Cell membrane Complex Enzyme Eukaryotic cell or cell component Microbe-host cell complex Microorganism or its component Other Other -- ion Pathway or action Protein Protein or gene Protein or gene complex Protein or protein complex Bacterial membrane or virus envelope Cell membrane Cytoplasm Eukaryotic cell or cell component Extracellular Golgi Golgi membrane Intercellular Intracellular Mitochondria Nucleocapsid/Cytoplasm Organelle Organelle -- Cell membrane Organelle -- Endoplasmic reticulum Organelle -- ER Organelle -- Golgi Organelle -- Golgi membrane Organelle -- Nucleus Organelle -- Phagolysosome Organelle -- Phagosome Organelle -- Ribosome Other Phagolysosome Phagosome Chaperone Defense, immunity protein Enzyme Enzyme activator Enzyme inhibitor Genomic S segment Infection Ligand binding or carrier Motor Nucleic acid binding Other Signal transducer Toxicity Transcription factor binding Transcription regulation Transporter Unknown IC Inferred by Curator IDA Inferred from Direct Assay IEA Inferred from Electronic Annotation IEP Inferred from Expression Pattern IGI Inferred from Genetic Interaction IMP Inferred from Mutant Phenotype IPI Inferred from Physical Interaction ISS Inferred from Sequence or Structural Similarity NAS Non-traceable Author Statement ND No biological Data available RCA inferred from Reviewed Computational Analysis TAS Traceable Author Statement NR Not Recorded Howe D, Mallavia LP Infection and immunity Coxiella burnetii exhibits morphological change and delays phagolysosomal fusion after internalization by J774A.1 cells 2000 10858189 PubMed Howe D, Melnicakova J, Barak I, Heinzen RA Cellular microbiology Maturation of the Coxiella burnetii parasitophorous vacuole requires bacterial protein synthesis but not replication 2003 12814437 PubMed Varghees S, Kiss K, Frans G, Braha O, Samuel JE Infection and immunity Cloning and porin activity of the major outer membrane protein P1 from Coxiella burnetii 2002 12438349 PubMed Heinzen RA, Hackstadt T, Samuel JE Trends in microbiology Developmental biology of Coxiella burnettii 1999 10217829 PubMed Baca OG, Paretsky D Microbiological reviews Q fever and Coxiella burnetii: a model for host-parasite interactions 1983 6348504 PubMed Bacterial Ligand Function: Ligand binding or carrier. Internalization into host cells occurs by microfilament-dependent parasite-directed endocytosis. The bacterial ligand(s) and host receptor mediating this process are undefined (Heinzen et al., 1999). In vivo, the initial target is the alveolar macrophage, although the organism can subsequently disseminate to replicate within a wide variety of tissues (Heinzen et al., 1999). Infection by either small cell variants (SCVs) or large cell variants (LCVs) eventually results in parasitophorous vacuoles harboring a mixture of cell types (Heinzen et al., 1999).(Heinzen et al., 1999) Cell Receptor Function: Ligand binding or carrier. Internalization into host cells occurs by microfilament-dependent parasite-directed endocytosis. The bacterial ligand(s) and host receptor mediating this process are undefined (Heinzen et al., 1999).Studies on the nature of the C. burnetii attachment site on the L-929 cell surface showed that only pronase and subtilisin treatment of the L cells significantly inhibited attachment of C. burnetii. This provided circumstantial evidence that proteins are at or near the site of Coxiella attachment. Whether or not there is a specific component to which the parasite attaches is as yet unknown (Baca and Paretsky, 1983).(Heinzen et al., 1999)(Baca et al., 1983) C. burnetii in Phagosome Function: . The nascent parasite-containing phagosomes mature through the endocytic pathway, eventually acquiring the properties of secondary lysosomes (Baca and Paretsky, 1983).(Baca et al., 1983) C. burnetii in Phagolysosome Function: . Cytochemical investigation revealed that the rickettsiae-containing vacuoles are phagolysosomes (Baca and Paretsky, 1983). Once entry into the cell is achieved, both phases of C. burnetii proliferate within vacuoles which eventually fuse and form a single vacuole which occupies most of the cell's volume. The infected cell attains a size several diameters greater than uninfected cells. The nucleus and cytoplasm become displaced to the cell's periphery (Baca and Paretsky, 1983).The lysosomal markers 5'-nucleotidase, acid phosphatase, cathepsin D and lysosomal-associated membrane glycoproteins 1 and 2 co-localize with the lumen of the parasitophorous vacuole (PV) or PV membrane, and the PV acidifies to a pH of approximately 4.8. C. burnetii has an absolute requirement for this moderately acidic pH to activate metabolism and exploits the only intracellular niche capable of establishing such a pH. The organism replicates to high numbers within this vacuole, albeit at a slow replication rate (8-12 h doubling time), despite the presence of toxic host factors, such as acid hydrolases and defensins, which are normally considered bactericidal (Heinzen et al., 1999).(Baca et al., 1983)(Heinzen et al., 1999) C. burnetii in Cytoplasm Function: . Occasionally, C. burnetii has been observed 'free' in the cytoplasm. The possibility that these free rickettsiae may have a closely opposed host membrane has not been excluded (Baca and Paretsky, 1983).(Baca et al., 1983) Small Cell Variant (SCV) in Phagolysosome Function: . Several reports present electron microscopic evidence suggesting that C. burnetii exhibits two morphological forms, a large and small form (Baca and Paretsky, 1983). A typical C. burnetii parasitophorous vacuole contains a continuum of morphological forms, within which are the morphologically distinct large cell variants (LCV) and small cell variants (SCV), which can be separated on the basis of different buoyant densities (Heinzen et al., 1999). The SCVs are typically between 0.2 and 0.5 um in size, rod shaped and very compact. The visible periplasmic space is replaced with an electron-dense region bounded by the outer and cytoplasmic membranes. The most distinctive ultrastructural characteristic of the SCV is the electron-dense chromatin. The SCVs also harbor a complex system of internal membranes arranged in whorls that could be contiguous with the cytoplasmic membrane (Heinzen et al., 1999). The LCV and the SCV divide by binary fission, and both are infectious in in vitro and in vivo models (Heinzen et al., 1999)>(Baca et al., 1983)(Heinzen et al., 1999) Small Cell Variant (SCV) Extracellular Function: . The SDC and SCV may represent the forms of the bacteria likely to survive as infectious particles extracellularly (Varghees et al., 2002).(Varghees et al., 2002) Large Cell Variant (LCV) in Phagolysosome Function: . Several reports present electron microscopic evidence suggesting that C. burnetii exhibits two morphological forms, a large and small form (Baca and Paretsky, 1983). A typical C. burnetii parasitophorous vacuole contains a continuum of morphological forms, within which are the morphologically distance large cell variants (LCV) and small cell variants (SCV), which can be separated on the basis of different buoyant densities (Heinzen et al., 1999). The LCVs can reach a length exceeding 1.0 um and are similar in form to typical Gram-negative bacteria in that they posess a clearly distinguishable outer membrane, periplasmic space and cytoplasmic membrane. The LCVs are more pleiomorphic than the SCVs, with a thinner cell wall and a very dispersed nucleoid (Heinzen et al., 1999). Evidence suggests that the LCV are more metabolically and replicatively active than SCVs. As such, they might play a more important role than the SCV in cell-to-cell spread within the host (Heinzen et al., 1999). The LCV and the SCV divide by binary fission, and both are infectious in in vitro and in vivo models (Heinzen et al., 1999).(Baca et al., 1983)(Heinzen et al., 1999) Spore-like Particle (SLP) in Phagolysosome Function: . The possible biogenesis of a spore-like particle (SLP) has also been suggested. SLPs have been observed as electron-dense polar bodies in the large cell variants (LCV) and are speculated to have endospore-like properties. McCaul and Williams surmise that the small cell variants (SCV) and/or SLPs are extracellular survival stages (Heinzen et al., 1999).The notion of sporogenesis by C. burnetii is of continuing debate. This alternative form of replication was originally proposed by McCaul and Williams in 1981 and is based on morphological data gathered by TEM examination of purified cells. The impetus for this proposal is the occasional appearance of an electron-dense, membrane bound SLP within the LCVs. SLPs are approximately 130-170 nm in diameter and are bounded by a limiting membrane. They are observed only in those cells morphologically identified as LCVs, with formation thought to occur by a process that resembles asymmetric cell division. From the center outward, the SLP is believed to be composed of a dense core containing DNA,a system of membranes, peptidoglycan and outer membrane. The antigenic character of the SLP remain elusive (Heinzen et al., 1999). A major impediment to the study of the SLP is an inability to obtain these particles in pure form. Until SLPS are purified and shown to be infectious, the existence of this developmental form in the C. burnetii developmental cycle must be considered hypothetical (Heinzen et al., 1999).(Heinzen et al., 1999) Large Cell Variant (LCV) Extracellular Function: . The observation that LCVs are infectious in vitro might have little relevance to natural transmission and infection because the fragile LCVs probably do not persist extracellularly in an infectious form for extended periods (Heinzen et al., 1999). The LCV are fragile, probably not surviving extracellularly for extended periods (Varghees et al., 2002).(Heinzen et al., 1999)(Varghees et al., 2002)