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Evaluation of the genetic control of macrophage susceptibility to infection with Coxiella burnetii

Grant number: 12/01612-7
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2012
Effective date (End): November 30, 2013
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Talita Duarte Fernandes
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The resistance against infectious agents, in general, is regulated by multiple genes that control different aspects of the host/parasite relationship. The use of inbred mouse strains and their informative populations to determine resistance and susceptibility phenotypes and to establish genetic variation patterns are fundamental tools for the identification of genes that contribute to the resistance of hosts. Coxiella burnetii is an intracellular pathogen highly adapted to subvert the cellular functions, including evasion of host immune responses. The difference in the susceptibility of macrophages from different murine strains to C. burnetii infection is still poorly understood. Even so, it is known that C. burnetii succumbs to peritoneal macrophages from C57BL/6 mice whereas cells from the A/J strain are susceptible to infection. This difference in susceptibility is also observed in response to infection by Legionella pneumophila, an intracellular pathogen phylogenetically close to C. burnetii. In the case of L. pneumophila, the A/J susceptibility has been mapped to a single gene within the locus lgn1 that encodes the nod-like receptor Naip5. Naip5 is essential to the activation of caspase-1 inflammasome thus culminating in infection control. Overall, the possibility of finding new genes that contribute to infection control, the importance of understanding the molecular basis of host-pathogen interaction, and the biomedical importance of C. burnetii justify the development of this research proposal, based on the following objectives: 1) evaluate by qPCR the susceptibility of bone marrow-derived macrophages and alveolar macrophages from the murine strains C57BL/6, A/J, BALB/c and DBA to infection by Coxiella burnetii; 2) evaluate the susceptibility pattern in the F1 generation from crossing the strains A/J x C57BL/6 (and possibly other strains with differences in susceptibility to infection) and 3) evaluate the involvement of Naip5 and the inflammasome in the higher susceptibility of macrophages from A/J to infection by C. burnetii. (AU)

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