skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: The skin microbiome facilitates adaptive tetrodotoxin production in poisonous newts
Rough-skinned newts produce tetrodotoxin or TTX, a deadly neurotoxin that is also present in some pufferfish, octopuses, crabs, starfish, flatworms, frogs, and toads. It remains a mystery why so many different creatures produce this toxin. One possibility is that TTX did not evolve in animals at all, but rather it is made by bacteria living on or in these creatures. In fact, scientists have already shown that TTX-producing bacteria supply pufferfish, octopus, and other animals with the toxin. However, it was not known where TTX in newts and other amphibians comes from. TTX kills animals by blocking specialized ion channels and shutting down the signaling between neurons, but rough-skinned newts appear insensitive to this blockage, making it likely that they have evolved defenses against the toxin. Some garter snakes that feed on these newts have also evolved to become immune to the effects of TTX. If bacteria are the source of TTX in the newts, the emergence of newt-eating snakes resistant to TTX must be putting evolutionary pressure on both the newts and the bacteria to boost their anti-snake defenses. Learning more about these complex relationships will help scientists better understand both evolution and the role of beneficial bacteria. Vaelli et al. have now shown that bacteria living on rough-skinned newts produce TTX. In the experiments, bacteria samples were collected from the skin of the newts and grown in the laboratory. Four different types of bacteria from the samples collected produced TTX. Next, Vaelli et al. looked at five genes that encode the channels normally affected by TTX in newts and found that all them have mutations that prevent them from being blocked by this deadly neurotoxin. This suggests that bacteria living on newts shape the evolution of genes critical to the animals’ own survival. Helpful bacteria living on and in animals have important effects on animals’ physiology, health, and disease. But understanding these complex interactions is challenging. Rough-skinned newts provide an excellent model system for studying the effects of helpful bacteria living on animals. Vaelli et al. show that a single chemical produced by bacteria can impact diverse aspects of animal biology including physiology, the evolution of their genes, and their interactions with other creatures in their environment.  more » « less
Award ID(s):
1655392
PAR ID:
10144954
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
eLife
Volume:
9
ISSN:
2050-084X
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract Antagonistic coevolution between natural enemies can produce highly exaggerated traits, such as prey toxins and predator resistance. This reciprocal process of adaptation and counter‐adaptation may also open doors to other evolutionary novelties not directly involved in the phenotypic interface of coevolution. We tested the hypothesis that predator–prey coevolution coincided with the evolution of conspicuous coloration on resistant predators that retain prey toxins. In western North America, common garter snakes (Thamnophis sirtalis) have evolved extreme resistance to tetrodotoxin (TTX) in the coevolutionary arms race with their deadly prey, Pacific newts (Tarichaspp.). TTX‐resistant snakes can retain large amounts of ingested TTX, which could serve as a deterrent against the snakes' own predators if TTX toxicity and resistance are coupled with a conspicuous warning signal. We evaluated whether arms race escalation covaries with bright red coloration in snake populations across the geographic mosaic of coevolution. Snake colour variation departs from the neutral expectations of population genetic structure and covaries with escalating clines of newt TTX and snake resistance at two coevolutionary hotspots. In the Pacific Northwest, bright red coloration fits an expected pattern of an aposematic warning to avian predators: TTX‐resistant snakes that consume highly toxic newts also have relatively large, reddish‐orange dorsal blotches. Snake coloration also seems to have evolved with the arms race in California, but overall patterns are less intuitively consistent with aposematism. These results suggest that interactions with additional trophic levels can generate novel traits as a cascading consequence of arms race coevolution across the geographic mosaic. 
    more » « less
  2. Abstract The Geographic Mosaic Theory of Coevolution predicts that coevolutionary arms races will vary over time and space because of the diverse ecological settings and population histories of interacting species across the landscape. Thus, understanding coevolution may require investigating broad sets of populations sampled across the range of the interaction. In addition, comparing coevolutionary dynamics between similar systems may reveal the importance of specific factors that structure coevolution.Here, we examine geographic patterns of prey traits and predator traits in the relatively unstudied interaction between the Sierra garter snake (Thamnophis couchii) and sympatric prey, the rough‐skinned newt (Taricha granulosa), Sierra newt (Ta. sierrae) and California newt (Ta. torosa). This system parallels, in space and phenotypes, a classic example of coevolution between predatory common garter snakes (Th. sirtalis) and their toxic newt prey exhibiting hotspots of newt tetrodotoxin (TTX) levels and matching snake TTX resistance.We quantified prey and predator traits from hundreds of individuals across their distributions, and functional trait matching at sympatric sites.We show strong regional patterns of trait covariation across the shared ranges ofTh. couchiiand newt prey. Traits differ significantly among localities, with lower newt TTX levels and snake TTX resistance at the northern latitudes, and higher TTX levels and snake resistance at southern latitudes. Newts and snakes in northern populations show the highest degree of functional trait matching despite possessing the least extreme traits. Conversely, newts and snakes in southern populations show the greatest mismatch despite possessing exaggerated traits, with some snakes so resistant to TTX they would be unaffected by any sympatric newt. Nevertheless, individual variation was substantial, and appears to offer the opportunity for continued reciprocal selection in most populations.Overall, the three species of newts appear to be engaged in a TTX‐mediated arms race withTh. couchii. These patterns are congruent with those seen between newts andTh. sirtalis, including the same latitudinal gradient in trait covariation, and the potential ‘escape’ from the arms race by snake predators. Such concordance in broad scale patterns across two distinct systems suggests common phenomena might structure geographic mosaics in similar ways. 
    more » « less
  3. Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5–2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity. 
    more » « less
  4. null (Ed.)
    Cells of all kinds often wage chemical warfare against each other. Hydrogen peroxide is often the weapon of choice on the microscopic battlefield, where it is used to incapacitate opponents or to defend against attackers. For example, some plants produce hydrogen peroxide in response to infection to fight off disease-causing microbes. Individual cells have also evolved defenses to prevent or repair ‘injuries’ caused by hydrogen peroxide. These are similar across many different species. They include enzymes called catalases, which break down hydrogen peroxide, and others to repair damage. However, scientists still do not fully understand how animals and other multicellular organisms might coordinate these defenses across their cells. Caenorhabditis elegans is a microscopic species of worm that lives in rotting fruits. It often encounters the threat of cellular warfare: many types of bacteria in its environment generate hydrogen peroxide, and some can make enough to kill the worms outright. Like other organisms, C. elegans also produces catalases to defend itself against hydrogen peroxide attacks. However, it must activate its defenses at the right time; if it did so when they were not needed, this would result in a detrimental energy ‘cost’ to the worm. Although C. elegans is a small organism containing only a defined number of cells, exactly why and how it switches its chemical defenses on or off remains unknown. Schiffer et al. therefore set out to determine how C. elegans controls these defenses, focusing on the role of the brain in detecting and processing information from its environment. Experiments looking at the brains of genetically manipulated worms revealed a circuit of sensory nerve cells whose job is to tell the rest of the worm’s tissues that they no longer need to produce defense enzymes. Crucially, the circuit became active when the worms sensed E. coli bacteria nearby. Bacteria in the same family as E. coli are normally found in in the same habitat as C. elegans and these bacteria are also known to make enzymes of their own to eliminate hydrogen peroxide around them. These results indicate that C. elegans can effectively decide, based on the activity of its circuit, when to use its own defenses and when to ‘freeload’ off those of neighboring bacteria. This work is an important step towards understanding how sensory circuits in the brain can control hydrogen peroxide defenses in multicellular organisms. In the future, it could help researchers work out how more complex animals, like humans, coordinate their cellular defenses, and therefore potentially yield new strategies for improving health and longevity. 
    more » « less
  5. Reguera, Gemma (Ed.)
    ABSTRACT Mucosal defenses are crucial in animals for protection against pathogens and predators. Host defense peptides (antimicrobial peptides, AMPs) as well as skin-associated microbes are key components of mucosal immunity, particularly in amphibians. We integrate microbiology, molecular biology, network-thinking, and proteomics to understand how host and microbially derived products on amphibian skin (referred to as the mucosome) serve as pathogen defenses. We studied defense mechanisms against chytrid pathogens, Batrachochytrium dendrobatidis (Bd) and B. salamandrivorans (Bsal), in four salamander species with different Batrachochytrium susceptibilities. Bd infection was quantified using qPCR, mucosome function (i.e., ability to kill Bd or Bsal zoospores in vitro ), skin bacterial communities using 16S rRNA gene amplicon sequencing, and the role of Bd-inhibitory bacteria in microbial networks across all species. We explored the presence of candidate-AMPs in eastern newts and red-backed salamanders. Eastern newts had the highest Bd prevalence and mucosome function, while red-back salamanders had the lowest Bd prevalence and mucosome function, and two-lined salamanders and seal salamanders were intermediates. Salamanders with highest Bd infection intensity showed greater mucosome function. Bd infection prevalence significantly decreased as putative Bd-inhibitory bacterial richness and relative abundance increased on hosts. In co-occurrence networks, some putative Bd-inhibitory bacteria were found as hub-taxa, with red-backs having the highest proportion of protective hubs and positive associations related to putative Bd-inhibitory hub bacteria. We found more AMP candidates on salamanders with lower Bd susceptibility. These findings suggest that salamanders possess distinct innate mechanisms that affect chytrid fungi. IMPORTANCE How host mucosal defenses interact, and influence disease outcome is critical in understanding host defenses against pathogens. A more detailed understanding is needed of the interactions between the host and the functioning of its mucosal defenses in pathogen defense. This study investigates the variability of chytrid susceptibility in salamanders and the innate defenses each species possesses to mediate pathogens, thus advancing the knowledge toward a deeper understanding of the microbial ecology of skin-associated bacteria and contributing to the development of bioaugmentation strategies to mediate pathogen infection and disease. This study improves the understanding of complex immune defense mechanisms in salamanders and highlights the potential role of the mucosome to reduce the probability of Bd disease development and that putative protective bacteria may reduce likelihood of Bd infecting skin. 
    more » « less