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Animals have evolved within the framework of microbes and are constantly exposed to diverse microbiota. Microbes colonize most, if not all, animal epithelia and influence the activity of many organs, including the nervous system. Therefore, any consideration on nervous system development and function in the absence of the recognition of microbes will be incomplete. Here, we review the current knowledge on the nervous systems of Hydraand its role in the host–microbiome communication. We show that recent advances in molecular and imaging methods are allowing a comprehensive understanding of the capacity of such a seemingly simple nervous system in the context of the metaorganism. We propose that the development, function and evolution of neural circuits must be considered in the context of host–microbe interactions and present Hydraas a strategic model system with great basic and translational relevance for neuroscience.

Although our understanding of the importance of the partnership of humans and their microbiome in health and disease is rapidly developing, its complexity is high and support for causality is scarce. Model organisms serve to tackle these limitations. Recent updates on the squid–vibrio symbiosis show mechanistic details that underlie the establishment and maintenance of a symbiotic association along the apical surfaces of an animal epithelium.

ABSTRACTThe emergence of multidrug-resistant bacteria highlights the need for new antibacterial agents. Arminin 1a is a novel antimicrobial peptide discovered during investigations of the epithelial defense of the ancient metazoan Hydra. Following proteolytic processing, the 31-amino-acid-long positively charged C-terminal part of arminin 1a exhibits potent and broad-spectrum activity against bacteria, including multiresistant human pathogenic strains, such as methicillin-resistant Staphylococcus aureus(MRSA) strains (minimal bactericidal concentration, 0.4 μM to 0.8 μM). Ultrastructural observations indicate that bacteria are killed by disruption of the bacterial cell wall. Remarkably, the antibacterial activity of arminin 1a is not affected under the physiological salt conditions of human blood. In addition, arminin 1a is a selective antibacterial agent that does not affect human erythrocyte membranes. Arminin 1a shows no sequence homology to any known antimicrobial peptide. Because of its high level of activity against multiresistant bacterial strains pathogenic for humans, the peptide arminin 1a is a promising template for a new class of antibiotics. Our data suggest that ancient metazoan organisms such as Hydrahold promise for the detection of novel antimicrobial molecules and the treatment of infections caused by multiresistant bacteria.

Die bemerkenswerte Regenerationsfähigkeit und potenzielle Unsterblichkeit von Hydraberuht auf einem Lebenszyklus, in dem Vermehrung ausschließlich ungeschlechtlich durch Knospung erfolgt. Dies setzt voraus, dass jeder Polyp mit einer großen Zahl von Stammzellen ausgestattet ist, die kontinuierlich zu Selbsterneuerung und Differenzierung befähigt sind. Neue Technologien erlauben es nun erstmalig, diese Zellen in vivo zu studieren und die beteiligten Gene zu charakterisieren. Hydraverspricht neben dem Verständnis von wichtigen Aspekten der Stammzellbiologie auch Einblick in den evolutionären Ursprung dieser Zellen.

During the course of a systematic screening of peptide signaling molecules in Hydra a novel peptide, Hym-355 (FPQSFLPRG-NH2), was identified. A cDNA encoding the peptide was isolated and characterized. Using both in situ hybridization and immunohistochemistry, Hym-355 was shown to be expressed in neurons and hence is a neuropeptide. The peptide was shown to specifically enhance neuron differentiation throughout the animal by inducing interstitial cells to enter the neuron pathway. Further, co-treatment with a PW peptide, which inhibits neuron differentiation, nullified the effects of both peptides, suggesting that they act in an antagonistic manner. This effect is discussed in terms of a feedback mechanism for maintaining the steady state neuron population in Hydra.

The freshwater polyp Hydra is the most frequently used model for the study of development in cnidarians. Recently we isolated four novel Arg-Phe-NH2 (RFamide) neuropeptides, the Hydra-RFamides I–IV, from Hydra magnipapillata. Here we describe the molecular cloning of three different preprohormones from H. magnipapillata, each of which gives rise to a variety of RFamide neuropeptides. Preprohormone A contains one copy of unprocessed Hydra-RFamide I (QWLGGRFG), II (QWFNGRFG), III/IV [(KP)HLRGRFG] and two putative neuropeptide sequences (QLMSGRFG and QLMRGRFG). Preprohormone B has the same general organization as preprohormone A, but instead of unprocessed Hydra-RFamide III/IV it contains a slightly different neuropeptide sequence [(KP)HYRGRFG]. Preprohormone C contains one copy of unprocessed Hydra-RFamide I and seven additional putative neuropeptide sequences (with the common N-terminal sequence QWF/LSGRFGL). The two Hydra-RFamide II copies (in preprohormones A and B) are preceded by Thr residues, and the single Hydra-RFamide III/IV copy (in preprohormone A) is preceded by an Asn residue, confirming that cnidarians use unconventional processing signals to generate neuropeptides from their precursor proteins. Southern blot analyses suggest that preprohormones A and B are each coded for by a single gene, whereas one or possibly two closely related genes code for preprohormone C. Northern blot analyses and in situ hybridizations show that the gene coding for preprohormone A is expressed in neurons of both the head and foot regions of Hydra, whereas the genes coding for preprohormones B and C are specifically expressed in neurons of different regions of the head. All of this shows that neuropeptide biosynthesis in the primitive metazoan Hydra is already rather complex.

As a molecular marker for head specification in Hydra, we have cloned an epithelial cell-specific gene which responds to early signals of head formation. The gene, designated ks1, encodes a 217-amino acid protein lacking significant sequence similarity to any known protein. KS1 contains a N-terminal signal sequence and is rich in charged residues which are clustered in several domains. ks1 is expressed in tentacle-specific epithelial cells (battery cells) as well as in a small fraction of ectodermal epithelial cells in the gastric region subjacent to the tentacles. Treatment with the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) causes a rapid increase in the level of ks1 mRNA in head-specific epithelial cells and also induces ectopic ks1 expression in cells of the gastric region. Sequence elements in the 5′-flanking region of ks1 that are related to TPA-responsive elements may mediate the TPA inducibility of ks1 expression. The pattern of expression of ks1 suggests that a ligand-activated diacylglycerol second messenger system is involved in head-specific differentiation.

The role of the cellular environment on hydra stem cell proliferation and differentiation was investigated by introduction of interstitial cells into host tissue of defined cellular composition. In epithelial tissue lacking all non-epithelial cells the interstitial cell population did not grow but differentiated into nerve cells and nematocytes. In host tissue with progressively increased numbers of nerve cells growth of the interstitial cell population was positively correlated to the nerve cell density. In agreement with previous observations (Bode et al. 1976), growth of the interstitial cell population was also found to be negatively correlated to the level of interstitial cells present. The strong correlation between the growth of the interstitial cell population and the presence of interstitial cells and nerve cells implies that interstitial cell proliferation is controlled by a feedback signal from interstitial cells and their derivatives. Our results suggest that the cellular environment of interstitial cells provides cues which are instrumental in stem cell decision making.

Single interstitial stem cells of male polyps of Hydra magnipapillatagive rise to clones that differentiate either male or female gametes. To test the sexual stability of these clones, stem cells were recloned. The results indicate that stem cells from female clones are stable in their sexual differentiation capacity; male stem cells, by comparison, switch sexual phenotype at the rate of 10-2per cell per generation. As a result, female polyps contain only female stem cells; male polyps contain a mixture of male and female stem cells. A model is presented in which the sexual phenotype of Hydrapolyps is controlled by (i) the switching rate of male and female stem cells and (ii) the repression of female differentiation by male stem cells.

The major heat shock protein (hsp) of Hydra vulgaris has recently been found to be a 60 kDa protein. Since in all organisms studied so far, the major heat shock protein is a 70 kDa protein, we have analyzed the relationship of hydra hsp60 to the highly conserved 70 kDa heat shock protein family. Genes and proteins related to the 70 kDa class of stress proteins are present in hydra. However, antibodies known to cross-react with hsp70 proteins in several different organisms do not cross-react with hydra hsp60 suggesting that hsp60 is not related to the conserved hsp70 proteins.

A cDNA clone encoding a 253 amino acid tropomyosin was isolated from Hydra in a differential screen for headspecific genes. The Hydra tropomyosin gene, designated trop1, is a single copy gene, lacks introns and is strongly expressed in tentacle-specific epithelial cells. Analysis of protein synthesis in head and gastric tissue indicated a high rate of tropomyosin synthesis in head tissue. Immunolocalization of tropomyosin in tentacle tissue revealed a cushion-like tropomyosin-containing structure within battery cells at the base of nematocytes. The structure appears to form part of the cytoskeletal anchor for nematocytes. Tropomyosin cushions were also observed in epithelial cells along the body column, which contain mounted stenotele nematocytes.

This work studies microbial interactions within the microbiome of the simple cnidarian Hydraand investigates whether microbial species coexistence and community stability depend on the host environment. We find that the outcome of the interaction between the two most dominant bacterial species in Hydra’s microbiome differs depending on the environment and results in a stable coexistence only in the host context. The interactive ecology between the host and the two most dominant microbes, but also the less abundant members of the microbiome, is critically important for achieving the native community composition. This indicates that the metaorganism environment needs to be taken into account when studying microbial interactions.

Inflammatory diseases, such as inflammatory bowel diseases, are dramatically increasing worldwide, but an understanding of the underlying factors is lacking. We here present an ecoevolutionary perspective on the emergence of inflammatory diseases.

Microbial communities are accompanied by a diverse array of viruses. Through infections of abundant microbes, these viruses have the potential to mediate competition within the community, effectively weakening competitive interactions and promoting coexistence. This is of particular relevance for host-associated microbial communities, because the diversity of the microbiota has been linked to host health and functioning. Here, we study the interaction between two key members of the microbiota of the freshwater metazoan Hydra vulgaris. The two commensal bacteria Curvibactersp. and Duganellasp. protect their host from fungal infections, but only if both of them are present. Coexistence of the two bacteria is thus beneficial for Hydra. Intriguingly, Duganellasp. appears to be the superior competitor in vitrodue to its higher growth rate when both bacteria are grown separately, but in co-culture the outcome of competition depends on the relative initial abundances of the two species. The presence of an inducible prophage in the Curvibactersp. genome, which is able to lytically infect Duganellasp., led us to hypothesize that the phage modulates the interaction between these two key members of the Hydramicrobiota. Using a mathematical model, we show that the interplay of the lysogenic life cycle of the Curvibacterphage and the lytic life cycle on Duganellasp. can explain the observed complex competitive interaction between the two bacteria. Our results highlight the importance of taking lysogeny into account for understanding microbe–virus interactions and show the complex role phages can play in promoting coexistence of their bacterial hosts.

ABSTRACTHistorically, mucosal immunity—i.e., the portion of the immune system that protects an organism’s various mucous membranes from invasion by potentially pathogenic microbes—has been studied in single-cell epithelia in the gastrointestinal and upper respiratory tracts of vertebrates. Phylogenetically, mucosal surfaces appeared for the first time about 560 million years ago in members of the phylum Cnidaria. There are remarkable similarities and shared functions of mucosal immunity in vertebrates and innate immunity in cnidarians, such as Hydraspecies. Here, we propose a common origin for both systems and review observations that indicate that the ultimately simple holobiont Hydraprovides both a new perspective on the relationship between bacteria and animal cells and a new prism for viewing the emergence and evolution of epithelial tissue-based innate immunity. In addition, recent breakthroughs in our understanding of immune responses in Hydrapolyps reared under defined short-term gnotobiotic conditions open up the potential of Hydraas an animal research model for the study of common mucosal disorders.

Microbial communities display complex population dynamics, both in frequency and absolute density. Evolutionary game theory provides a natural approach to analyse and model this complexity by studying the detailed interactions among players, including competition and conflict, cooperation and coexistence. Classic evolutionary game theory models typically assume constant population size, which often does not hold for microbial populations. Here, we explicitly take into account population growth with frequency-dependent growth parameters, as observed in our experimental system. We study the in vitropopulation dynamics of the two commensal bacteria (Curvibactersp. (AEP1.3) and Duganellasp. (C1.2)) that synergistically protect the metazoan host Hydra vulgaris(AEP) from fungal infection. The frequency-dependent, nonlinear growth rates observed in our experiments indicate that the interactions among bacteria in co-culture are beyond the simple case of direct competition or, equivalently, pairwise games. This is in agreement with the synergistic effect of anti-fungal activity observed in vivo. Our analysis provides new insight into the minimal degree of complexity needed to appropriately understand and predict coexistence or extinction events in this kind of microbial community dynamics. Our approach extends the understanding of microbial communities and points to novel experiments.