Determining Important Pulmonary Regulators of Immunity to the Bacterium Francisella tularensis

Abstract

The regulation of pulmonary immune homeostasis is important in maintaining immune ignorance to harmless stimuli, to avoid a continuous inflammatory environment. Yet, it must also allow for the production of appropriate protective immune responses against potentially harmful pathogens. However, some pathogens can subvert the immune response to increase survival. An important example is Francisella tularensis, a highly infectious Gram-negative intracellular bacterium that dampens the immune response early in infection to aid bacterial replication. Understanding the function of host pulmonary regulatory pathways during F. tularensis infection may allow novel therapeutic targets to be identified. This PhD thesis identifies an unexpected pathway that promotes host responses during bacterial infection of the lung. Thus, expression of the CD200 receptor (CD200R), a molecule previously associated with dampening immune responses in the lung, is required to limit infection by the lethal intracellular bacterium F. tularensis. Lack of CD200R expression enhanced infectious burden in vitro and in vivo. Exacerbated pulmonary F. tularensis burden was determined to be neutrophil-dependent, with depletion of neutrophils in vivo during F. tularensis infection abrogating the increased bacterial burden in lungs of CD200R-/- mice. Mechanistically, it was determined that CD200R-/- neutrophils having a significantly decreased ability to produce ROS compared to WT, thus contributing to a reduced capability to deal with F. tularensis infection. Data in this thesis suggests that the absence of CD200R on neutrophils aids the colonisation and proliferation of F. tularensis in the lung via reduction of neutrophil ROS production; highlighting the important role this pathway plays in promoting immunity to infection. Maintaining the antimicrobial properties of neutrophils via the CD200R pathway may represent a novel therapeutic approach for treating intracellular pathogens.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Tracy Hussell (Supervisor)