On the components of adaptive immune response involved in the control of a primary and secondary infection by Brucella melitensis

Abstract

Brucellosis is a bacterial zoonose caused by organisms belonging to the genus Brucella. These bacteria are facultative intracellular pathogens that cause abortion in domestic (cattle, goats, sheeps, etc.) and wild (deers, bisons, etc.) animals and a febrile chronic illness in humans. The disease exists worldwide and continues to have a great health significance and economic importance in developing countries. Despite past and current efforts to eradicate brucellosis by vaccination and culling within cattle and herds, as many as 500 000 new human cases are reported annually worldwide. Vaccines against brucellosis were initially developed on an empirical basis. The current studies are moving towards a more rational design but are hindered by an incomplete knowledge of the in vivo life style of Brucella and the immune mechanisms involved in the establishment of a protective memory. Despite progresses, several fields of host adaptive immunity remain highly controversial such as the implication of B cells, CD4+ and CD8+ T cells. While it is commonly accepted that Brucella infection induces a Th1 immune response characterized by the production of IFN-γ that activates bactericidal mechanisms of macrophages, little has been described with regards to a potential implication of the Th2 response or the recently described Th17 response. Objectives of this thesis were therefore to determinate the implication of lymphocyte subsets and signaling pathways after primary infection with Brucella melitensis and characterize their roles in the development of a protective secondary immune response in the murine experimental model. In the first part of this study we clearly confirm the central role of MHC-II-dependent antigen presentation to CD4+ T cells and the IFN-γ-mediated Th1 response in the control of B. melitensis primary infection. We also report that the absence of B cells, MHC-I-dependent antigen presentation, Th2 and Th17 responses appears to have no important positive or negative impact on the course of infection. In the second part of this work, we show that Brucella is able to persist several weeks in the blood of infected mice. Surprisingly, we found that bacteria are initially localized extracellularly and then infect erythrocytes where they are already detectable after 24h. Finally, the last part demonstrates that humoral immunity and CD4+ Th1 cells are both necessary and complementary for a sterilizing immune response upon a secondary infection with B. melitensis. Circulating specific antibodies and IFN-γ production by CD4+ T cells activated at the site of infection after the re-call infection appear as key immunological markers of protection in the murine experimental model of Brucella infection. In conclusion, this work improves our understanding of the nature of murine immune response developed following B. melitensis infection and tries to provide correlates of protection that could help to define rational strategies for designing new vaccines against brucellosis. This study also reveals for the first time that erythrocytes constitute an unexpected niche for Brucella, and maybe a currently undescribed way of transmission by blood-sucking arthropods.

Date of Award	15 Mar 2013
Original language	English
Awarding Institution	University of Namur
Supervisor	JEAN-JACQUES LETESSON (Supervisor), Éric Muraille (Co-Supervisor), Carine Michiels (President), Oberdan Leo (Jury), Bruno Goddeeris (Jury) & Cynthia Baldwin (Jury)