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Now showing items 1 - 16 of 22

  • Innate immunity to adenovirus: lessons from mice

    Atasheva, Svetlana   Yao, Jia   Shayakhmetov, Dmitry M.  

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  • Interleukin 1 alpha and the inflammatory process

    Di Paolo, Nelson C.   Shayakhmetov, Dmitry M.  

    Inflammation occurs after disruption of tissue homeostasis by cell stress, injury or infection and ultimately involves the recruitment and retention of cells of hematopoietic origin, which arrive at the affected sites to resolve damage and initiate repair. Interleukin 1 alpha (IL-1 alpha) and IL-1 beta are equally potent inflammatory cytokines that activate the inflammatory process, and their deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. Although much attention has been given to understanding the biogenesis of IL-1 beta, the biogenesis of IL-1 alpha and its distinctive role in the inflammatory process remain poorly defined. In this review we examine key aspects of IL-1 alpha biology and regulation and discuss its emerging importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases.
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  • Adenovirus sensing by the immune system

    Atasheva, Svetlana   Shayakhmetov, Dmitry M.  

    The host immune system developed multiple ways for recognition of viral pathogens. Upon disseminated adenovirus infection, the immune system senses adenovirus invasion from the moment it enters the bloodstream. The soluble blood factors, FX, antibodies, and complement, can bind and activate plethora of host-protective immune responses. Adenovirus binding to the cellular 133 integrin and endosomal membrane rupture trigger activation of IL-1 alpha/IL-1R1 proinflammatory cascade leading to attraction of cytotoxic immune cells to the site of infection. Upon cell entry, adenovirus exposes its DNA genome in the cytoplasm and triggers DNA sensors signaling. Even when inside the nucleus, the specialized cellular machinery that recognizes the double-strand DNA breaks become activated and triggers viral DNA replication arrest. Thus, the host employs very diverse mechanisms to prevent viral dissemination.
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  • Interleukin-1 Receptor 2 Keeps the Lid on Interleukin-1 alpha

    Di Paolo, Nelson C.   Shayakhmetov, Dmitry M.  

    The molecular mechanisms that regulate functional activation of IL-1 alpha remain elusive. In this issue of Immunity, Zheng et al. (2013) describe a molecular system implicating interleukin-1 receptor-2 (IL-1R2) as a principal cytosolic factor that controls functional IL-1 alpha activation during necrosis.
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  • Coagulation Factor X Activates Innate Immunity to Human Species C Adenovirus

    Doronin, Konstantin   Flatt, Justin W.   Di Paolo, Nelson C.   Khare, Reeti   Kalyuzhniy, Oleksandr   Acchione, Mauro   Sumida, John P.   Ohto, Umeharu   Shimizu, Toshiyuki   Akashi-Takamura, Sachiko   Miyake, Kensuke   MacDonald, James W.   Bammler, Theo K.   Beyer, Richard P.   Farin, Frederico M.   Stewart, Phoebe L.   Shayakhmetov, Dmitry M.  

    Although coagulation factors play a role in host defense for "living fossils" such as horseshoe crabs, the role of the coagulation system in immunity in higher organisms remains unclear. We modeled the interface of human species C adenovirus (HAdv) interaction with coagulation factor X (FX) and introduced a mutation that abrogated formation of the HAdv-FX complex. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of nuclear factor kappa B-dependent early-response genes that are activated by HAdv-FX complex downstream of TLR4/MyD88/TRIF/TRAF6 signaling. Our study implicates host factor "decoration" of the virus as a mechanism to trigger an innate immune sensor that responds to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell.
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  • Virus Infection Recognition and Early Innate Responses to Non-Enveloped Viral Vectors

    Shayakhmetov, Dmitry M.  

    Numerous human genetic and acquired diseases could be corrected or ameliorated if viruses are harnessed to safely and effectively deliver therapeutic genes to diseased cells and tissues in vivo. Innate immune and inflammatory response represents one of the key stumbling blocks during the development of viral-based therapies. In this review, current data on the early innate immune responses to viruses and to the most commonly used gene therapy vectors (using adenovirus and adeno-associated virus) will be discussed. Recent findings in the field may help develop new approaches to moderate these innate immune anti-viral responses and thus improve the safety of viral vectors for human gene therapy applications.
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  • 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.
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    Adenovirus fiber mutated in the regions involved in the recognition and the binding of blood factor proteins, and adenoviruses comprising such fibers are provided.
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  • The influence of blood on in vivo adenovirus bio-distribution and transduction RID G-3778-2011

    Baker, Andrew H.   Mcvey, John H.   Waddington, Simon N.   Di Paolo, Nelson C.   Shayakhmetov, Dmitry M.  

    Intravascular delivery of adenovirus (Ad) vectors is being developed for liver-directed gene therapy for targeting disseminated disease in cancer therapeutics and for targeting non-hepatic tissues and organs through vector engineering strategies. The utility of Ad vectors is not limited to serotype 5 (Ad5), and many alternate human serotypes and non-human serotypes of Ad are currently being investigated. Critical to intravascular delivery of Ad is the interaction of the virus with host blood cells and plasma proteins, because immediate contact is observed following injection. Although incompletely understood, recent studies suggest that these interactions are critical in dictating the particle bio-distribution and resulting transduction properties of Ad in vivo. For example, plasma proteins-in particular, vitamin K-dependent coagulation zymogens-are able to directly bind to Ad, and "bridge" the virus to receptors in the liver. Unraveling and characterizing these mechanisms will be of fundamental importance both for understanding basic Ad biology in vivo and for refinement and optimization of Ad vectors for human gene therapy.
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  • Efficient gene transfer into human CD34+ cells by a retargeted adenovirus vector

    Shayakhmetov, Dmitry M.   Papayannopoulou, Thalia   Stamatoyannopoulos, George   Lieber, Andre  

    Efficient infection with adenovirus (Ad) vectors based on serotype 5 (Ad5) requires the presence of coxsackievirus-adenovirus receptors (CAR) and alphav integrins on cells. The paucity of these cellular receptors is thought to be a limiting factor for Ad gene transfer into hematopoietic stem cells. In a systematic approach, we screened different Ad serotypes for interaction with noncycling human CD34+ cells and K562 cells on the level of virus attachment, internalization, and replication. From these studies, serotype 35 emerged as the variant with the highest tropism for CD34+ cells. A chimeric vector (Ad5GFP/F35) was generated which contained the short-shafted Ad35 fiber incorporated into an Ad5 capsid. This substitution was sufficient to transplant all infection properties from Ad35 to the chimeric vector. The retargeted, chimeric vector attached to a receptor different from CAR and entered cells by an alphav integrin-independent pathway. In transduction studies, Ad5GFP/F35 expressed green fluorescent protein (GFP) in 54% of CD34+ cells. In comparison, the standard Ad5GFP vector conferred GFP expression to only 25% of CD34+ cells. Importantly, Ad5GFP transduction, but not Ad5GFP/F35, was restricted to a specific subset of CD34+ cells expressing alphav integrins. The actual transduction efficiency was even higher than 50% because Ad5GFP/F35 viral genomes were found in GFP-negative CD34+ cell fractions, indicating that the cytomegalovirus promoter used for transgene expression was not active in all transduced cells. The chimeric vector allowed for gene transfer into a broader spectrum of CD34+ cells, including subsets with potential stem cell capacity. Fifty-five percent of CD34+ c-Kit+ cells expressed GFP after infection with Ad5GFP/F35, whereas only 13% of CD34+ c-Kit+ cells were GFP positive after infection with Ad5GFP. These findings represent the basis for studies aimed toward stable gene transfer into hematopoietic stem cells.
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  • The Transcription Factor IRF3 Triggers "Defensive Suicide" Necrosis in Response to Viral and Bacterial Pathogens

    Di Paolo, Nelson C.   Doronin, Konstantin   Baldwin, Lisa K.   Papayannopoulou, Thalia   Shayakhmetov, Dmitry M.  

    Although molecular components that execute noninflammatory apoptotic cell death are well defined, molecular pathways that trigger necrotic cell death remain poorly characterized. Here, we show that in response to infection with adenovirus or Listeria monocytogenes, macrophages in vivo undergo rapid proinflammatory necrotic death that is controlled by interferon-regulatory factor 3 (IRF3). The transcriptional activity of IRF3 is, surprisingly, not required for the induction of necrosis, and it proceeds normally in mice deficient in all known regulators of necrotic death or IRF3 activation, including RIPK3, caspases 1, 8, or 11, STING, and IPS1/MAVS. Although L. monocytogenes triggers necrosis to promote the infection, IRF3-dependent necrosis is required for reducing pathogen burden in the models of disseminated infection with adenovirus. Therefore, our studies implicate IRF3 as a principal and nonredundant component of a physiologically regulated necrotic cell-death pathway that operates as an effective innate immune mechanism of host protection against disseminated virus infection.
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  • Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

    Zaiss, Anne K.   Foley, Erin M.   Lawrence, Roger   Schneider, Lina S.   Hoveida, Hamidreza   Secrest, Patrick   Catapang, Arthur B.   Yamaguchi, Yu   Alemany, Ramon   Shayakhmetov, Dmitry M.   Esko, Jeffrey D.   Herschman, Harvey R.  

    Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. Exte1(HEP) mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5-fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte Ext1 gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from Ext1(HEP) mice. However, in contrast to the case with AAV2, Ads transduction was not significantly reduced in the livers of Ext1(HEP) mice. EX remained essential for Ad5 transduction in vivo in Exte1(HEP) mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction in vivo. This study reopens the question of how adenovirus enters cells in vivo.
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  • Interdependence between Interleukin-1 and Tumor Necrosis Factor Regulates TNF-Dependent Control of Mycobacterium tuberculosis Infection

    Di Paolo, Nelson C.   Shafiani, Shahin   Day, Tracey   Papayannoupoulou, Thalia   Russell, David W.   Iwakura, Yoichiro   Sherman, David   Urdahl, Kevin   Shayakhmetov, Dmitry M.  

    The interleukin-1 receptor I (IL-1RI) is critical for host resistance to Mycobacterium tuberculosis (Mtb), yet the mechanisms of IL-1RI-mediated pathogen control remain unclear. Here, we show that without IL-1RI, Mtb-infected newly recruited Ly6G(hi) myeloid cells failed to upregulate tumor necrosis factor receptor I (TNF-RI) and to produce reactive oxygen species, resulting in compromised pathogen control. Furthermore, simultaneous ablation of IL-1RI and TNF-RI signaling on either stroma or hematopoietic cells led to early lethality, indicating non-redundant and synergistic roles of IL-1 and TNF in mediating macrophage-stroma cross-talk that was critical for optimal control of Mtb infection. Finally, we show that even in the presence of functional Mtb-specific adaptive immunity, the lack of IL-1 alpha and not IL-1 beta led to an exuberant intracellular pathogen replication and progressive non-resolving inflammation. Our study reveals functional interdependence between IL-1 and TNF in enabling Mtb control mechanisms that are critical for host survival.
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  • Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells RID B-3342-2008

    Junt, Tobias   Moseman, E. Ashley   Iannacone, Matteo   Massberg, Steffen   Lang, Philipp A.   Boes, Marianne   Fink, Katja   Henrickson, Sarah E.   Shayakhmetov, Dmitry M.   Di Paolo, Nelson C.   Van Rooijen, Nico   Mempel, Thorsten R.   Whelan, Sean P.   von Andrian, Ulrich H.  

    Lymph nodes prevent the systemic dissemination of pathogens such as viruses that infect peripheral tissues after penetrating the body's surface barriers. They are also the staging ground of adaptive immune responses to pathogen-derived antigens(1,2). It is unclear how virus particles are cleared from afferent lymph and presented to cognate B cells to induce antibody responses. Here we identify a population of CD11b(+)CD169(+)MHCII(+) macrophages on the floor of the subcapsular sinus (SCS) and in the medulla of lymph nodes that capture viral particles within minutes after subcutaneous injection. Macrophages in the SCS translocated surface-bound viral particles across the SCS floor and presented them to migrating B cells in the underlying follicles. Selective depletion of these macrophages compromised local viral retention, exacerbated viraemia of the host, and impaired local B-cell activation. These findings indicate that CD169(+) macrophages have a dual physiological function. They act as innate 'flypaper' by preventing the systemic spread of lymph-borne pathogens and as critical gatekeepers at the lymph-tissue interface that facilitate the recognition of particulate antigens by B cells and initiate humoral immune responses.
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  • Dmitry M. Rudkevich: A Tribute Seven Years after His Premature Passing

    Zyryanov, Grigory V.  

    This publication is dedicated to the memory of Professor Dmitry M. Rudkevich (1963-2007), my great friend and adviser, a person with a big heart, and a brilliant scientist. Professor Dmitry M. Rudkevich was the first who brought me into the amazing world of supramolecular chemistry and molecular recognition.
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  • A History of Russian Literature: 11th-17th Centuriesby Dmitry Likhachev; K. M. Cook-Horujy

    Review by: Alexander Boguslawski  

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