Dr Marina Ezcurra
Marina Ezcurra received her PhD from the Karolinska Institute in 2011. Her PhD research was a collaborative project between Karolinska and MRC-LMB, Cambridge, and she studied neural circuits and behavior using C. elegans in Bill Schafer’s group. During her PhD, Marina Ezcurra identified extrasynaptic mechanisms by which nutritional status modulates nociception, involving neuropeptidergic and dopaminergic signaling. She went on to do a postdoc working on ageing with David Gems at University College London. During her postdoc, Marina Ezcurra developed methods to monitor the development of multiple age-related diseases in vivo in C. elegans, leading to the discovery of a previously unknown process, Intestinal Biomass Conversion. This mechanism enables the C. elegans intestine to be broken down to produce vast amounts of yolk, resulting in polymorbidity and mortality in ageing nematodes. This work illustrates how ageing and age-related diseases can be the result of run-on of wildtype gene function rather than stochastic molecular damage. Current research in Marina Ezcurra’s group focuses on how host-microbiome interactions affect host ageing and is funded by The Wellcome Trust and Royal Society. Marina Ezcurra is a trustee board members of The British Society of Research on Ageing.
For full information Marina's work, visit her research website: marinaezcurralab.com
Genomic approaches are greatly advancing our knowledge of the human microbiome and its role in health and disease states. It is becoming clear that the composition of the microbiota varies greatly between individuals, contributes to many diseases and plays an active role in human health. A number of recent studies have shown that the gut microbiota modulates important aspects of human physiology, including the ageing process and the myriad of associated diseases, and also the gut-brain-axis, resulting in effects on neural chemistry, behaviours, psychiatric and neurodegenerative diseases. Thus, the microbiota presents an avenue to target novel treatments to a number of diseases and to modulate brain plasticity and cognitive function during ageing.
Due to the inherent complexity and heterogeneity of the human microbiome this complex relationship between the host and its microbiota is very difficult to disentangle in mammalian systems. We are using the nematode C. elegans combined with its native microbiome but also with bacterial models to identify the microbial and host pathways underlying microbiome effects on the gut-brain axis during ageing. On one side, the combination of C. elegans with bacterial models offers exceptional experimental systems allowing the systematic manipulation of the host and its microbiota, and the use of all the tools these models offer to gain mechanistic insight into microbiome effects on host physiology. On the other side, studying C. elegans with its native microbiome allows the study of ecologically relevant host-symbiont interactions.
MSc-R project available for September 2019
Using Caenorhabditis elegans as a model to explore the pathogenic role(s) of microbial gut parasites joint supervision with Dr Tasos Tsasousis
Microbial gut parasites such as Blastocystis, Entamoeba, Giardia and Cryptosporidium have been long associated with severe gastrointestinal diseases, but recent reports have also demonstrated their presence in asymptomatic individuals and animals. These observations suggest that the pathogenicity of these organisms is controversial and that they might form part of the normal gut microbiome. Thus, there is a need to understand the role of these parasites in the host’s health & disease. To elucidate some of these roles, we are using Caenorhabditis elegans as a model to explore the biology of microbial gut parasites in the host. This nematode has several unique characteristics making it ideal to study host-microbe interactions, e.g. is transparent so that microbe colonization can be easily monitored, is amenable to genetic manipulation and the presence of microorganisms can be controlled. The aim of this project is to use C. elegans as a model to explore not only the effect of these parasites have in the host, but also on the rest of the gut microbiome. The student will work on developing C. elegans gut colonization protocols and in vitro culturing systems for these parasites, but also new methods for exploring and understanding the parasite-microbiome-host interactions. The student will gain experience in various culturing methods (nematodes, parasites and bacteria), microscopy, metabolomics and large-scale data analysis of metagenomics sequencing.
Effects of host-microbiome interactions on the ageing nervous system The composition of the microbiome plays an important role in human physiology, with microbial diversity being associated with health, and decreased diversity associated with ageing and ill-health. Studies in humans have shown links between microbiome composition and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, suggesting that the microbiome contributes to these diseases and perhaps the ageing process itself. Due to the large degree of complexity of the mammalian microbiome, causation has not yet been established and mechanisms underlying host-microbiome effects on health remain unknown. There is a strong need to establish simple, genetically tractable models allowing the untangling of these complex interactions.
Our group uses the model organism C. elegans to dissect the mechanisms underlying host-microbiome interactions and their effects on host health, with a focus on the ageing nervous system. We have shown that the microbiome has strong effects on disease progression in C. elegans models of Parkinson’s and Alzheimer’s disease. This project will involve screening probiotic strains for effects on neurodegenerative disease models with the aim to identify strains that improve late-life health. The underlying processes, including host-microbiome interactions affecting innate immunity, mitochondrial biology, protein homeostasis and stress responses, will be investigated. The nature of the relevant microbial signalling pathways will be investigated through biochemical and genetic approaches.
The project will involve developing skills in modern neuroscience, genetics, bioinformatics, biochemistry, microbiology, and microscopy. Additional research costs: £1200
Murphy, C., Dobson, A., Boulton-McDonald, R., Houchou, L., Svermova, T., Ren, Z., Subrini, J., Vazquez-Prada, M., Hoti, M., Rodriguez-Lopez, M., Ibrahim, R., Gregoriou, A., Gkantiragas, A., Bähler, J., Ezcurra, M. and Alic, N. (2019). Longevity is determined by ETS transcription factors in multiple tissues and diverse species. PLOS Genetics [Online] 15:e1008212. Available at: https://doi.org/10.1371/journal.pgen.1008212.Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila, reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop, an ETS transcriptional repressor, and Foxo, a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo. In combination, Aop can both moderate or synergise with Foxo, dependent on promoter context. Moreover, Foxo and Aop oppose the gene-regulatory activity of Pnt, an ETS transcriptional activator. Directly knocking down Pnt recapitulates aspects of the Aop/Foxo transcriptional programme and is sufficient to extend lifespan. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines expression of metabolic genes, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are often conserved amongst ETS TFs, prompting us to examine whether other Drosophila ETS-coding genes may also affect ageing. We show that five out of eight Drosophila ETS TFs play a role in fly ageing, acting from a range of organs and cells including the intestine, adipose and neurons. We expand the repertoire of lifespan-limiting ETS TFs in C. elegans, confirming their conserved function in ageing and revealing that the roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species.
Sornda, T., Ezcurra, M., Kern, C., Galimov, E., Au, C., de la Guardia, Y. and Gems, D. (2019). Production of YP170 Vitellogenins Promotes Intestinal Senescence in Caenorhabditis elegans. The Journals of Gerontology: Series A [Online]. Available at: https://doi.org/10.1093/gerona/glz067.During aging, etiologies of senescence cause multiple pathologies, leading to morbidity and death. To understand aging requires identification of these etiologies. For example, C. elegans hermaphrodites consume their own intestinal biomass to support yolk production, which in later life drives intestinal atrophy and ectopic yolk deposition. Yolk proteins (vitellogenins) exist as 3 abundant species: YP170, derived from vit-1 - vit-5, and YP115 and YP88, derived from vit-6. Here we show that inhibiting YP170 synthesis leads to a reciprocal increase in YP115/YP88 levels and vice versa, an effect involving post-transcriptional mechanisms. Inhibiting YP170 production alone, despite increasing YP115/YP88 synthesis, reduces intestinal atrophy as much as inhibition of all YP synthesis, which increases lifespan. By contrast, inhibiting YP115/YP88 production alone accelerates intestinal atrophy and reduces lifespan, an effect that is dependent upon increased YP170 production. Thus, despite copious abundance of both YP170 and YP115/YP88, only YP170 production is coupled to intestinal atrophy and shortened lifespan. In addition, increasing levels of YP115/YP88 but not of YP170 increases resistance to oxidative stress; thus, longevity resulting from reduced vitellogenin synthesis is not attributable to oxidative stress resistance.
Ezcurra, M., Benedetto, A., Sornda, T., Gilliat, A., Au, C., Zhang, Q., van Schelt, S., Petrache, A., Wang, H., de la Guardia, Y., Bar-Nun, S., Tyler, E., Wakelam, M. and Gems, D. (2018). C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies. Current Biology [Online] 28:2544-2556.e5. Available at: https://doi.org/10.1016/j.cub.2018.06.035.Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause
senescent pathology. In C. elegans a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology,
but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagymediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-toyolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not
from damage accumulation, but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis).
Wang, H., Zhao, Y., Ezcurra, M., Benedetto, A., Gilliat, A., Hellberg, J., Ren, Z., Galimov, E., Athigapanich, T., Girstmair, J., Telford, M., Dolphin, C., Zhang, Z. and Gems, D. (2018). A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans. npj Aging and Mechanisms of Disease [Online] 4. Available at: https://doi.org/10.1038/s41514-018-0025-3.Many diseases whose frequency increases with advancing age are caused by aging (senescence),
but the mechanisms of senescence remain poorly understood. According to G.C. Williams and
M.V. Blagosklonny, a major etiological determinant of senescence is late-life, wild-type gene
action and non-adaptive execution of biological programs (or quasi-programs). These generate a
wide range of senescent pathologies causing illness and death. Here we investigate the etiology
of a prominent senescent pathology in the nematode C. elegans, uterine tumors, in the light of
the Williams Blagosklonny theory. Uterine tumors develop from unfertilized, immature oocytes
which execute incomplete embryogenetic programs. This includes extensive endomitosis,
leading to formation of chromatin masses and cellular hypertrophy. The starting point of
pathogenesis is exhaustion of sperm stocks. The timing of this transition between program and
quasi-program can be altered by blocking sperm production (causing earlier tumors) or supplying
additional sperm by mating (delaying tumor onset). Other pathophysiological determinants are
yolk consumption by tumors, and bacterial proliferation within tumors. Uterine tumors resemble
mammalian ovarian teratomas (tera, Greek: monster) in that both develop from oocytes that fail
to mature after meiosis I, and both are the result of quasi-programs. Moreover, older but not
younger uterine tumors show expression of markers of later embryogenesis, i.e. are teratoma-like.
These results show how uterine tumors in C. elegans form as the result of run-on of
embryogenetic quasi-programs. They also suggest fundamental etiological equivalence between
teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.
Ezcurra, M. (2018). Dissecting cause and effect in host-microbiome interactions using the combined worm-bug model system. Biogerontology [Online] 19:567-578. Available at: https://doi.org/10.1007/s10522-018-9752-x.High-throughput molecular studies are greatly advancing our knowledge of the human
microbiome and its specific role in governing health and disease states. A myriad of ongoing
studies aim at identifying links between microbial community disequilibria (dysbiosis) and
human diseases. However, due to the inherent complexity and heterogeneity of the human
microbiome we need robust experimental models that allow the systematic manipulation of
variables to test the multitude of hypotheses arisen from large-scale ‘meta-omic’ projects.
The nematode C. elegans combined with bacterial models offers an avenue to dissect cause
and effect in host-microbiome interactions. This combined model allows the genetic
manipulation of both host and microbial genetics and the use of a myriad of tools, to identify
pathways affecting host health. A number of recent high impact studies have used C.
elegans to identify microbial pathways affecting ageing and longevity, demonstrating the
power of the combined C. elegans-bacterial model. Here I will review the current state of the
field, what we have learned from using C. elegans to study gut microbiome and host
interactions, and the potential of using this model system in the future.
Zhao, Y., Gilliat, A., Ziehm, M., Turmaine, M., Wang, H., Ezcurra, M., Yang, C., Phillips, G., McBay, D., Zhang, W., Partridge, L., Pincus, Z. and Gems, D. (2017). Two forms of death in ageing Caenorhabditis elegans. Nature Communications [Online] 8. Available at: https://doi.org/10.1038/ncomms15458.Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age. Our results imply the presence of multiple causes of death. Specifically, we identify two classes of corpse: early deaths with a swollen pharynx (which we call ‘P deaths’), and later deaths with an atrophied pharynx (termed ‘p deaths’). The effects of interventions on lifespan can be broken down into changes in the frequency and/or timing of either form of death. For example, glp-1 mutation only delays p death, while eat-2 mutation reduces P death. Combining pathology and mortality analysis allows mortality profiles to be deconvolved, providing biological meaning to complex survival and mortality profiles.