This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Snakebite is a medical emergency causing rapid onset of both local tissue-destructive and potentially lethal systemic haemorrhagic and neurotoxic pathologies. Snakebite primarily afflicts remote, impoverished, rural farming communities in regions with weak medical and ambulatory infrastructures. It annually kills approximately 138,000 people and 400,000 surviving victims suffer a substantially-reduced quality of life due to the multiple effects of permanent physical and psychological disabilities. Rapid access to effective healthcare is a major problem for these deeply disadvantaged snakebite victims, but necessary, because current antivenom treatment needs to delivered in a hospital setting. Unfortunately, delays in health seeking behaviour often result in antivenom therapy being ineffective at treating snakebite toxins, particularly those that cause local tissue damage around the bite site, leaving many victims with long term morbidity. Recently we have begun to identify and characterise the cytotoxins found in various snake venoms that are responsible for stimulating the effects responsible for causing local morbidity (e.g. inflammation, blistering, necrosis). While venom toxins initiate this process, the relative contribution of secondary host processes to envenoming pathology remains almost completely unstudied. NETosis, a form of neutrophil cell death that contributes to the host defence against pathogens via the formation of neutrophil extracellular traps (NETs), likely plays a major role in local tissue damage following envenoming by entrapping venom toxins, physically blocking blood vessels and liberating endothelial cell-damaging histones, resulting in necrosis. Dysregulation of NETosis is a well-established pathological process associated with many conditions (e.g. atherosclerosis, diabetes, sepsis) and evidence that treatment of mice with NET-degrading DNAse I abolishes venom-induced local tissue damage suggests a major role in snakebite morbidity. Despite these exciting preliminary findings, the generality and extent of the contributory role of NETosis to local snakebite pathology remains unknown, and currently hampers the exploitation of NETosis as a potential adjunct drug target for tackling snakebite morbidity. This project will therefore focus on defining the relative contribution of NETosis and liberated histones to local (and secondarily systemic) envenoming pathology. We will identify the mechanisms by which NETosis is induced by different snake venoms, and the toxins responsible for initiating this process, and then define the pathophysiological consequences of NETosis using cell, organ on a chip and animal models of envenoming, as well as clinical samples from snakebite victims. We will then use this information to rationally explore whether NETs and/or histones are valid drug targets for the development of adjunct therapeutics to reduce the severity of snakebite envenoming. The successful applicant will join the dynamic and well-funded team at LSTM’s Centre for Snakebite Research and Interventions (CSRI). |
| Where does this project lie in the translational pathway? | T1 - Basic Research,T2 - Human /Clinical Research |
| Expected Outputs | Technical Outputs: - Define the relative contribution of NETosis and histone liberation to the severity of snakebite envenoming in both preclinical models and clinical samples. - New, preclinically-tested adjunct therapeutics with demonstrable efficacy at reducing the severity of snakebite morbidity, and with translation potential to delivering this benefit globally Institutional Impact: - Delivery of products to reduce morbidity for rural, remote snakebite victims - REF-returnable publications Student Career Enhancement: - Acquisition of a variety of laboratory technical skills - Opportunities and mentorship to present biomedical research designed to address a neglected tropical disease at national and international conferences - Opportunities and mentorship to publish high-impact, influential papers - Potential opportunity to experience different academic environments with our collaborators - Numerous opportunities at LSTM to understand the diverse cultural, fiscal and medical barriers to good health in rural remote tropical regions |
| Training Opportunities | The student will be exposed to a wide variety of research training opportunities, as they will join a well-funded, multi-disciplinary and dynamic team of post docs, students and technicians. Thus, they will have an opportunity to acquire additional clinical and lab skill sets to those described above. In terms of career development, the student will receive ample and diverse training commensurate with developing an appropriately competitive CV for acquiring funding to support their career after the PhD. |
| Skills Required | A biomedical science or immunology or cell biology background would be desirable. Critical thinking skills, a passion for research, and a meticulous nature, are highly sought after. |
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Key Publications associated with this project |
Katkar et al. 2016. NETosis and lack of DNase activity are key factors in Echis carinatus venom-induced tissue destruction. Nat Commun. 7, 11361. https://www.nature.com/articles/ncomms11361 |
| Girish et al. 2019. Research into the causes of venom-induced mortality and morbidity identifies new therapeutic opportunities. Am. J. Trop. Med. Hyg. 100, 1043-1048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493937/ | |
| Swethakumar et al. 2020. The action of Echis carinatus and Naja naja venoms on human neutrophils; an emphasis on NETosis. Biochim. Biophys. Acta Gen. Subj. 1864(6), 129561. https://pubmed.ncbi.nlm.nih.gov/32068016/ | |
| Ryan et al. 2021. Immunological responses to envenomation. Frontiers Immunol. 12, 661082. https://www.frontiersin.org/articles/10.3389/fimmu.2021.661082/full | |
| Hall et al. 2023. Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. Nature Communications 14, 7812 https://www.nature.com/articles/s41467-023-43510-w |