About the Project
Bacterial infections are still a major health threat. The emergence of antibiotic resistance among serious bacterial pathogens is putting our global world at high risk of multidrug resistant epidemics. These infections may become untreatable with currently available antibiotics. Salmonella Typhi is a life-threatening bacterial pathogen. It is the cause of typhoid fever and it is the second most common bacterial pathogen in the world after Mycobacterium tuberculosis. Typhoid affects 27 million people and kills 200,000 mostly in developing countries1. Recent reports showed that multidrug resistant Salmonella Typhi are rapidly spreading from places where they originated to other regions of the world, often in different continents2. Therefore, alternative strategies to treat typhoid will have to be searched to be prepared for future epidemics.
In contrast to other Salmonellae, Salmonella Typhi can only infect humans. We are interested in understanding the molecular bases of Salmonella Typhi infection and, in particular, the mechanisms underpinning its host-restriction. By examining the molecular mechanisms at the host-pathogen interface we recently discovered a novel macrophage antimicrobial pathway3,4. We showed that an intracellular trafficking pathway dependent on the Rab GTPase Rab32 is fundamental to restrict Salmonella Typhi infection to humans by clearing Salmonella Typhi from macrophages of non-susceptible species. However, the anti-microbial mechanism responsible for killing Salmonella Typhi in non-susceptible macrophages is still unknown. We use multiple approaches to investigate this mechanism, including live fluorescent imaging, proteomic, biochemistry, and Salmonella genetics and genome-wide shRNA and CRISPR/Cas9 screens. This project, in particular, intends to get insights into the Rab32-dependent transport pathway in mouse macrophages, by elucidating the dynamics of recruitment of the Rab32-dependent trafficking machinery to the Salmonella-containing vacuole and identifying other components and regulators of this trafficking pathway. Identifying positive and negative regulators of the Rab32 pathway will have a critical impact on the development of new strategies to cure bacterial infections. Indeed, this could identify approaches to boost the anti-microbial activity of the pathway and innate resistance to bacterial infections.
As a PhD student in the laboratory of Professor Stefania Spanò, you will join a vibrant research environment exploring mechanisms of Host-Pathogen Interactions using cutting-edge technologies (https://www.abdn.ac.uk/staffnet/profiles/stefania.spano). We are an international and interactive group, and part of an outstanding network of international scientists. You will be trained in numerous techniques, including molecular microbiology, molecular biology, mammalian cell cultures, CRISPR/Cas9, RNA interference, lentiviral expression systems, fluorescence and electron microscopy, qPCR, immunoaffinity purification.
Funding Notes
This project is funded by the European Research Council. The award is available to UK/EU students only.
Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a 2.2 Honours degree may be considered provided they have a Commendation or Distinction at Masters level.
Applicants are strongly advised to contact Professor Spano to discuss the project before submitting a formal application.
References
1. Waddington et al. J. Infect. 68 Suppl 1, S38 (2014).
2. Wong et al. Nat Genet. 47:632-9 (2015).
3. Spanò and Galán, Science, 338:960-3 (2016).
4. Spanò et al., Cell Host and Microbe, 19(2):216-226 (2016).