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Cell death modulation by Coxiella burnetii effectors

Grant number: 18/23689-8
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): March 15, 2019
Effective date (End): March 14, 2020
Field of knowledge:Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
Principal Investigator:Dario Simões Zamboni
Grantee:Robson Kriiger Loterio
Supervisor: Hayley Newton
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Melbourne, Australia  
Associated to the scholarship:16/24275-7 - Identification of Coxiella burnetii proteins involved in the modulation of the inflammasome activasion and in the intracellular signaling pathways in macrophages, BP.DD

Abstract

Coxiella burnetii is a Gram-negative bacterium and causative agent of Q fever in humans. The bacterium is highly adapted to infect alveolar macrophages and subvert their functions, including the avoidance of TLR recognition, the inhibition of apoptosis and the modulation of diverse vesicle traffic pathways. Its virulence is dependent on the translocation of bacterial proteins (called effectors) into the host cytoplasm through the Dot/Icm T4BSS, creating a spacious intracellular vacuole that support bacterial replication. Similar to Coxiella, Legionella pneumophila virulence depends on its T4BSS, however, Legionella is more suitable for genetic manipulation, a feature that support the use of Legionella as surrogate host to express Coxiella effectors. Initially, we generated a library of 66 L. pneumophilla flaA mutants expressing Coxiella effectors. We screened this library and identified 3 Coxiella effectors that may be involved in the manipulation of macrophage functions. Expression of these 3 effectors, CBUA0015, CBUA0006 and CBU1543, by L. pneumophila led to decreased pyroptosis (measured by LDH release and pore formation assays) and increased cytokine production (IL-1² and IL-6). Thus, we aim to visit the laboratory of Dr. Hayley Newton to further study these effectors. We aim to express these effectors in eukaryotic cells, identify the possible eukaryotic partner of these effectors and obtain Coxiella mutants for each effector. This study may help to elucidate the function of these effectors, providing information for our understanding of the evasive mechanisms used by intracellular pathogens to subvert the host cell mechanisms. In addition, this study will lead to the identification of target molecules and pathways to the development of immunological therapies. (AU)

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