Jean Celli, Ph.D.

Head, Tularemia Pathogenesis Section

Dr. Celli received his Ph.D. in microbiology from the Université Pierre et Marie Curie, Paris, France in 1997. After completing postdoctoral training in 2001 in the laboratory of Dr. B. Brett Finlay at the University of British Columbia, Vancouver, Canada, Dr. Celli accepted a research scientist position from the Institut National de la Santé et de la Recherche Médicale (INSERM) to work at the Centre d’Immunologie de Marseille-Luminy, Marseille, France. In 2004, he was recruited to NIH as a tenure-track investigator in the Laboratory of Intracellular Parasites. He is a member of the American Society for Microbiology.

Description of Research Program

The focus of our research is to understand the molecular mechanisms by which intracellular bacterial pathogens circumvent host defense mechanisms and, in particular, survive and replicate within mammalian cells. To study these processes, we use Francisella tularensis (the causative agent of tularemia) and Brucella abortus (the causative agent of brucellosis) as model pathogens. Essential to the pathogenesis of these intracellular bacteria is their ability to survive and replicate within macrophages of the host. We are combining microbiology, genomics, and cell biology approaches to identify the mechanisms that allow Francisella and Brucella to evade the degradative pathways and generate an intracellular replicative niche.

Research projects on Francisella tularensis aim to: 1) better define the intracellular life cycle of this bacterium inside macrophages, using confocal microscopy and live cell imaging methodologies to understand the mechanisms of Francisella evasion from intracellular killing; and 2) identify Francisella genes required for intracellular survival and replication through both trancriptional profiling inside macrophages and mutagenesis approaches.

Brucella abortus evades interactions with late compartments of the endocytic degradative pathway and promotes interactions of its vacuole with the host endoplasmic reticulum (ER) to generate an ER-derived organelle that is permissive for replication. Biogenesis of this unique organelle requires functional ER exit sites and is dependent upon the Brucella VirB type IV secretion system, a machinery dedicated to the translocation of bacterial proteins into the host cell. Such proteins are likely to modulate host functions to alter intracellular trafficking of the Brucella-containing vacuole (BCV) and allow bacterial survival.

Research projects on Brucella use bacterial genetics, genomics, and cell biology approaches to: 1) understand the mechanisms of BCV-ER fusion; 2) identify proteins translocated by the VirB apparatus and their host cell targets in order to understand the biogenesis of the Brucella replicative organelle at the molecular level.

Figure 1. Scanning electron micrograph of a bone marrow-derived macrophage (pseudocolored in blue) infected with Francisella tularensis strain LVS (peusodcolored in yellow) for 24h. After fixation, macrophages are mechanically fractured open to reveal replicating intracellular bacteria. Bacteria are located either in the cytosol or within autophagic vacuoles. Micrograph courtesy of Elizabeth Fischer.

Figure 2. Model of intracellular trafficking and survival of Brucella inside macrophages. After phagocytic uptake, intracellular Brucella resides within a vacuole (BCV) that interacts with early endosomes. These early BCVs avoid fusion with late endocytic compartments, yet acquire LAMP-1, and interact with endoplasmic reticulum (ER) exit sites (ERES) within the first hours after infection (A). Such interactions are sustained over time and lead to limited fusion events with the ER (B), ultimately generating an ER-derived organelle permissive for Brucella replication (C). Biogenesis of the replicative organelle requires the Brucella VirB type IV secretion system and Sar1-dependent functions of the ER exit sites.

Figure 3. (A). Differential Interference Contrast (DIC) and fluorescence micrograph of a bone marrow-derived macrophage infected with GFP-expressing Brucella abortus. Bacteria (green) are seen replicating in the perinuclear area of the cell. (B). Confocal microscopy micrograph of a murine bone marrow-derived macrophage infected with GFP-expressing Brucella abortus for 24 h. Intracellular Brucella (green) replicate within ER-derived vacuoles (calnexin staining, red) segregated from the endocytic pathway. (LAMP-1 staining, blue).

Research Group Members

Jean Celli, Tara Wehrly, Jessica Edwards, Tony Ng, Tregei Starr and Audrey Chong 

Selected Publications

View list in PubMed.

C. Checroun, T. D Wehrly, E. R. Fisher, S. F. Hayes and J. Celli. 2006 Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment following cytoplasmic replication. Proc. Natl. Acad. Sci. USA, 103(39): 14578-14583.

Celli J, Salcedo SP, Gorvel J-P. Brucella coopts the small GTPase Sar1 for intracellular replication. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1673-8.

Celli J, de Chastellier C, Franchini D-M, Pizarro-Cerda J, Moreno E, Gorvel JP. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med. 2003. 198: 545-556.

Knodler LA, Celli J, Hardt W-D, Vallance BA, Yip C, Finlay BB. Salmonella effectors within a single pathogenicity island are differentially expressed and translocated by separate type III secretion systems. Mol Microbiol. 2002. 43(5): 1089-1104.

Knodler LA, Celli J, Finlay BB. Pathogenic trickery: deception of host cell processes. Nat Rev Mol Cell Biol. 2001. 2: 578-588.

Celli J, Olivier M, Finlay BB. Enteropathogenic Escherichia coli mediates antiphagocytosis through the inhibition of PI 3-kinase-dependent pathways. EMBO J .2001. 20(6): 1245-1258.

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