About the Project
Many species of parasitic nematodes migrate through the mammalian lung as part of their development, resulting in lung damage. The lung migratory stage is associated with a strong local Type 2 inflammatory response, which is important for repair of the injured lung in part through IL-4 receptor-dependent macrophage activation (1). Products generated by these macrophages are involved in both parasite control and the subsequent repair (2). The majority of work in this area has focused on a murine model of hookworm infection, which causes severe lung injury. The Allen Lab has a major interest in the biology of filarial nematodes, responsible for river blindness and lymphatic filariasis, and uses a murine model of filarial infection, Litomosoides sigmodontis, to study the host response to filarial infection (3). The parasite is transmitted via mite bite and migrates via the lymphatics to reside in the pleural space, where local macrophages activated via the IL-4 receptor are critical players in infection outcome (4). It was recently described that L. sigmodontis migrates through the lung (5) but almost nothing is known about the host response during this stage of the infection, or the subsequent consequences for the parasite. The laboratories of Allen, Sutherland and MacDonald have extensive experience with models of type 2 mediated lung pathology and helminth infection. This PhD project will evaluate for the first time the immunology associated with lung migration of a filarial nematode and assess the consequences for lung repair and parasite control, with significant implications for understanding the role of macrophages and dendritic cells during type 2-mediated pulmonary inflammation. These finding will have relevance to both helminth infection and allergic inflammation.
https://www.research.manchester.ac.uk/portal/judi.allen.html
https://www.research.manchester.ac.uk/portal/tara.sutherland.html
https://www.research.manchester.ac.uk/portal/andrew.macdonald.html
References
1 - Gause, W. C., Wynn, T. A., & Allen, J. E. (2013). Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nature Reviews Immunology, 13, 607–614.
2 - Sutherland, T. E., Logan, N., Ruckerl, D., Humbles, A. A., Allan, S. M., Papayannopoulos, V., et al. (2014). Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. Nature Immunology, 15, 1116–1125.
3 - Allen, J. E., Adjei, O., Bain, O., Hoerauf, A., Hoffmann, W. H., Makepeace, B. L., Schulz-Key, H., Tanya, V. N., Trees, A. J., Wanji, S., & Taylor, D. W. (2008) Of mice, cattle, and humans: the immunology and treatment of river blindness. PLoS Negl Trop Dis, 2(4).
4 - Ruckerl, D. & JE Allen. J.E. (2014) Macrophage proliferation, provenance & plasticity in macroparasite infection. Immunuological Reviews. 262: 113-133
5 - Karadjian, G., Fercoq, F., Pionnier, N., Vallarino-Lhermitte, N., LEFOULON, E., Nieguitsila, A., et al. (2017). Migratory phase of Litomosoides sigmodontis filarial infective larvae is associated with pathology and transient increase of S100A9 expressing neutrophils in the lung. PLoS Neglected Tropical Diseases, 11(5), e0005596.
Continue with Facebook
