Gregory M Barton

University of California, Berkeley, Berkeley, California, United States

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Publications (45)762.72 Total impact

  • Jonathan C Kagan, Gregory M Barton
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    ABSTRACT: The problem of recognizing and disposing of non-self-organisms, whether for nutrients or defense, predates the evolution of multicellularity. Accordingly, the function of the innate immune system is often intimately associated with fundamental aspects of cell biology. Here, we review our current understanding of the links between cell biology and pattern-recognition receptors of the innate immune system. We highlight the importance of receptor localization for the detection of microbes and for the initiation of antimicrobial signaling pathways. We discuss examples that illustrate how pattern-recognition receptors influence, and are influenced by, the general membrane trafficking machinery of mammalian cells. In the future, cell biological analysis likely will rival pure genetic analysis as a tool to uncover fundamental principles that govern host-microbe interactions.
    Cold Spring Harbor perspectives in biology 11/2014; · 9.63 Impact Factor
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    ABSTRACT: The classic anti-viral cytokine interferon (IFN)-β can be induced during parasitic infection, but relatively little is know about the cell types and signaling pathways involved. Here we show that inflammatory monocytes (IMs), but not neutrophils, produce IFN-β in response to T. gondii infection. This difference correlated with the mode of parasite entry into host cells, with phagocytic uptake predominating in IMs and active invasion predominating in neutrophils. We also show that expression of IFN-β requires phagocytic uptake of the parasite by IMs, and signaling through Toll-like receptors (TLRs) and MyD88. Finally, we show that IMs are major producers of IFN-β in mesenteric lymph nodes following in vivo oral infection of mice, and mice lacking the receptor for type I IFN-1 show higher parasite loads and reduced survival. Our data reveal a TLR and internalization-dependent pathway in IMs for IFN-β induction to a non-viral pathogen.Immunology and Cell Biology advance online publication, 26 August 2014; doi:10.1038/icb.2014.70.
    Immunology and Cell Biology 08/2014; · 3.93 Impact Factor
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    ABSTRACT: Pathogens utilize features of the host response as cues to regulate virulence gene expression. Salmonella enterica serovar Typhimurium (ST) sense Toll-like receptor (TLR)-dependent signals to induce Salmonella Pathogenicity Island 2 (SPI2), a locus required for intracellular replication. To examine pathogenicity in the absence of such cues, we evaluated ST virulence in mice lacking all TLR function (Tlr2(-/-)xTlr4(-/-)xUnc93b1(3d/3d)). When delivered systemically to TLR-deficient mice, ST do not require SPI2 and maintain virulence by replicating extracellularly. In contrast, SPI2 mutant ST are highly attenuated after oral infection of the same mice, revealing a role for SPI2 in the earliest stages of infection, even when intracellular replication is not required. This early requirement for SPI2 is abolished in MyD88(-/-)xTRIF(-/-) mice lacking both TLR- and other MyD88-dependent signaling pathways, a potential consequence of compromised intestinal permeability. These results demonstrate how pathogens use plasticity in virulence strategies to respond to different host immune environments.
    Cell host & microbe 02/2014; 15(2):203-13. · 13.02 Impact Factor
  • Bettina L Lee, Gregory M Barton
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    ABSTRACT: Over the past decade we have learned much about nucleic acid recognition by the innate immune system and in particular by Toll-like receptors (TLRs). These receptors localize to endosomal compartments where they are poised to recognize microbial nucleic acids. Multiple regulatory mechanisms function to limit responses to self DNA or RNA, and breakdowns in these mechanisms can contribute to autoimmune or inflammatory disorders. In this review we discuss our current understanding of the cell biology of TLRs involved in nucleic acid recognition and how localization and trafficking of these receptors regulates their function.
    Trends in cell biology 01/2014; · 12.12 Impact Factor
  • Meghan A Koch, Gregory M Barton
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    ABSTRACT: IgA antibodies help maintain intestinal immune homeostasis with resident commensal species; however, the precise mechanisms regulating IgA induction and the epitopes recognized by these antibodies remain incompletely understood. In this issue of Cell Host & Microbe, Tyler et al. (2013) demonstrate that TLR5-dependent induction of anti-flagellin antibodies prevents commensal association with the intestinal mucosa by limiting bacterial motility.
    Cell host & microbe 11/2013; 14(5):488-90. · 13.02 Impact Factor
  • Nature Immunology 10/2013; 14(11):1101-2. · 26.20 Impact Factor
  • Nicholas Arpaia, Gregory M Barton
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    ABSTRACT: The mammalian immune system has evolved in the presence of microbes, both pathogenic and commensal. The consequences of microbial recognition by the host has led to the development of compensatory mechanisms by both the host and microbe to either resist or tolerate the existence of the other. In this review we discuss examples of this co-evolutionary relationship. Because of space considerations and for conceptual clarity, we have focused on detection of bacteria by the Toll-like receptor (TLR) family and highlight examples of bacterial strategies to evade, subvert and in some cases even utilize these receptors.
    Current opinion in microbiology 01/2013; · 7.87 Impact Factor
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    ABSTRACT: UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. The mechanisms by which UNC93B1 mediates these regulatory effects remain unclear. Here, we demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. Thus, our study describes a mechanism for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases.DOI:http://dx.doi.org/10.7554/eLife.00291.001.
    eLife Sciences 01/2013; 2:e00291. · 8.52 Impact Factor
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    ABSTRACT: Neutrophils and inflammatory monocytes (IMs) are white blood cells (leukocytes) essential for the efficient function of the innate immune system, the body’s first line of defense against infection. Recognition of microbes often occurs through molecular patterns (ligands) binding to a class of proteins called Toll-like receptors (TLRs). When microbial ligands bind to a single TLR, IMs are able to produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNFa). In contrast, neutrophils produce TNFa upon activation by bacteria, which contain multiple TLR ligands. This is important because dead body cells present ligands capable of activating TLRs, so production of TNFa by neutrophils might promote unnecessary inflammation. This project attempts to identify the specific signals neutrophils require for TNFa production in vitro. Neutrophils could either be responding through a combination of TLR ligands or through a different class of receptors altogether, such as NOD-like receptors or C-type lectin receptors (CLRs), which both signal differently than TLRs. During experimentation, naïve bone marrow cells were tested to ensure that leukocytes used had not yet been activated by any ligand. Naïve cells were subsequently activated by various ligands: (1) single TLR ligands such as LPS and CpG, (2) combinations of TLR ligands, (3) zymosan, a ligand for both dectin-1 (CLR) and TLR2, and (4) both live and heat-killed bacteria. Intracellullar cytokine staining illustrated TNFa production. Zymosan has induced TNFa production in neutrophils. Further research aims at identifying the mechanism by which neutrophil-TNFa production is regulated in addition to viewing TNFa production in vivo during an infection.
    2012 Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Conference; 10/2012
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    ABSTRACT: Pathogens commonly utilize endocytic pathways to gain cellular access. The endosomal pattern recognition receptors TLR7 and TLR9 detect pathogen-encoded nucleic acids to initiate MyD88-dependent proinflammatory responses to microbial infection. Using genome-wide RNAi screening and integrative systems-based analysis, we identify 190 cofactors required for TLR7- and TLR9-directed signaling responses. A set of cofactors were crossprofiled for their activities downstream of several immunoreceptors and then functionally mapped based on the known architecture of NF-κB signaling pathways. Protein complexes and pathways involved in ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress responses were found to modulate innate recognition of endosomal nucleic acids. Additionally, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was characterized as necessary for ubiquitin-dependent TLR9 targeting to the endolysosome. Proteins and pathways identified here should prove useful in delineating strategies to manipulate innate responses for treatment of autoimmune disorders and microbial infection.
    Cell host & microbe 03/2012; 11(3):306-18. · 13.02 Impact Factor
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    Nicholas Arpaia, Gregory M Barton
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    ABSTRACT: TLRs are a family of innate receptors whose specificities are predetermined in the germline. Therefore, TLRs have evolved to recognize conserved features of microbes. Viruses typically lack the conserved features common to other pathogen classes, so the innate immune system has evolved to recognize viral nucleic acid as a hallmark of viral infection. In this review we discuss examples of TLR-mediated viral recognition and the functional consequences of this recognition for antiviral immunity.
    Current opinion in virology. 12/2011; 1(6):447-54.
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    ABSTRACT: The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction.
    Cell 11/2011; 147(4):868-80. · 31.96 Impact Factor
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    ABSTRACT: Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9 exposes the host to potential self-recognition and autoimmunity. It has been proposed that intracellular compartmentalization is largely responsible for reliable self versus nonself discrimination by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to activation, which may further reinforce receptor compartmentalization and tolerance to self, yet this possibility remains untested. Here we report that residues within the TLR9 transmembrane (TM) region conferred the requirement for ectodomain proteolysis. TLR9 TM mutants responded to extracellular DNA, and mice expressing such receptors died from systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and appeared to require recognition of self-DNA by dendritic cells. To our knowledge, these results provide the first demonstration that TLR-intrinsic mutations can lead to a break in tolerance.
    Immunity 11/2011; 35(5):721-32. · 19.80 Impact Factor
  • Maria Mouchess, Gregory Barton
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    ABSTRACT: Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9 exposes the host to potential self-recognition and autoimmunity. It has been proposed that intracellular compartmentalization is largely responsible for reliable self/non-self discrimination by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to activation, which may further restrict receptor compartmentalization and reinforce self/non-self discrimination, yet this possibility remains untested. Here we report that residues within the TLR9 transmembrane (TM) region confer the requirement for ectodomain proteolysis. TLR9 TM mutants responded to extracellular DNA and mice expressing such receptors died from systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and appears to require recognition of self-DNA by dendritic cells. These results provide the first demonstration that TLR-intrinsic mutations can lead to a break in tolerance and support the hypothesis that ectodomain processing has evolved to reinforce self/non-self discrimination by nucleic acid-sensing TLRs.
    2011 Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Conference; 10/2011
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    ABSTRACT: Multiple receptors within the innate immune system have evolved to recognize nucleic acids as signatures of viral infection. It is believed that this specificity is essential for viral detection, as viruses often lack other invariant features that can serve as suitable targets for innate receptors. One such innate receptor, TLR9, has been implicated in the detection of many dsDNA viruses. In this study, we investigate the detection of murine gammaherpesvirus 68 (MHV68) by TLR9. We find that the genomic DNA of the murine CMV, a very potent inducer of innate responses. Genome-wide analysis of the number of stimulatory versus nonstimulatory CpG motifs present in the genome of each virus reveals that the MHV68 genome contains only a fraction of the number of immunostimulatory motifs present in murine CMV. Notably, MHV68 appears to have selectively suppressed the number of stimulatory motifs through cytosine to thymine conversion. These data suggest that certain viruses may have evolved and modified their genomic content to avoid recognition by nucleic acid-sensing receptors of the innate immune system.
    The Journal of Immunology 06/2011; 187(2):887-96. · 5.52 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulence mechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S. typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicate that S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.
    Cell 03/2011; 144(5):675-88. · 31.96 Impact Factor
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    ABSTRACT: Toll-like receptor (TLR) 9 requires proteolytic processing in the endolysosome to initiate signaling in response to DNA. However, recent studies conflict as to which proteases are required for receptor cleavage. We show that TLR9 proteolysis is a multistep process. The first step removes the majority of the ectodomain and can be performed by asparagine endopeptidase (AEP) or cathepsin family members. This initial cleavage event is followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. This dual requirement for AEP and cathepsins is observed in all cell types that we have analyzed, including mouse macrophages and dendritic cells. In addition, we show that TLR7 and TLR3 are processed in an analogous manner. These results define the core proteolytic steps required for TLR9 function and suggest that receptor proteolysis may represent a general regulatory strategy for all TLRs involved in nucleic acid recognition.
    Journal of Experimental Medicine 03/2011; 208(4):643-51. · 13.21 Impact Factor
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    Sarah E Ewald, Gregory M Barton
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    ABSTRACT: Trafficking and activation of the nucleic acid sensing TLRs is subject to unique regulatory requirements imposed by the risk of self-recognition. Like all TLRs these receptors traffick through the Golgi, however, access to the secretory pathway is controlled by a binding partner present in the ER. Receptor activation in the endolysosome is regulated through a proteolytic mechanism that requires activity of compartment-resident proteases, thereby preventing activation in other regions of the cell. Advances in our understanding of the cell biology of these receptors have been paralleled by efforts to understand their precise roles in autoimmunity. Mouse models have revealed that TLR7 and TLR9 make unique contributions to the types of self-molecules recognized in disease and possibly disease severity. Currently, methods of inhibiting TLR7 and TLR9 are being tested in clinical trials for systemic lupus erythamatosus.
    Current opinion in immunology 02/2011; 23(1):3-9. · 10.88 Impact Factor
  • Roman Barbalat, Gregory M Barton
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    ABSTRACT: Upon birth, the intestine converts from a sterile environment to a home for commensal microorganisms. How immune homeostasis is maintained during this transition is not well understood. Here, Chassin et al. (2010) demonstrate that microRNA-146a regulates the responsiveness of intestinal epithelial cells during microbial colonization of the neonatal intestine.
    Cell host & microbe 10/2010; 8(4):303-4. · 13.02 Impact Factor
  • Nature Immunology 06/2010; · 26.20 Impact Factor

Publication Stats

5k Citations
762.72 Total Impact Points

Institutions

  • 2007–2014
    • University of California, Berkeley
      • • Department of Molecular and Cell Biology
      • • Division of Immunology and Pathogenesis
      Berkeley, California, United States
  • 2013
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2008–2011
    • CSU Mentor
      Long Beach, California, United States
  • 2001–2008
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Yale University
      • Department of Immunobiology
      New Haven, CT, United States
  • 2002
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
    • University of Washington Seattle
      • Department of Immunology
      Seattle, WA, United States
  • 1999–2000
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States