Person: Fitzgerald, Michael
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Fitzgerald
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Michael
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Fitzgerald, Michael
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Publication 136 HIV-1 Nef regulates activity of endoplasmic reticulum chaperone calnexin(JAIDS Journal of Acquired Immune Deficiency Syndromes, 2014) Jennelle, Lucas; Hunegnaw, Ruth; Dubrovsky, Larisa; Pushkarsky, Tatiana; Fitzgerald, Michael; Sviridov, Dmitri; Bukrinsky*, MichaelHIV-1 Nef promotes viral replication by downmodulating a number of cell surface transmembrane proteins, such as CD4, MHC-I and MHC-II, which are targeted by Nef to various degradation pathways. Nef is also responsible for downregulation of cellular cholesterol transporter ABCA1, and this effect contributes to development of atherosclerosis in HIV infected patients. Surprisingly, in contrast to CD4 and MHC I, to which Nef has to bind to exert downregulation, binding to ABCA1 turned out to be unnecessary for inactivation of ABCA1 by Nef. Here, we identified a novel mechanism by which Nef influences activity of host cell and viral proteins. We show that Nef interacts with an endoplasmic reticulum chaperone calnexin, which is essential for folding and maturation of glycosylated proteins. Nef disrupts calnexin interaction with ABCA1, thus impairing functionality of this protein, but increases affinity and enhances interaction of calnexin with gp160, promoting maturation and functionality of viral Env proteins. Knock-down of calnexin lead to reduced fusion activity of HIV-1 envelope and reduced virion infectivity, as well as to defective cholesterol efflux, which is mediated by ABCA1. However, gp160 and ABCA1 interacted with calnexin differently: while gp160 binding to calnexin was dependent on glycosylation, interaction of ABCA1 with calnexin was glycosylation-independent. Therefore, Nef binds to calnexin and stimulates interaction between calnexin and gp160 at the expense of ABCA1 and probably other ER proteins. These results provide a mechanistic explanation for previously unexplained effect of Nef on functionality of ABCA1, and suggest a mechanism for upregulation of HIV infectivity by Nef through stimulation of Env maturation.Publication High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3(2014) De Nardo, Dominic; Labzin, Larisa I.; Kono, Hajime; Seki, Reiko; Schmidt, Susanne V.; Beyer, Marc; Xu, Dakang; Zimmer, Sebastian; Lahrmann, Catharina; Schildberg, Frank A.; Vogelhuber, Johanna; Kraut, Michael; Ulas, Thomas; Kerksiek, Anja; Krebs, Wolfgang; Bode, Niklas; Grebe, Alena; Fitzgerald, Michael; Hernandez, Nicholas J.; Williams, Bryan; Knolle, Percy; Kneilling, Manfred; Röcken, Martin; Lütjohann, Dieter; Wright, Samuel D.; Schultze, Joachim L.; Latz, EickeHigh Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.Publication Genomic epidemiology of the Escherichia coli O104:H4 outbreaks in Europe, 2011(Proceedings of the National Academy of Sciences, 2012) Grad, Yonatan; Lipsitch, Marc; Feldgarden, M.; Arachchi, H. M.; Cerqueira, G. C.; Fitzgerald, Michael; Godfrey, P.; Haas, Brandon Russell; Murphy, C. I.; Russ, C.; Sykes, Sean; Walker, B. J.; Wortman, J. R.; Young, Sarah; Zeng, Q.; Abouelleil, A.; Bochicchio, J.; Chauvin, S.; DeSmet, T.; Gujja, S.; Mccowan, Caryn Alissa; Montmayeur, A.; Steelman, S.; Frimodt-Moller, J.; Petersen, A. M.; Struve, C.; Krogfelt, K. A.; Bingen, E.; Weill, F.-X.; Lander, Eric; Nusbaum, C.; Birren, B. W.; Hung, Deborah; Hanage, WilliamThe degree to which molecular epidemiology reveals information about the sources and transmission patterns of an outbreak depends on the resolution of the technology used and the samples studied. Isolates of Escherichia coli O104:H4 from the outbreak centered in Germany in May–July 2011, and the much smaller outbreak in southwest France in June 2011, were indistinguishable by standard tests. We report a molecular epidemiological analysis using multiplatform whole-genome sequencing and analysis of multiple isolates from the German and French outbreaks. Isolates from the German outbreak showed remarkably little diversity, with only two single nucleotide polymorphisms (SNPs) found in isolates from four individuals. Surprisingly, we found much greater diversity (19 SNPs) in isolates from seven individuals infected in the French outbreak. The German isolates form a clade within the more diverse French outbreak strains. Moreover, five isolates derived from a single infected individual from the French outbreak had extremely limited diversity. The striking difference in diversity between the German and French outbreak samples is consistent with several hypotheses, including a bottleneck that purged diversity in the German isolates, variation in mutation rates in the two E. coli outbreak populations, or uneven distribution of diversity in the seed populations that led to each outbreak.Publication ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content(Nature Publishing Group, 2017) Nowyhed, Heba N.; Chandra, Shilpi; Kiosses, William; Marcovecchio, Paola; Andary, Farah; Zhao, Meng; Fitzgerald, Michael; Kronenberg, Mitchell; Hedrick, Catherine C.ABCA7 is an ABC transporter expressed on the plasma membrane, and actively exports phospholipid complexes from the cytoplasmic to the exocytoplasmic leaflet of membranes. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid antigens in the context of CD1d-mediated antigen presentation. In this study, we demonstrate that ABCA7 regulates the development of NKT cells in a cell-extrinsic manner. We found that in Abca7−/− mice there is reduced expression of CD1d accompanied by an alteration in lipid raft content on the plasma membrane of thymocytes and antigen presenting cells. Together, these alterations caused by absence of ABCA7 negatively affect NKT cell development and function.Publication Large-Scale Chemical–genetics Yields New M. Tuberculosis Inhibitor Classes(Springer Science and Business Media LLC, 2019-06-19) LaVerriere, Emily; Meyer, Elisabeth; Kawate, Tomohiko; Gomez, James; Gardner, Michelle; Cigarroa Kennedy, Sofia; Wakabayashi, Shoko; Watson, Christopher; Fitzgerald, Michael; Johnson, Eachan; Office, Emma; Stanley, Mary; Audette, Rebecca; Bandyopadhyay, Nirmalya; Betancourt, Natalia; Delano, Kayla; Da Silva, Israel; Davis, Joshua; Gallo, Christina; Golas, Aaron; Guinn, Kristine; Korn, Rebecca; McConnell, Jennifer; Moss, Caitlin; Murphy, Kenan; Nietupski, Raymond; Papavinasasundaram, Kadamba; Pinkham, Jessica; Pino, Paula; Proulx, Megan; Ruecker, Nadine; Song, Naomi; Thompson, Matthew; Trujillo, Carolina; Metcalf-Wallach, Joshua; Ioerger, Thomas; Lander, Eric; Hubbard, Brian; Serrano-Wu, Michael; Ehrt, Sabine; Rubin, Eric; Sassetti, Christopher; Schnappinger, Dirk; Hung, DeborahNew antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, probing >8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified >40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating PROSPECT’s ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.