Newton laboratory: Virulence strategies of intracellular bacterial pathogens
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We study the emerging and dangerous human pathogens Coxiella burnetii, the causative agent of Q fever, and Legionella species, the causative agents of Legionnaires' disease. These pathogens replicate inside human cells to cause disease. This requires the pathogen to employ creative strategies to hijack the host cell and create a unique niche that can support bacterial replication. In order to cause disease, the pathogens must develop means to avoid host defenses and obtain essential nutrients for replication. Most intracellular bacterial pathogens achieve this through the use of specialized secretion systems that transport a cohort of virulence proteins, termed effectors, into the host cytosol. Coxiella and Legionella both use the Dot/Icm Type IV Secretion System to deliver effectors into human cells. This secretion system is essential for both pathogens to replicate intracellularly and cause disease. The Dot/Icm system is only active when the bacteria reach the specific host niche that they manipulate. We are interested in understanding how the pathogens sense these environmental cues and what the host triggers are that contribute to activation of the Dot/Icm system.
Figure 1: Rapidly after uptake the LCV is Sec22b positive. Sec22b (green), a host SNARE important for vesicular trafficking between the ER and Golgi, is recruited to the LCV in a manner dependent on the Dot/Icm System. Legionella longbeachae in red and host nuclei in blue.
Despite sharing this central mechanism to facilitate intracellular replication, Coxiella and Legionella establish distinct vacuolar replicative niches within eukaryotic cells. The Legionella-containing vacuole (LCV) evades endocytic maturation and disguises the nature of the vacuole by interacting with secretory vesicles (Figure 1). In contrast, the Coxiella-containing vacuole (CCV) is trafficked to the acidic and proteolytic lysosomal compartment where the bacteria become metabolically active and manipulate the compartment to support replication (Figure 2 & 3). As such Coxiella virulence is dependent on both the host endocytic trafficking pathway and the Coxiella Dot/Icm effectors which act to modulate the lysosomally derived CCV into a highly fusogenic and anti-apoptotic vacuole within which the bacteria replicate to extremely high numbers (Figure 3).
Figure 2: Coxiella burnetii replicate to high numbers in a lysosome-like vacuole. Bacteria (red) reach high numbers 5 days after infection of HeLa cells (nuclei in blue) within a vacuole reminiscent of a lysosome (LAMP1, a lysosomal marker, in green).
These diverse intracellular niches of Coxiella and Legionella are mediated through their homologous Dot/Icm Type IV Secretion Systems. The pathogens distinct and unique cohorts of effector proteins control this diversity. To date approximately 300 Legionella and 100 Coxiella Dot/Icm effectors have been identified and we are interested in understanding how these unique cohorts of effectors facilitate intracellular replication and disease. Our research focuses on characterizing the biochemical functions and relative importance of effector proteins of the Dot/Icm system as well as how they impact on the eukaryotic cell biology.
Figure 3: Coxiella burnetii relies on both host and bacterial factors for intracellular replication.
Chen Ai Khoo, Research Assistant
Patrice Newton, NHMRC Research Officer
Jennifer Moffatt, NHMRC Research Officer
Eleanor Latomanski, PhD student
Rebecca Wood, PhD student
Miku Kuba, Honours student
Prof Liz Hartland, Department of Microbiology and Immunology, University of Melbourne
Prof Craig Roy, Department of Microbial Pathogenesis, Yale University
Dr Dario Zamboni, Innate Immunity and Microbial Pathogenesis Laboratory, University of Sao Paulo
Dr Fiona Sansom, Veterinary Science Faculty, University of Melbourne
Dr Diana Stojanovski, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne
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For further information about this research, please contact Head of Laboratory Dr Hayley Newton
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