The functional migration of immune cells during Leishmania infection is imperative for the activation of a protective immune response. In particular, migration of dendritic cells (DCs) towards the lymphatic vessel network and CCL19-producing lymph node is a key step in the induction of adaptive immunity. Consequently, manipulation of chemokines and chemokine receptors presents a potential mechanism by which parasites can evade protective host immunity. Therefore, the aim of this thesis was to investigate whether Leishmania mexicana can influence immune cell migration and identify the mechanisms underpinning this. Using a combination of in vitro and in vivo studies, the key finding presented in this thesis is that L. mexicana modulates DC migration following infection. While uptake of L. mexicana by DCs is associated with reduced surface expression of CCR7, this does not entirely account for the failure of DC migration and therapeutic targeting of DCs does not enhance protective immunity. Crucially, it is through production of cysteine protease B that L. mexicana can suppress migration of infected and bystander DCs. Parasites lacking cysteine protease B are less able to prevent DC migration and the activity of this important virulence factor is shown to be associated with cleavage of CCL19. In further experiments, it is also demonstrated that effective DC migration following L. mexicana infection may also be influenced by interactions with neutrophils and their NETs and by an early source of interleukin-4/13 acting directly on DCs. Primarily, these findings demonstrate how L. mexicana can utilise immunomodulatory virulence products, like cysteine protease B to manipulate the host immune response. Understanding these mechanisms is invaluable for the development of new drug and vaccine targets against L. mexicana, but may also aid in the development of new treatments for similar chronic infections.
|Date of Award||21 Oct 2015|
- University Of Strathclyde
|Sponsors||University of Strathclyde & BBSRC (Biotech & Biological Sciences Research Council)|
|Supervisor||Owain Millington (Supervisor) & James Alexander (Supervisor)|