AbstractBrucella melitensis is a facultative intracellular bacterium responsible for one of the most common zoonosis in the world, mainly transmitted by oral ingestion of contaminated food and aerosol. Infected humans usually have an undulant fever that can become a chronic disease if it is not treated. Abortion and sterility are the major symptoms in domestic and wild animals. The classical intraperitoneal (i.p.) model of infection in mice has been useful for discovering virulence factors of Brucella and characterizing effectors of protective host immunity. But this model is not representative of the natural route of infection and much remains unknown regarding the immune response and mechanisms developed by Brucella to persist in the host. Consequently, we decided to develop an intranasal (i.n.) model of infection to study the immune response of mice against Brucella melitensis infection.
In the first part of the study, using wild type and genetically deficient C57BL/6 mice, we analyzed the nature and the function of immune cellular populations controlling Brucella infection, including the action of specific components of mucosal immunity. We confirmed the crucial role of IFN-γ-producing CD4 Th1 cells in the control of the primary i.n. infection by Brucella melitensis. We also observed an early role for γδ T lymphocytes and production of IL-17A in the control of the bacterial load in lungs. We showed that B lymphocyte deficiency does not affect the efficiency of the primary or secondary immune response against Brucella.
In the second part of the work, using susceptible IL12p40-deficient BALB/c mice, we characterized the preferential cellular niche for Brucella in the spleen during the persistent phase of infection. We confirmed that Brucella melitensis exhibits a tropism for the myeloid lineage in susceptible IL12p40-deficient BALB/c mice. The large majority of infected cells expressed CD11c and CD205 markers, which are specific for dendritic cells. But they are lipid-rich and they display high levels of arginase1, a typical marker of IL-4-induced alternatively activated M2 macrophages. To determine if these cells are Th2-induced M2 macrophages, we analysed the impact of IL-4/STAT6 signaling deficiency on the course of infection and the phenotype of infected cells in IL12p40-deficient mice. We observed no differences between IL-12p40 and IL-12p40/STAT6 deficient mice, demonstrating that infected cells are not dependent on IL-4 and cannot be considered as alternatively activated M2 macrophages induced by the Th2 response.
In conclusion, this work provides a better understanding of the immune response induced by Brucella melitensis in an i.n. model of infection, and describes, for the first time, the phenotype of a preferential cellular niche of the pathogen in susceptible mice during the chronic phase of infection.
|Date of Award||4 Dec 2014|
|Supervisor||JEAN-JACQUES LETESSON (Supervisor), BENOIT MUYLKENS (Jury), Kris Huygen (Jury), Camille LOCHT (Jury), Jacques Godfroid (Jury) & Eric MURAILLE (Supervisor)|
Relationship between Brucella melitensis and the associated immune response after intranasal infection in mice
Hanot-Mambres, D. (Author). 4 Dec 2014
Student thesis: Doc types › Doctor of Sciences