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Now showing items 1 - 7 of 7

  • Inflammation and Infection in Critical Care Medicine

    Martin-Loeches, Ignacio   Bosinger, Steven  

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  • Nef-Mediated CD3-TCR Downmodulation Dampens Acute Inflammation and Promotes SIV Immune Evasion

    Joas, Simone   Sauermann, Ulrike   Roshani, Berit   Klippert, Antonina   Daskalaki, Maria   Mätz-Rensing, Kerstin   Stolte-Leeb, Nicole   Heigele, Anke   Tharp, Gregory K.   Gupta, Prachi Mehrotra   Nelson, Sydney   Bosinger, Steven   Parodi, Laura   Giavedoni, Luis   Silvestri, Guido   Sauter, Daniel   Stahl-Hennig, Christiane   Kirchhoff, Frank  

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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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  • mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation

    Sinclair, Charles   Bommakanti, Gayathri   Gardinassi, Luiz   Loebbermann, Jens   Johnson, Matthew Joseph   Hakimpour, Paul   Hagan, Thomas   Benitez, Lydia   Todor, Andrei   Machiah, Deepa   Oriss, Timothy   Ray, Anuradha   Bosinger, Steven   Ravindran, Rajesh   Li, Shuzhao   Pulendran, Bali  

    Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103(+) DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b(+) DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T(H)2) to neutrophilic T(H)17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation.
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  • Alterations of redox and iron metabolism accompany the development of HIV latency

    Shytaj, Iart Luca   Lucic, Bojana   Forcato, Mattia   Penzo, Carlotta   Billingsley, James   Laketa, Vibor   Bosinger, Steven   Stanic, Mia   Gregoretti, Francesco   Antonelli, Laura   Oliva, Gennaro   Frese, Christian K   Trifunovic, Aleksandra   Galy, Bruno   Eibl, Clarissa   Silvestri, Guido   Bicciato, Silvio   Savarino, Andrea   Lusic, Marina  

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  • Correlates of Protection Against SIVmac251 Infection in Rhesus Macaques Immunized With Chimpanzee-Derived Adenovirus Vectors.

    Tuyishime, Steven   Haut, Larissa H   Kurupati, Raj K   Billingsley, James M   Carnathan, Diane   Gangahara, Sailaja   Styles, Tiffany M   Xiang, ZhiQuan   Li, Yan   Zopfs, Malte   Liu, Qin   Zhou, XiangYang   Lewis, Mark G   Amara, Rama R   Bosinger, Steven   Silvestri, Guido   Ertl, Hildegund C J  

    We report on prime-boost vaccine regimens with two simian adenovirus (Ad) vectors (SAdV) or two human serotype Ad vectors (HAdV) expressing Gag and gp160 of simian immunodeficiency virus (SIV)mac239 tested in HAdV-seropositive rhesus macaques (RMs) repeatedly challenged rectally with low doses of SIVmac251. Both vaccine regimens reduced set point and peak viral loads (PVL) and accelerated viral clearance. In SAdV-vaccinated controller genotype RMs resistance against infection correlated with levels of envelope (Env)-specific antibody (Ab) titers. In both vaccine groups CD8+T cells controlled viral loads (VL) upon infection. Circulating CD4+ and CD8+ T cells showed significant changes in their transcriptome over time following vaccination, which differed between the vaccine groups. T cells from SIV-resistant RMs had unique transcriptional profiles indicating that both follicular T helper (TFH) cell responses and highly activated CD8+ T cells may play a role in protection. Copyright =C2=A9 2018. Published by Elsevier B.V.
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  • Enhanced methamphetamine metabolism in rhesus macaque as compared with human: an analysis using a novel method of liquid chromatography with tandem mass spectrometry, kinetic study, and substrate docking.

    Earla, Ravinder   Kumar, Santosh   Wang, Lei   Bosinger, Steven   Li, Junhao   Shah, Ankit   Gangwani, Mohitkumar   Nookala, Anantha   Liu, Xun   Cao, Lu   Jackson, Austin   Silverstein, Peter S   Fox, Howard S   Li, Weihua   Kumar, Anil  

    Methamphetamine (MA), which remains one of the widely used drugs of abuse, is metabolized by the cytochrome P450 (P450) family of enzymes in humans. However, metabolism of methamphetamine in macaques is poorly understood. Therefore, we first developed and validated a very sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using solid phase extraction of rhesus plasma with a lower limit of quantitation at 1.09 ng/ml for MA and its metabolites, 4-hydroxy methamphetamine (4-OH MA), amphetamine (AM), 4-OH amphetamine (4-OH AM), and norephedrine. We then analyzed plasma samples of MA-treated rhesus, which showed >10-fold higher concentrations of AM (29 ng/ml) and 4-OH AM (28 ng/ml) than MA (2 ng/ml). Because the plasma levels of MA metabolites in rhesus were much higher than in human samples, we examined MA metabolism in human and rhesus microsomes. Interestingly, the results showed that AM and 4-OH AM were formed more rapidly and that the catalytic efficiency (Vmax/Km) for the formation of AM was 8-fold higher in rhesus than in human microsomes. We further examined the differences in these kinetic characteristics using three selective inhibitors of each human CYP2D6 and CYP3A4 enzymes. The results showed that each of these inhibitors inhibited both d- and l-MA metabolism by 20%-60% in human microsomes but not in rhesus microsomes. The differences between human and rhesus CYP2D6 and CYP3A4 enzymes were further assessed by docking studies for both d and l-MA. In conclusion, our results demonstrated an enhanced MA metabolism in rhesus compared with humans, which is likely to be caused by differences in MA-metabolizing P450 enzymes between these species. Copyright =C2=A9 2014 by The American Society for Pharmacology and Experimental Therapeutics.
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