Role of dendritic cells in Mycobacterium avium subspecies paratuberculosis infection

Abstract

<p>Mycobacterium avium subspecies paratuberculosis ( M. paratuberculosis) is an intracellular pathogenic bacillus that causes severe granulomatous enteritis and lymphadenitis in ruminants and is a public health concern. The host immune responses against M. paratuberculosis infection are not completely understood. Limited information is available describing how M. paratuberculosis infection affects dendritic cells (DC) function and the role of DC in the formation and organization of M. paratuberculosis induced granuloma. Given the central role of DC in the initiation and regulation of the host immune response, the studies described in this dissertation examined the modulation of DC by M. paratuberculosis, and also the effects of M. paratuberculosis vaccination on the DC function upon M. paratuberculosis challenge.;M. paratuberculosis infected monocyte-derived DC showed some evidences of maturation, but infected DC were unable to present antigen via MHC II and produce pro-inflammatory cytokines. Secondly, M. paratuberculosis subcutaneous infection model system was used to study DC function in M. paratuberculosis infection in vivo. Compared to M. paratuberculosis vaccine induced granulomas, CD11c+ DC-like cells were present in lower numbers and had an incomplete maturation phenotype within M. paratuberculosis induced granulomas. These DC-like cells induced antigen-specific CD4 T cell response while providing poor co-stimulation and cytokine signals. Thirdly, the maturation status and function of DC in the lymph node draining M. paratuberculosis infection site (CLN) were determined. Greater numbers of CD11c+ cells and B cells were found in the CLN in vaccinated animals compared to the CLN in non-vaccinated animals. These DC-like cells had a mature phenotype and produced high levels of IL-12 and IL-10. Vaccinated animals CLN had high CD4 T lymphocyte recall response upon antigen-loaded DC re-stimulation and produced high levels of IFN-gamma and IL-4.;Taken together, the studies in this dissertation demonstrate that M. paratuberculosis infects DC and results in impaired or incomplete DC activation and maturation. M. paratuberculosis infected DC are unable to provide optimal co-stimulatory and cytokine signals to antigen-specific T lymphocytes, resulting in low IFN-gamma production. M. paratuberculosis vaccination affects DC function upon M. paratuberculosis challenge, inducing a mixed pro-and anti-inflammatory response.</p>