Creat membership Creat membership
Sign in

Forgot password?

  • Forgot password?
    Sign Up
  • Confirm
    Sign In
home > search

Now showing items 1 - 16 of 105

  • Effector-triggered immunity and pathogen sensing in metazoans

    Lopes Fischer, Natasha   Naseer, Nawar   Shin, Sunny   Brodsky, Igor E.  

    Download Collect
  • The Evolving Erythrocyte:Red Blood Cells as Modulators of Innate Immunity

    Anderson, H. Luke   Brodsky, Igor E.   Mangalmurti, Nilam S.  

    The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation.
    Download Collect
  • Activation and Evasion of Inflammasomes by Yersinia

    Philip, Naomi H.   Zwack, Erin E.   Brodsky, Igor E.  

    The innate immune system plays an essential role in initiating the early response against microbial infection, as well as instructing and shaping subsequent responses. Microbial pathogens are enormously diverse in terms of the niches they occupy, their metabolic properties and requirements, and the cellular pathways that they target. Nevertheless, innate sensing of pathogens triggers a relatively stereotyped set of responses that involve transcriptional induction of key inflammatory mediators, as well as post-translational assembly and activation of a multiprotein inflammatory complex termed 'the inflammasome.' Along with classical Pattern Recognition Receptors, the inflammasome activation pathway has emerged as a key regulator of tissue homeostasis and immune defense. Components of the inflammasome generally exist within the cell in a soluble, monomeric state, and oligomerize in response to diverse enzymatic activities associated with infection or cellular stress. Inflammasome assembly triggers activation of the pro-enzyme caspase-1, resulting in the cleavage of caspase-1 targets. The most extensively studied targets are the cytokines of the IL-1 family, but the recent discovery of Gasdermin D as a novel target of caspase-1 and the related inflammatory caspase, caspase-11, has begun to mechanistically define the links between caspase-1 activation and cell death. Cell death is a hallmark of macrophage infection by many pathogens, including the gram-negative bacterial pathogens of the genus Yersinia. Intriguingly, the activities of the Yersinia-secreted effector proteins and the type III secretion system (T3SS) itself have been linked to both inflammasome activation and evasion during infection. The balance between these activating and inhibitory activities shapes the outcome of Yersinia infection. Here, we describe the current state of knowledge on interactions between Yersinia and the inflammasome system, with the goal of integrating these findings within the general framework of inflammasome responses to microbial pathogens.
    Download Collect
  • RNA Helicase DHX33 Puts a New Twist on NLRP3 Inflammasome Activation

    Brodsky, Igor E.  

    The mechanisms by which NLRP3 senses inflammasome-activating stimuli remain poorly defined. In this issue of Immunity, Mitoma et al. (2013) demonstrate that the RNA helicase DHX33 binds to cytosolic dsRNAs to trigger NLRP3 inflammasome activation.
    Download Collect
  • Pyroptosis: Macrophage Suicide Exposes Hidden Invaders

    Brodsky, Igor E.   Medzhitov, Ruslan  

    Download Collect
  • Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

    Alenghat, Theresa   Osborne, Lisa C.   Saenz, Steven A.   Kobuley, Dmytro   Ziegler, Carly G. K.   Mullican, Shannon E.   Choi, Inchan   Grunberg, Stephanie   Sinha, Rohini   Wynosky-Dolfi, Meghan   Snyder, Annelise   Giacomin, Paul R.   Joyce, Karen L.   Hoang, Tram B.   Bewtra, Meenakshi   Brodsky, Igor E.   Sonnenberg, Gregory F.   Bushman, Frederic D.   Won, Kyoung-Jae   Lazar, Mitchell A.   Artis, David  

    The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria(1-6). However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(Delta IEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(Delta IEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(Delta IEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(Delta IEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.
    Download Collect
  • Extensive evolutionary and functional diversity among mammalian AIM2-like receptors

    Brunette, Rebecca L.   Young, Janet M.   Whitley, Deborah G.   Brodsky, Igor E.   Malik, Harmit S.  

    Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.
    Download Collect
  • Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis

    Peterson, Lance W.   Philip, Naomi H.   Dillon, Christopher P.   Bertin, John   Gough, Peter J.   Green, Douglas R.   Brodsky, Igor E.  

    Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-kappa B and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4-and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. In this article, we report a key role for TNF/TNFR1 in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-kappa B and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this subpopulation was necessary for maximal apoptosis in the population of highly injected cells, and TNFR-deficient mice displayed enhanced susceptibility to Yersinia infection. These data demonstrate an important role for collaboration between TNF and pattern recognition receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense.
    Download Collect
  • Targeting of immune signalling networks by bacterial pathogens

    Brodsky, Igor E.   Medzhitov, Ruslan  

    Host defence against microbial pathogens requires appropriate coordination of multiple signalling pathways. These pathways are triggered by innate immune recognition of conserved microbial molecules, and initiate an inflammatory cascade that involves recruitment of leukocytes to the site of infection, activation of antimicrobial effector mechanisms and induction of an adaptive immune response that promotes clearance of infection and long-term immune memory. Microbial pathogens possess specialized proteins termed virulence factors, which interfere with host defence at several levels. Many virulence factors from diverse pathogens have been identified in recent years and their functions linked to disruption of essential processes of immune defence, from signalling to phagocytosis. Although the diversity of pathogens and virulence factors is immense, common themes have emerged with regard to how microbial pathogens interfere with immune responses. Here we discuss recent advances in our understanding of how virulence factors target innate and adaptive immune responses, focusing on bacterial pathogens. We also propose that pathogens responsible for causing acute infection tend to target central components (hubs) of cellular signalling pathways, causing global disruption of the host response. By contrast, pathogens that cause chronic or persistent infections tend to target more peripheral signalling network components (nodes) to promote pathogen persistence.
    Download Collect
  • Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock

    Manda, Pratyusha   Feng, Yanjun   Lyons, John D.   Berger, Scott B.   Otani, Shunsuke   DeLaney, Alexandra   Tharp, Gregory K.   Maner-Smith, Kristal   Burd, Eileen M.   Schaeffer, Michelle   Hoffman, Sandra   Capriotti, Carol   Roback, Linda   Young, Cedrick B.   Liang, Zhe   Ortlund, Eric A.   DiPaolo, Nelson C.   Bosinger, Steven   Bertin, John   Gough, Peter J.   Brodsky, Igor E.   Coopersmith, Craig M.   Shayakhmetov, Dmitry M.   Mocarski, Edward S.  

    The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from cas pase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-beta-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.
    Download Collect
  • RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense

    Peterson, Lance W.   Philip, Naomi H.   DeLaney, Alexandra   Wynosky-Dolfi, Meghan A.   Asklof, Kendra   Gray, Falon   Choa, Ruth   Bjanes, Elisabet   Buza, Elisabeth L.   Hu, Baofeng   Dillon, Christopher P.   Green, Douglas R.   Berger, Scott B.   Gough, Peter J.   Bertin, John   Brodsky, Igor E.  

    Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed "effector-triggered immunity." The Gram-negative bacterial pathogen Yersinia inactivates critical proteins of the NF-kappa B and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. Yersinia-induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-kappa B, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that Yersinia-induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase-induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling.
    Download Collect
  • NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens

    Brodsky, Igor E.   Monack, Denise  

    The host response against diverse bacterial pathogens involves activation of specialized immune cells and elaboration of pro-inflammatory cytokines that help to coordinate appropriate host defense. Members of the interleukin-1 (IL-1) cytokine family, IL-1 beta and IL-18, are central players in this process. Extracellular release of the mature, active form of these cytokines requires their processing by the cysteine protease caspase-1, which therefore serves as a key regulator of the inflammatory response. In addition to its role in secretion of pro-inflammatory cytokines, caspase-1 is also required for a form of cell death, recently termed pyroptosis, that occurs in macrophages infected by certain bacterial pathogens. Caspase-1 itself is synthesized as a pro-enzyme, which must first be activated by autocatalytic cleavage. This activation requires recruitment of caspase-1 into multiprotein complexes known as inflammasomes. The Nod-like receptor (NLR) family of cytosolic proteins play an important role in detecting inflammatory stimuli and subsequently mediate inflammasome assembly. A common feature of NLR proteins that trigger inflammasome assembly in response to bacterial infection is that they appear to sense membrane perturbation or delivery of bacterial components into the cytosol through bacterial pore-forming toxins or bacterial secretion systems. This review will discuss the recent developments regarding caspase-1 activation in response to bacterial infection, cross-talk between caspase-1 and other pathways involved in regulating cell death, and recent findings that a number of bacterial pathogens possess mechanisms to inhibit caspase-1 activation. (C) 2009 Elsevier Ltd. All rights reserved.
    Download Collect
  • Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

    Dondelinger, Yves   Delanghe, Tom   Priem, Dario   Wynosky-Dolfi, Meghan A.   Sorobetea, Daniel   Rojas-Rivera, Diego   Giansanti, Piero   Roelandt, Ria   Gropengiesser, Julia   Ruckdeschel, Klaus   Savvides, Savvas N.   Heck, Albert J. R.   Vandenabeele, Peter   Brodsky, Igor E.   Bertrand, Mathieu J. M.  

    Download Collect
  • Reduced Secretion of YopJ by Yersinia Limits In Vivo Cell Death but Enhances Bacterial Virulence

    Brodsky, Igor E.   Medzhitov, Ruslan   Isberg, Ralph R.  

    Download Collect
  • Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

    Feeley, Eric M.   Pilla-Moffett, Danielle M.   Zwack, Erin E.   Piro, Anthony S.   Finethy, Ryan   Kolb, Joseph P.   Martinez, Jennifer   Brodsky, Igor E.   Coers, Joern  

    Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as "patterns of pathogenesis" associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersiniacontaining vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3-deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3-dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.
    Download Collect
  • BCR-Induced Ca2+ Signals Dynamically Tune Survival, Metabolic Reprogramming, and Proliferation of Naive B Cells

    Berry, Corbett T.   Liu, Xiaohong   Myles, Arpita   Nandi, Satabdi   Chen, Youhai H.   Hershberg, Uri   Brodsky, Igor E.   Cancro, Michael P.   Lengner, Christopher J.   May, Michael J.   Freedman, Bruce D.  

    Download Collect
1 2 3 4 5 6 7


If you have any feedback, Please follow the official account to submit feedback.

Turn on your phone and scan

Submit Feedback