| الوصف: |
Natural Killer (NK) cells are important effector cells for control of cytomegalovirus (CMV) infection. Understanding the mechanisms which contribute to antiviral control by NK cells may inform on the development of safe and effective treatments for viral infection such as NK cell-based therapies. The first aim of this thesis was to identify genes required for control of cytomegalovirus replication using an in vivo MCMV infection screen. Several genes of interest which affected acute viral replication control were discovered from the in vivo screen including Fam111a, Fam114a2, Far1, Heatr9, Serpinb9b and Sytl3. The second aim was to examine how gene(s) of interest regulate NK cell functions. The novel gene Synaptotagmin-like 3 (Sytl3) was chosen for further investigation as it was almost exclusively expressed by mouse (and human) NK cells and Sytl3 deficiency led to a significant impairment in MCMV\ud replication control. Members of the sytl family have been implicated in vesicular trafficking events due to their ability to bind Rab27 proteins which are important in secretory pathways (Taruho S. Kuroda et al., 2002). Interestingly, Sytl3 deficient NK cells had reduced\ud degranulation in response to a variety of stimuli and my studies revealed that sytl3 may drive microtubule organising centre (MTOC) polarisation towards the immunological synapse, which is a key step for efficient degranulation. Therefore, this work provides novel insight into NK cell effector function whereby optimal degranulation in response to MCMV (and possibly other stimuli) contributes to the effective control of acute viral infection. |
