Jean Celli

Washington State University, پولمن، واشینگتن, Washington, United States

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Publications (64)403.25 Total impact

  • Jean Celli
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    ABSTRACT: Bacteria of the genus Brucella are intracellular vacuolar pathogens of mammals that cause the worldwide zoonosis brucellosis, and reside within phagocytes of infected hosts to promote their survival, persistence and proliferation. These traits are essential to the bacterium's ability to cause disease and have been the subject of much investigation to gain an understanding of Brucella pathogenic mechanisms. Although the endoplasmic reticulum-derived nature of the Brucella replicative niche has been long known, major strides have recently been made in deciphering the molecular mechanisms of its biogenesis, including the identification of bacterial determinants and host cellular pathways involved in this process. Here I will review and discuss the most recent advances in our knowledge of Brucella intracellular pathogenesis, with an emphasis on bacterial exploitation of the host endoplasmic reticulum-associated functions, and how autophagy-related processes contribute to the bacterium's intracellular cycle. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 04/2015; 17(7). DOI:10.1111/cmi.12452 · 4.82 Impact Factor
  • Jean Celli, Renée M Tsolis
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    ABSTRACT: The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria.
    Nature Reviews Microbiology 12/2014; DOI:10.1038/nrmicro3393 · 23.32 Impact Factor
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    ABSTRACT: Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human ortholog of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium-infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore, an epithelial cell-intrinsic noncanonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface.
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    ABSTRACT: The Francisella FTT0831c/FTL_0325 gene encodes amino acid motifs to suggest it is a lipoprotein and that it may interact with the bacterial cell wall as a member of the OmpA-like protein family. Previous studies have suggested that FTT0831c is surface-exposed and required for virulence of Francisella tularensis by subverting the host innate immune response (Mahawar et al., 2012. J. Biol. Chem. 287: 25216-29). We also find that FTT0831c is required for murine pathogenesis and intramacrophage growth of Schu S4, but propose a different model to account for the proinflammatory nature of the resultant mutants. First, inactivation of FTL_0325 from LVS or FTT0831c from Schu S4 resulted in temperature-dependent defects in cell viability and morphology. Loss of FTT0831c was also associated with an unusual defect in LPS O-antigen synthesis, but loss of FTL_0325 was not. Full restoration of these properties was observed in complemented strains expressing FTT0831c in trans, but not in strains lacking the OmpA motif, suggesting cell wall contact is required. Finally, growth of the LVS FTL_0325 mutant in Mueller-Hinton broth at 37°C resulted in the appearance of membrane blebs at the poles and midpoint, prior to the formation of enlarged round cells that showed evidence of compromised cellular membranes. Taken together, these data are more consistent with the known structural role of OmpA-like proteins in linking the OM to the cell wall and, as such, maintenance of structural integrity preventing altered surface exposure or release of TLR2 agonists during rapid growth of Francisella in vitro and in vivo.
    Infection and immunity 04/2014; 82(7). DOI:10.1128/IAI.00102-14 · 4.16 Impact Factor
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    ABSTRACT: ABSTRACT Host cytokine responses to Brucella abortus infection are elicited predominantly by the deployment of a type IV secretion system (T4SS). However, the mechanism by which the T4SS elicits inflammation remains unknown. Here we show that translocation of the T4SS substrate VceC into host cells induces proinflammatory responses. Ectopically expressed VceC interacted with the endoplasmic reticulum (ER) chaperone BiP/Grp78 and localized to the ER of HeLa cells. ER localization of VceC required a transmembrane domain in its N terminus. Notably, the expression of VceC resulted in reorganization of ER structures. In macrophages, VceC was required for B. abortus-induced inflammation by induction of the unfolded protein response by a process requiring inositol-requiring transmembrane kinase/endonuclease 1. Altogether, these findings suggest that translocation of the T4SS effector VceC induces ER stress, which results in the induction of proinflammatory host cell responses during B. abortus infection. IMPORTANCE Brucella species are pathogens that require a type IV secretion system (T4SS) to survive in host cells and to maintain chronic infection. By as-yet-unknown pathways, the T4SS also elicits inflammatory responses in infected cells. Here we show that inflammation caused by the T4SS results in part from the sensing of a T4SS substrate, VceC, that localizes to the endoplasmic reticulum (ER), an intracellular site of Brucella replication. Possibly via binding of the ER chaperone BiP, VceC causes ER stress with concomitant expression of proinflammatory cytokines. Thus, induction of the unfolded protein response may represent a novel pathway by which host cells can detect pathogens deploying a T4SS.
    mBio 12/2013; 4(1). DOI:10.1128/mBio.00418-12 · 6.88 Impact Factor
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    ABSTRACT: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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    ABSTRACT: Autophagy is a key innate immune response to intracellular parasites that promotes their delivery to degradative lysosomes following detection in the cytosol or within damaged vacuoles. Like Listeria and Shigella, which use specific mechanisms to avoid autophagic detection and capture, the bacterial pathogen Francisella tularensis proliferates within the cytosol of macrophages without demonstrable control by autophagy. To examine how Francisella evades autophagy, we screened a library of F. tularensis subsp. tularensis Schu S4 HimarFT transposon mutants in GFP-LC3-expressing murine macrophages by microscopy for clones localised within autophagic vacuoles after phagosomal escape. Eleven clones showed autophagic capture at six hours post-infection, whose HimarFT insertions clustered to four genetic loci involved in lipopolysaccharidic and capsular O-antigen biosynthesis. Consistent with the HimarFT mutants, in-frame deletion mutants of two representative loci, FTT1236 and FTT1448c (manC), lacking both LPS and capsular O-antigen, underwent phagosomal escape but were cleared from the host cytosol. Unlike wild type Francisella, the O-antigen deletion mutants were ubiquitinated, and recruited the autophagy adaptor p62/SQSTM1 and LC3 prior to cytosolic clearance. Autophagy-deficient macrophages partially supported replication of both mutants, indicating that O-antigen-lacking Francisella are controlled by autophagy. These data demonstrate the intracellular protective role of this bacterial surface polysaccharide against autophagy.
    Cellular Microbiology 11/2013; DOI:10.1111/cmi.12246 · 4.82 Impact Factor
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    ABSTRACT: IglE is a small, hypothetical protein encoded by the duplicated Francisella Pathogenicity Island (FPI). Inactivation of both copies of iglE rendered F. tularensis SchuS4 avirulent and incapable of intracellular replication, owing to an inability to escape the phagosome. This defect was fully reversed following single copy expression of iglE in trans from attTn7 under the control of the Francisella rpsL promoter, thereby establishing that the loss of iglE, and not polar effects on downstream vgrG gene expression, was responsible for the defect. IglE is exported to the Francisella outer membrane as a ∼13.9-kDa lipoprotein based on a combination of selective Triton X-114 solubilization, radiolabelling with (3)H-palmitic acid, and sucrose density gradient membrane partitioning studies. Lastly, a genetic screen using the LVS iglE null strain resulted in the identification of key regions in the carboxyl terminus of IglE that are required for intracellular replication of Francisella tularensis in J774 macrophages. Thus, IglE is essential for Francisella tularensis virulence. Our data support a model that likely includes here-to-date unknown protein-protein interactions at or near the bacterial cell surface.
    Infection and immunity 08/2013; DOI:10.1128/IAI.00595-13 · 4.16 Impact Factor
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    ABSTRACT: The intracellular pathogenic bacterium Brucella generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of the host cell secretory pathway. rBCV biogenesis requires the expression of the Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that modulate membrane trafficking along the endocytic and secretory pathways. To date, only a few T4SS substrates have been identified, whose molecular functions remain unknown. Here, we used an in silico screen to identify putative T4SS effector candidate proteins using criteria such as limited homology in other bacterial genera, the presence of features similar to known VirB T4SS effectors, GC content and presence of eukaryotic-like motifs. Using β-lactamase and CyaA adenylate cyclase reporter assays, we identified eleven proteins translocated into host cells by Brucella, five in a VirB T4SS-dependent manner, namely BAB1_0678 (BspA), BAB1_0712 (BspB), BAB1_0847 (BspC), BAB1_1671 (BspE) and BAB1_1948 (BspF). A subset of the translocated proteins targeted secretory pathway compartments when ectopically expressed in HeLa cells, and the VirB effectors BspA, BspB and BspF inhibited protein secretion. Brucella infection also impaired host protein secretion in a process requiring BspA, BspB and BspF. Single or combined deletions of bspA, bspB and bspF affected Brucella ability to replicate in macrophages and persist in the liver of infected mice. Taken together, these findings demonstrate that Brucella modulates secretory trafficking via multiple T4SS effector proteins that likely act coordinately to promote Brucella pathogenesis.
    PLoS Pathogens 08/2013; 9(8):e1003556. DOI:10.1371/journal.ppat.1003556 · 8.06 Impact Factor
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    ABSTRACT: Francisella tularensis is a highly infectious bacterium whose virulence relies on its ability to rapidly reach the macrophage cytosol and extensively replicate in this compartment. We previously identified a novel Francisella virulence factor, DipA (FTT0369c), which is required for intramacrophage proliferation and survival, and virulence in mice. DipA is a 353 amino acid protein with a Sec-dependent signal peptide, four Sel1-like repeats (SLR), and a C-terminal coiled-coil (CC) domain. Here, we determined through biochemical and localization studies that DipA is a membrane-associated protein exposed on the surface of the prototypical F. tularensis subsp. tularensis strain SchuS4 during macrophage infection. Deletion and substitution mutagenesis showed that the CC domain, but not the SLR motifs, of DipA is required for surface exposure on SchuS4. Complementation of the dipA mutant with either DipA CC or SLR domain mutants did not restore intracellular growth of Francisella, indicating that proper localization and the SLR domains are required for DipA function. Co-immunoprecipitation studies revealed interactions with the Francisella outer membrane protein FopA, suggesting that DipA is part of a membrane-associated complex. Altogether, our findings indicate that DipA is positioned at the host-pathogen interface to influence the intracellular fate of this pathogen.
    PLoS ONE 06/2013; 8(6):e67965. DOI:10.1371/journal.pone.0067965 · 3.53 Impact Factor
  • Jean Celli, Thomas C Zahrt
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    ABSTRACT: Francisella tularensis is a zoonotic intracellular pathogen and the causative agent of the debilitating febrile illness tularemia. Although natural infections by F. tularensis are sporadic and generally localized, the low infectious dose, with the ability to be transmitted to humans via multiple routes and the potential to cause life-threatening infections, has led to concerns that this bacterium could be used as an agent of bioterror and released intentionally into the environment. Recent studies of F. tularensis and other closely related Francisella species have greatly increased our understanding of mechanisms used by this organism to infect and cause disease within the host. Here, we review the intracellular life cycle of Francisella and highlight key genetic determinants and/or pathways that contribute to the survival and proliferation of this bacterium within host cells.
    Cold Spring Harbor Perspectives in Medicine 04/2013; 3(4). DOI:10.1101/cshperspect.a010314 · 7.56 Impact Factor
  • Jean Celli
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    ABSTRACT: Antimicrobial autophagy is a host cellular process that captures and delivers intracellular parasites to lysosomes following their targeting as cargo via ubiquitination. Huett et al. (2012) show that the LRR- and RING-domain-containing E3 ubiquitin ligase LRSAM1 recognizes various bacteria and generates a ubiquitin signal that initiates the autophagic cascade.
    Cell host & microbe 12/2012; 12(6):735-6. DOI:10.1016/j.chom.2012.11.007 · 12.19 Impact Factor

Publication Stats

3k Citations
403.25 Total Impact Points

Institutions

  • 2014–2015
    • Washington State University
      • College of Veterinary Medicine
      پولمن، واشینگتن, Washington, United States
  • 2012–2013
    • National Institutes of Health
      • Laboratory of Intracellular Parasites (LICP)
      Maryland, United States
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2006–2013
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States
  • 2003–2005
    • Centre d'Immunologie de Marseille-Luminy
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2000–2003
    • University of British Columbia - Vancouver
      • Department of Biochemistry and Molecular Biology
      Vancouver, British Columbia, Canada
  • 1992
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France