title: Effector Protein Cig2 Decreases Host Tolerance of Infection by Directing Constitutive Fusion of Autophagosomes with the Coxiella-Containing Vacuole.
abstract: Coxiella burnetii replicates in an acidified lysosome-derived vacuole. Biogenesis of the Coxiella-containing vacuole (CCV) requires bacterial effector proteins delivered into host cells by the Dot/Icm secretion system. Genetic and cell biological analysis revealed that an effector protein called Cig2 promotes constitutive fusion of autophagosomes with the CCV to maintain this compartment in an autolysosomal stage of maturation. This distinguishes the CCV from other pathogen-containing vacuoles that are targeted by the host autophagy pathway, which typically confers host resistance to infection by delivering the pathogen to a toxic lysosomal environment. By maintaining the CCV in an autolysosomal stage of maturation, Cig2 enabled CCV homotypic fusion and enhanced bacterial virulence in the Galleria mellonella (wax moth) model of infection by a mechanism that decreases host tolerance. Thus, C. burnetii residence in an autolysosomal organelle alters host tolerance of infection, which indicates that Cig2-dependent manipulation of a lysosome-derived vacuole influences the host response to infection.
  
  
  
  Coxiella burnetii is an obligate, intracellular bacterial pathogen that replicates inside a unique, lysosome-like compartment called the Coxiella-containing vacuole (CCV). Over 130 bacterial effector proteins are delivered into the host cell cytosol by the C. burnetii Dot/Icm type IV secretion system. Although the Dot/Icm system is essential for pathogenesis, the functions of most effectors remain unknown. Here we show that the effector protein Cig2 is essential for converting the CCV to an organelle that is similar to the autolysosome. Cig2 function promotes constitutive fusion between the CCV and autophagosomes generated by selective autophagy. Cig2-directed biogenesis of an autolysosomal vacuole is essential for the unique fusogenic properties of the CCV and for virulence in an animal model of disease. This work highlights how bacterial subversion of the host autophagy pathway can influence the cell biological properties of the CCV and influence the host response to infection.
authors.affiliation: Department of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Kohler
authors.affiliation: Department of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shawna  C O
authors.initials: ShC
authors.lastname: Reed
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Shireen A
authors.initials: SA
authors.lastname: Sarraf
authors.affiliation: Department of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Arteaga
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Hayley J
authors.identifier: 0000-0002-9240-2001
authors.initials: HJ
authors.lastname: Newton
authors.affiliation: Department of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA craig.roy@yale.edu.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D016997:Coxiella burnetii / Q000472:pathogenicity*; D004195:Disease Models, Animal; D060467:Disease Resistance; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000382:microbiology; D054884:Host-Pathogen Interactions; D007915:Lepidoptera; D014617:Vacuoles / Q000378:metabolism* / Q000382:microbiology*
chemical_list: D001426:Bacterial Proteins