Program Description
A significant number of bacterial diseases is caused by pathogens with an intracellular cycle essential to their virulence. The focus of our research is to understand the molecular mechanisms by which such pathogens circumvent host defense mechanisms and survive and replicate within mammalian cells. We use Francisella tularensis and Brucella abortus, whose pathogenesis relies on their ability to survive and replicate within macrophages of the host. By combining microbiology, cell biology, and genomics approaches, we aim to identify the molecular mechanisms that allow these pathogens to evade host cell degradative pathways, generate an intracellular replicative niche, and egress from host cells.
Credit: NIAID
Type IV secretion and Brucella intracellular pathogenesis
Brucella abortus is the causative agent of brucellosis, the most common zoonosis worldwide. Following uptake by phagocytic cells, this bacterium resides in a membrane-bound vacuole, the Brucella-containing vacuole (BCV), that matures along the endocytic degradative pathway (eBCV) before interacting with the host endoplasmic reticulum (ER) to generate an ER-derived replicative organelle (rBCV). Biogenesis of this unique organelle relies upon the Brucella VirB type IV secretion apparatus, a nanomachine dedicated to the translocation of bacterial proteins into the host cell. Such proteins likely modulate host functions to control intracellular trafficking of the BCV. Current research on Brucella aims to understand the biogenesis of the rBCV, through the identification and functional characterization of VirB effector proteins and their host targets.
The image at right is a confocal fluorescence micrograph of a murine bone marrow-derived macrophage infected with Brucella abortus expressing a red fluorescent protein for 24 hours. Brucella (in red) replicated with ER-derived vacuoles (calnexing staining in blue) segregated from the endocytic pathway (LAMP1-staining, in green).
Credit: NIAID
Francisella intracellular pathogenesis
Francisella tularensis is a highly infectious bacterium of Biodefense concern that causes tularemia, a zoonosis with potentially lethal consequences. Intracellular survival and proliferation of this pathogen rely upon phagosomal excape and replication within the cytosol. We have identified novel virulence genes required for intracellular proliferation through transcriptional profiling of intracellular Francisella, based upon their upregulation. Our current research aims at characterizing the functions of these genes in intracellular pathogenesis to better understand Francisella molecular virulence mechanisms.
The figure to the left is a confocal fluorescence micrograph of a murine bone marrow-derived macrophage infected with Francisella tularensis for 24 hours. Bacteria (labeled using an anti-LPS antibody, in green) replicate freely within the cytosol following escape from the endocytic pathway (LAMP-1 staining, in red).
Bacterial interactions with the host autophagic pathway
The highly conserved process of host macroautophagy (herein autophagy), which delivers intracellular content and organelles to the degradative lysosomal compartment, plays an important intracellular innate immune role by controlling the fate of many vacuolar or cytosolic microbes. Following replication in the ER, Brucella subvers specific autophagy-associated proteins to convert rBCVs into autophagosome-like organelles (aBCVs) that promote cell-to-cell spread, thereby co-opting autophagy to its own benefit. Alternatively, F. tularensis likely interferes with autophagic recognition to survive and proliferate within the macrophage cytosol. Our current research focuses on 1) characterizing the mechanisms of autophagy-dependent Brucella egress and reinfection and 2) identifying and characterizing the mechanisms of Francisella autophagy avoidance.
Biography
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, 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 NIAID as a tenure-track investigator in the Laboratory of Intracellular Parasites. He is a member of the American Society for Microbiology and the American Society for Cell Biology.
Research Group
From left to right: Audrey Chong, Jean Celli, Robert Child, Elizabeth Case, Sebenzile Myeni, Tara Wehrly.
Selected Publications
Starr T, Child R, Wehrly TD, Hansen B, Hwang S, López-Otin C, Virgin HW, Celli J. Selective subversion of autophagy complexes promotes completion of the Brucella intracellular cycle. Cell Host Microbe. 2012 Jan 19;11(1):33-45.
Knodler LA, Vallance BA, Celli J, Winfree S, Hansen B, Montero M, Steele-Mortimer O. Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17733-8.
Wehrly TD, Chong A, Virtaneva K, Sturdevant DE, Child R, Edwards JA, Brouwer D, Nair V, Fischer ER, Wicke L, Curda AJ, Kupko JJ 3rd, Martens C, Crane DD, Bosio CM, Porcella SF, Celli J. Intracellular biology and virulence determinants of Francisella tularensis revealed by transcriptional profiling inside macrophages. Cell Microbiol. 2009 Jul;11(7):1128-50.
Starr T, Ng TW, Wehrly TD, Knodler LA, Celli J. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic. 2008 May;9(5):678-94.
Checroun C, Wehrly TD, Fischer ER, Hayes SF, Celli J. Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication. Proc Natl Acad Sci USA. 2006 Sep 26;103(39):14578-83.
Celli J, Salcedo SP, Gorvel JP. Brucella coopts the small GTPase Sar1 for intracellular replication. Proc Nat Acad Sci U S A. 2005 Feb 1;102(5):1673-8.
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