Studies on the relation between antigen presentation and mycobacterial trafficking and on the importance of coronin 1 in mycobacterial pathogenesis, neutrophil- and B lymphocyte functions

摘要

The immune system developed to prevent infections with pathogenic intruders without inducinguduncontrolled reactions that could be harmful to the host. As a result, the activation of the immuneudsystem is a well-controlled process including recognition of the invading bacteria and cooperationudbetween different cell types. However, some pathogens can still avoid this immune surveillance byudusing multiple and sophisticated mechanisms. A particular notorious example is Mycobacteriumudtuberculosis. About one third of the global population has been exposed to this pathogen and whileuda healthy person can deal with this infection it can lead to severe symptoms inudimmunocompromised patients.udPathogenic mycobacteria are recognized and internalized inside macrophages where they can blockudthe maturation of their phagosomes into lysosomes thereby residing and surviving inside host cells.udFirstly, we showed that mycobacteria lacking the virulence factor PknG, an eukaryotic-likeudserine/threonine protein kinase, could not resist to lysosomal delivery inside professional antigenudpresenting cells. It was then demonstrated that this efficient transfer of the mycobacterium to theudlysosomes did not modify the presentation of mycobacterial peptides on MHC molecules whenudcompared to wild type mycobacteria residing inside phagosomes. This suggests that the traffickingudof mycobacteria to different organelles does not influence the quality of the antigen presentation.udCoronin 1 is a leukocyte-specific protein that is recruited and retained around phagosomesudcontaining pathogenic mycobacteria. In the second part of this thesis, we demonstrate thatudmycobacteria cannot resist lysosomal delivery when infecting macrophages lacking coronin 1udexpression. However, this dramatic change in trafficking is not due to an altered signaling uponudTLRs triggering but to the calcineurin activity that is affected in the absence of coronin 1.udThirdly we showed that the absence of coronin 1 did not affect the main functions of neutrophils.udThe morphology of the neutrophils lacking coronin 1 was not affected as well as several actindependentudprocesses such as adhesion, spreading, phagocytosis and chemotaxis. The oxidativeudburst was also not disturbed in the absence of coronin 1.udFourthly, this thesis describes the capacity of the immune system to respond against antigens inudmice lacking coronin 1. The absence of coronin 1 did not compromise the ability of the animals toudmount an immune response even if coronin 1 was essential for calcium release in B lymphocytesudupon BCR triggering. These results argue for a general role of coronin 1 in mediating cytosolicudCa2+ mobilization rather than regulating actin-dependent processes.udTaken together, the results presented in this thesis provide indications for a better understanding ofudmycobacteria-host interactions and coronin 1 functions in leukocytes.