Abstract
ABSTRACTCoxiella 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.
Highlights
Coxiella burnetii is an obligate, intracellular, bacterial pathogen that is the causative agent of Q fever, which is a flu-like illness that can occur when humans are exposed to C. burnetii shed by infected animals [1, 2]
LC3 remained associated with vacuoles containing wildtype C. burnetii for the duration of infection, whereas LC3 was not detected on vacuoles containing the cig2::Tn mutant at any stage of infection
The recruitment of LC3 to vacuoles containing C. burnetii requires the function of Cig2, which is an effector protein that is delivered into host cells only once bacteria have established residence in an acidified late endosomal compartment
Summary
Coxiella burnetii is an obligate, intracellular, bacterial pathogen that is the causative agent of Q fever, which is a flu-like illness that can occur when humans are exposed to C. burnetii shed by infected animals [1, 2]. Acidification of the vacuole containing C. burnetii results in activation of the Dot/Icm type IV secretion system (T4SS), which delivers a repertoire of over 100 bacterial proteins called “effectors” into the host cell cytosol [4,5,6,7,8,9]. The external membrane of the autophagosome fuses with the membrane of a lysosome to create a hybrid organelle called an autolysosome. This fusion event results in the delivery of the internal autophagic vesicle containing cargo called an “autophagic body” into the lumen of the lysosome. Once the autophagic cargo has been degraded, lysosomes are regenerated [23]
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