as coral-specific effects. The most surprising finding was that MDP specifically induced three members of the GiMAP gene family, which has been implicated in immunity in mammals but is absent from Drosophila and Caenorhabditis. Like their mammalian homologs, GiMAP genes are arranged in a tandem cluster in the coral genome.
A phylogenomic survey of this gene family implies ancient origins, multiple independent losses and lineage-specific expansions during animal evolution. Whilst functional convergence cannot be ruled out, GiMAP expression in corals may reflect an ancestral role in immunity, perhaps in phagolysosomal processing.
KeywordsInnate immunity Evolution GTPase Coral disease Cnidaria Transcriptomics
Understanding immune responses in corals represents a convergence of two very different research agendas. Firstly, as early diverging animals, corals and their relatives provide novel perspectives on the evolution of immune systems. Secondly, on a more practical level, the hope is that understanding immune responses may provide insights into, and ways of managing, the coral diseases that are devastating many reefs.
Coral diseases are contributors to the global decline of reefs, and there is a perception that these often act synergistically with other stressors in bringing about coral mortality (for example, ). For some coral diseases, bacteria have been implicated as causative agents [2, 3], whilst black band disease is thought to reflect necrosis of the coral tissue underlying a microbial mat . Surprisingly little is known about immune mechanisms in corals or other cnidarians, but it is clear that anthozoans have homologs of much of the innate immune repertoire of mammals, including Toll/TLR and complement pathway components [5–7] and NODs/NLRs [8, 9]. One of the most intriguing findings to emerge from comparisons between the coral Acropora and the sea anemone Nematostella, the two anthozoan cnidarians for which whole genome sequence data are available, is the relative complexity of the predicted immune repertoire of the coral . Many domains associated with immune functions in higher animals (Bilateria) are over-represented in the coral by comparison with the sea anemone. For example, where Nematostella has a single canonical Toll-like receptor , Acropora has at least four , and the NACHT domain complexity of Acropora is at least an order of magnitude greater than those of Nematostella or man  and includes novel domain combinations .
Although there is a large literature on coral disease, studies to date have been largely descriptive. Symptoms have been described and associated microorganisms sequenced, but in only one case has a bacterium isolated from a coral been unequivocally established as a causative agent by reinfecting a coral and reproducing the symptoms . Progress has been inhibited by the difficulty of culturing many coral-inhabiting bacteria, but the field is now rapidly moving forward (reviewed in [11, 12]). Similarly, reports on the innate immune responses of corals to damage or infection have proliferated in recent years (reviewed by Mydlarz et al  and Palmer and Traylor-Knowles ). As the latter have pointed out, the innate immune response involves three steps: (1) recognition, (2) transmission of this recognition via signaling pathways to effectors, and (3) an effector response. There has been progress in studying each of these steps. Candidate pattern recognition receptors have been identified by homology searching of genome and transcriptome data for Toll-like receptors, integrins and lectins and, in the case of the A. millepora lectin gene Millectin, upregulation has been demonstrated in response to immune challenge . The identification of complement C3 homologs in Acropora millepora and Porites lobata, has been interpreted as “indicative of lectin-mediated cellular immune functions” .
Phenoloxidase (PO) activities have been demonstrated in many corals, and roles for these have been proposed in generating bactericidal radicals as well as in melanin synthesis . Melanin resulting from PO-catalysed polymerization of phenolic compounds can encapsulate pathogens and/or wall off damaged cells, and its synthesis in response to injury or infection has been demonstrated in a number of corals (reviewed in . In Porites cylindrica, an early response to injury is plug formation by degranulation of melanin-containing epithelial cells, followed by infiltration of the area by migratory amoebocytes that are thought to add collagen to the plug, leading to speculation that corals use immune cells and wound healing processes similar to those of higher animals . Transglutaminase activity, which in higher animals has a coagulation function and thus could contribute to wound sealing, has also been demonstrated in Porites cylindrica.
Whereas the work discussed above was based largely on candidate genes and pathways, Vidal-Dupiol et al. [18, 19] took a different approach, using subtractive hybridization to identify Pocillopora damicornis genes regulated in response to infection with Vibrio coralliiltycus. This approach resulted in the discovery of Damicornin , the first anti-microbial peptide (AMP) to be identified from a coral. Although no other AMPs produced by corals have been identified to date, there is mounting evidence that some of the microbes normally found in the mucus of healthy corals may produce peptides that hold other, harmful, bacteria in check (reviewed in ).
For the staghorn coral Acropora millepora, a “near complete” transcriptome assembly is available , permitting comprehensive and relatively unbiased analyses of coral immune responses. To better understand how corals respond to immune challenge, we exposed single colonies of A. millepora to muramyl dipeptide (MDP) and polyinosinic:polycytidylic acid (poly I:C), two defined immunogens provoking distinct but well characterised responses in higher animals, and then determined the acute response at the whole transcriptome level using high throughput sequencing (Illumina RNA-seq). MDP is a minimal common peptidoglycan constituent of both Gram positive and Gram negative bacteria, whereas poly I:C is essentially a viral mimic due to its structural similarity to double stranded RNA. In mammals, the immune responses to these compounds are fairly well understood, providing a reference against which the molecular responses of coral can be compared. In the mouse, MDP-like compounds released as a result of phagolysosomal processing of bacteria are thought to be ligands of the NACHT-domain protein NOD2 , activating NF-kb signaling  and leading to expression of AMPs and cytokines . Poly I:C is a ligand for the murine TLR3 receptor, activating MAP-kinases and NF-kb by distinct molecular pathways . In Drosophila, NF-kb dependent expression of AMPs is triggered by infection by diverse infective agents through the Toll receptor (reviewed in ), but NOD-like proteins are not present. Drosophila Toll-7 has recently been shown to be a pattern recognition receptor for a viral ligand, inducing antiviral autophagy independently of both NF-kb and JAK-STAT pathways .
Comparative analyses of MDP and poly I:C challenged corals reveals similarities with the responses both of arthropods and mammals, as well as coral-specific effects. Three genes belonging to the GiMAP/IAN family, associated with immunity in mammals, were amongst the genes most highly up-regulated upon MDP challenge. This ancient gene family has a patchy distribution across the animal kingdom that is characterised by many independent losses and lineage-specific expansions. Although convergence cannot be ruled out, GiMAP expression during immune challenge in coral may reflect an ancient function, perhaps in phagolysosomal processing.
The molecular responses to challenge with MDP or poly I:C are largely discrete
A general suppression of calcification under immune challenge is implied by the down-regulation of galaxin-like 2 (Cluster011429) and cluster001458, which encodes a voltage gated calcium channel-like VWA protein. Likewise, the down-regulation of Cluster000091, which encodes a multi-domain fatty acid synthase protein, and lipases (Clusters 026990 and 018720) suggests a general suppression of metabolism under immune challenge, as is also seen under acute acidification .
A Gene Ontology enrichment analysis of the response to each immunogen indicates that in both treatments a single category (GO:0070199; establishment of protein localization to chromosome, in the Biological Process ontology, p < 0.05) is significantly overrepresented. This is consistent with the differential expression of histones and zinc finger proteins outlined below.
Specific responses to challenge with poly I:C
Specific responses to challenge with MDP
Coral members of the GiMAP/IAN family are up-regulated by the bacterial PAMP MDP but not by poly I:C
Structure and organisation of the coral GiMAP loci
In addition to the three genes identified in the immune stimulation experiments, searching the A. millepora transcriptome yielded four other sequences encoding proteins containing both an AIG1-like domain and a C-terminal Hint domain (Additional file 4). The pfam01079 Hint domain is based on an alignment of intein domains of Hedgehog proteins, implying that these coral AIG1 proteins undergo protein splicing.
AIG1 domains are patchily distributed across the eukaryotes
To better understand evolutionary relationships of AIG1 sequences, maximum likelihood (ML) and Bayesian inference (BI) methods of phylogenetic analysis were applied (Figure 7 and Additional files 5 and 6). Representative plant Toc34 sequences were included in these analyses for comparative purposes. Several of the ambiguous AIG1-like sequences from animals clustered with the plant Toc34 sequences in phylogenetic analyses (Figure 7). With the exception of these Toc34-like sequences, the majority of AIG1 sequences grouped primarily by taxonomy – generally by species, although a few individual sequences did not conform to this general trend. The three coral GiMAPs that are tightly linked form a strongly supported cluster in phylogenetic analyses, but the position of this clade in the broader analysis is not clear. Representatives of other types of coral AIG1 domain were phylogenetically distinct from the three linked genes, suggesting deep divergence. The phylogenomic analyses indicate that, as has been observed for several other gene families [42–44], AIG1/GiMAP genes have undergone multiple independent losses during evolution – at least seven independent losses within the animal kingdom alone – and several lineage-specific expansions.
The data presented here suggest that the acute transcriptional response of coral to immune challenge has some elements in common not only with mammals but also, perhaps more unexpectedly, with arthropods, as well as unique components. For example, in arthropods, an early response to challenge is proteolytic activation of pro-polyphenol oxidase (proPO) via a serine proteinase cascade (reviewed in ); we hypothesise that the trypsin-like serine protease (Cluster023274) that is highly up-regulated after MDP challenge may play an analogous role in the proPO activation observed upon damage to A. millepora and a species of Porites. Other coral genes up-regulated following MDP challenge have homologs characterised in the context of vertebrate immunity, the standout example being the three Acropora GiMAP/IAN genes. The pattern of up-regulation in response to the defined immunogen MDP suggests roles for the coral GiMAPs in the immune response to bacteria.
It is unclear why the AIG1 domain that characterises GiMAP proteins is present in corals but appears to have been lost in other cnidarians. Several other domains associated with immunity in higher animals are over-represented in coral compared to Nematostella; for example, the coral repertoires of both Toll-like receptors and NACHT domain proteins are more extensive and complex than those of the sea anemone , possibly reflecting the requirements of the symbiotic lifestyle of coral.
Understanding the roles of GiMAPs in coral immunity is complicated not only by the difficulty of coral as an experimental system but also by the fact that little is known about how the corresponding proteins function in vertebrates. A number of the mammalian GiMAP family proteins function in B- and T-cell development, maturation and selection; several interact with specific Bcl2 family members, participating in the regulation of apoptosis during lymphocyte development . GiMAP4/IAN1 interacts with the pro-apoptotic Bax protein, whilst GiMAP3/IAN4 and GiMAP5/IAN5 interact specifically with the anti-apoptotic proteins Bcl2 and Bcl-xL . It has been suggested that these interactions occur via the extended C-terminal domains of the mammalian GiMAP proteins , but this remains to be verified. Plant homologs of the mammalian GiMAPs are known , and several of these have been implicated in immunity; in Arabidopsis, AIG1 (AtIAN8) is induced by both the plant pathogenic bacterium Pseudomonas syringae and the fungal pathogen Phytophthora infestans, and atIAN3 and atIAN11 are strongly up-regulated on nematode infection . However, Arabidopsis IANs are also induced by abiotic stressors such as heat or cold [39, 41], suggesting general stress-response roles rather than specific functions in immunity. Moreover, there are no clear precedents for functional conservation between plant and animal immune systems, and convergence has often been mistaken for conservation. For example, the same combinations of domains function in pattern recognition in both plants and animals; the R-proteins implicated in plant immunity share domains in common with both the Toll/TLR and NLR proteins that are the primary pattern recognition molecules in animals. Whereas this was once thought to reflect conservation of function, it is now viewed as convergence [49, 50], most likely driven by the limited range of domains that can function in pattern recognition.
Although the known roles of the mammalian GiMAPs - regulation of the survival and proliferation of lymphocyte lineages - undoubtedly reflect vertebrate-specific functions, this does not preclude older and more widely conserved functions for GiMAP proteins. If conserved roles are assumed, one possibility is that GiMAPs function at the level of phagolysosomal processing, which is a universal requirement for animal immune responses. The autophagy pathway has essential roles in immune responses (reviewed in ) and in mammals, several other GTPases have critical roles in the induction of autophagy, phagosome maturation and the destruction of pathogens contained in vacuoles . Moreover, the structural properties of the GiMAP proteins are consistent with potential roles in membrane trafficking at phagolysosomal membranes, or perhaps (by analogy with septin “caging”; ) in constraining and compartmentalising pathogens within the cell. Consistent with an ancient role of this sort for the GiMAP family, mammalian GiMAP5 has been shown to be associated with lysosomes . Hence, although neither derived functions nor convergence can be ruled out, the up-regulation observed in corals during immune challenge may reflect an ancestral function of this kind for the GiMAP gene family in the animal kingdom.
During the acute response of the coral A. millepora to MDP challenge, three genes encoding P-loop NTPases of the GiMAP/IAN-type were strongly up-regulated, raising the possibility of common roles in coral and mammal (and possibly also plant) immunity. A phylogenomic survey of the GiMAP gene family implies ancient origins, multiple independent losses and lineage-specific expansions during animal evolution. Whilst functional convergence cannot be ruled out, GiMAP expression in corals may reflect an ancestral role in immunity, perhaps in phagolysosomal processing.
Colonies of Acropora millepora (<40 cm diameter) were collected from the reef flat adjacent to Heron Island on the Southern Great Barrier Reef (23.44°S, 151.91°E), and transported to Heron Island Research Station where they were acclimated in 1000 L raceways under constant flow-through seawater for a period of 5 days prior to immune challenge. Control colonies (injected with buffer only; n = 4) were held in a separate raceway from colonies that were to be injected with defined immunogens (n = 4 per immunogen). Prior to use, immunogens (from InvivoGen, San Diego, CA 92121) MDP (Cat# tlrl-mdp) or poly I:C (Cat# tlrl-pic) were dissolved in sterile 3X phosphate buffered saline (pH7.4) at concentrations of 10 μg/ml. For each colony treated, a single lateral polyp within 1.5 cm of the apical tip was injected with a 200 μl aliquot of immunogen via a 27G needle. One hour after exposure, the 3 cm branch tip including the injection site was broken from the colony and snap frozen in liquid nitrogen prior to storage at -80°C. Coral manipulations were carried out under GBRMPA permit G08/24594.1.
RNA extraction and high throughput sequencing
mRNA was isolated as previously described . RNA-seq libraries were prepared and sequenced by GeneWorks Pty (Australia) on an Illumina Genome Analyzer I. For each condition (control, MDP and pIC), four libraries of single end 35 bp sequences were obtained, yielding an average of 2.8 million reads per library. These samples are biological replicates, coming from different coral colonies. The sequencing data have been deposited in the GEO database with accession ID GSE46389. The reads were mapped onto the latest A. millepora transcriptome assembly  using the Bowtie mapping software v0.12.7 . Differential gene expression was inferred based on these counts using the edgeR package with common dispersion estimates , comparing each treatment (MDP and pIC) to the controls. P-values for differential gene expression were corrected for multiple testing using the Benjamini and Hochberg method , and an adjusted p-value threshold of 0.05 was used.
GiMAPs were identified with BlastP and HMMER (hmmer.org) searches, using the AIG1 domain (pfam04548), focusing on species for which sequenced well- annotated whole genome data are available. In equivocal cases, assignments were made on the basis of a BLAST e-value difference of at least 1E-4 between similarity to the AIG1 domain and alternatives. Sequences were aligned with MAFFT 6.717b  using the accurate L-INS-I method. Positions containing over 95% gaps were removed from the alignment. The dataset and the alignment used for phylogenetic analyses are provided as Additional files 7 and 8. Maximum likelihood trees were inferred with PhyML 3.0  using the LG amino acid substitution model , with four substitution rate categories approximating a gamma distribution whose rate was estimated, and an invariant category. The starting trees were computed using BioNJ and the topologies were optimised by nearest neighbour interchange and sub-tree pruning and regrafting. The branch support was estimated using approximate likelihood tests  and with the bootstrap procedure, using 100 replicates. For Bayesian Inference, Mr Bayes 3.2-cvs was used as described in Forêt et al. .
GTPases of immunity associated proteins
Immune-associated nucleotide-binding proteins
Muramyl dipeptide-a bacterial cell wall derivative
One of three characteristic domains of NLRs
Nucleotide Oligomerisation Domain receptors-cytoplasmic proteins that regulate inflammatory and apoptotic responses
Pathogen-associated molecular pattern
- poly I:
C: Polyinosinic:polycytidylic acid-a viral mimic
Toll-like receptor- the main extracellular pattern receptors of animals, hence proteins that play a key role in the innate immune response.
The authors gratefully acknowledge the support of the Australian Research Council, both directly as a Discovery Grant (#DP1095343) to DM, SF and EB, and indirectly via the ARC Centre of Excellence for Coral Reef Studies. YW acknowledges the receipt of an Australian Postgraduate Research Scholarship, and research support from James Cook University.
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