Exploitation of clathrin by Coxiella burnetii
AuthorLatomanski, Eleanor Anne
AffiliationMicrobiology & Immunology
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-09-18.
© 2019 Eleanor Anne Latomanski
Effector proteins, and intracellular bacteria more broadly, pose a unique opportunity to not only understand bacterial pathogenesis, but also to unravel more about the cell biology behind the host processes that these bacteria target. Clathrin and clathrin-mediated endocytosis are commonly exploited by bacteria for entry into human host cells. Uniquely, Coxiella burnetii is the only bacterial pathogen that requires clathrin as an integral part to facilitate intracellular replication. Coxiella replicates within a lysosome-like compartment termed the Coxiella-containing vacuole (CCV), and translocates effector proteins into the host cytoplasm. The effector Cig57 is responsible for hijacking clathrin for the benefit of Coxiella, redirecting it to the CCV in a manner dependent on the clathrin-related protein FCHO2. This research shows that Cig57, FCHO2 and clathrin itself are all required for the Coxiella lifecycle, supporting the model wherein clathrin heavy chain is directed to the CCV to enable full virulence of Coxiella inside the human host. Cig57 does not act alone to exploit and re-direct host cellular clathrin. Two genes downstream of cig57, cbu1752 and cbu1754, both encode effector proteins. All three protein products interact in a complex with FCHO2 in human cells, and CBU1752 physically interacts directly with clathrin heavy chain. Both CBU1752 and CBU1754 also enable optimal intracellular replication and are necessary for clathrin accumulation on the CCV, indicating the non-redundant nature of these effectors which work together for a common goal. These findings show that clathrin heavy chain is a highly modulated and vital factor for Coxiella replication inside cells. Further to the work on clathrin and FCHO2, work in this Thesis shows that clathrin contributes to the fusion of autophagosomes with the CCV. In the absence of clathrin, autophagosomes can no longer deliver LC3B to the CCV nor contribute to the growing CCV membrane. This highlights a non-canonical role for clathrin heavy chain, distinct from endocytosis, during Coxiella infection. The exploitation of clathrin may constitute novel mechanisms for the bacteria to acquire nutrients for replication, membrane for the expanding CCV, or enable increased stability of this large intracellular compartment. Together, these data provide novel insights into effector biology, particularly in the co-operative nature of effectors which together act to manipulate clathrin. Not only are effector protein relationships complex and heavily intertwined, but so is the clathrin molecule and its relationship to a wide range of host processes. Exploitation of the full range of clathrin activities by inter-connected effectors enables Coxiella to achieve optimal growth and intracellular success, and opportunities for researchers to further understand both mammalian and bacterial biology.
KeywordsCoxiella; bacteria; pathogen; effector; clathrin; endocytosis; autophagy
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