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Infect Immun. 2019 Dec 9. pii: IAI.00534-19. doi: 10.1128/IAI.00534-19. [Epub ahead of print]

Biogenesis of the spacious Coxiella-containing vacuole depends on host transcription factors TFEB and TFE3.

Author information

1
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
2
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia.
3
Biological Optical Microscopy Platform, The University of Melbourne, Parkville, VIC, Australia.
4
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. hnewton@unimelb.edu.au.

Abstract

Coxiella burnetii is an obligate intracellular bacterial pathogen that replicates inside the lysosome-derived Coxiella-containing vacuole (CCV). To establish this unique niche, C. burnetii requires the Dot/Icm type IV secretion system (T4SS) to translocate a cohort of effector proteins into the host cell that modulate multiple cellular processes. To characterize the host-pathogen interactions that occur during C. burnetii infection, SILAC based proteomics was used to identify changes in the host proteome during infection of a human-derived macrophage cell line. These data revealed that the abundance of many proteins involved in host cell autophagy and lysosome biogenesis were increased in infected cells. Thus, the role of host transcription factors TFEB and TFE3, which regulate the expression of a network of genes involved in autophagy and lysosomal biogenesis, were examined in the context of C. burnetii infection. During infection with C. burnetii, both TFEB and TFE3 were activated as demonstrated by transport of these proteins from the cytoplasm into the nucleus. Nuclear translocation of these transcription factors was shown to be dependent on the T4SS as a Dot/Icm mutant showed reduced nuclear translocation of TFEB and TFE3. This was supported by the observation that blocking bacterial translation with chloramphenicol resulted in the movement of TFEB and TFE3 back into the cytoplasm. Silencing of tfeb and tfe3, alone or in combination, significantly reduced the size of the CCV, which indicates that these host transcription factors facilitate expansion and maintenance of the organelle that supports C. burnetii intracellular replication.

PMID:
31818957
DOI:
10.1128/IAI.00534-19

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