Biochemistry

Theresa Gioannini, PhD

Gioannini

Contact Information

Address: 51 Newton Road, 4-403 BSB
Iowa City, IA 52242

Biography

Dr. Theresa Gioannini lost her battle with multiple myeloma on Saturday, January 4, 2014.

Dr. Gioannini received a B.S. in Chemistry from St. Mary-of-the-Woods College in 1971 and an M.S. and Ph.D. in Chemistry from New York University in 1976 and 1978.  Dr. Gioannini began her career at New York University and Buruch College, earning the rank of Full Professor at Buruch College in 1993 prior to her academic career at the University of Iowa.In 1998, she and Jerrold Weiss joined the Inflammation Program in Internal Medicine and was granted the position of Adjunct Professor of Biochemistry.  For the last 15 years, Professor Gioannini contributed to the Biochemistry undergraduate educational program and conducted research on toll-like receptors, most recently publishing in Nature and Innate Immunity.  She will be greatly missed by colleagues, students and family.

 

Research

http://biochem.uiowa.edu/gioannini/

Toll-like receptors couple molecular recognition of conserved and structurally unique microbial molecules to rapid mobilization of innate immune effector systems and subsequently induction of adaptive immunity. Toll-like receptor 4 (TLR4) is essential for the recognition of even minute amounts of endotoxin (E), unique glycolipids abundantly present on the surface of Gram negative bacteria (GNB). Variations in E structure – as occurs naturally among GNB – and variations in levels of host cell proteins involved in E binding and signal transduction make possible great diversification of host cell responses to E.Efficientpotent responses to E require the sequential action of extracellular and cell surface host proteins: lipopolysaccharide-binding protein (LBP), CD14, and MD-2 for delivery to and activation of TLR4.  E-dependent responses elicited through TLR4 lead to activation of either MyD88- and/or TRIF-dependent signaling pathways.  Novel reagents and experimental approaches we have developed allow detection and quantitative analysis of specific, high affinity (pM) E- protein and TLR4 interactions under physiologically relevant conditions and have permitted further knowledge of the mechanism of action of several natural and synthetic regulators of TLR4 activation. Increasing evidence suggests physiologic and patho-physiologic roles of TLR4 extending beyond host responses to invading GNB. Our work is focused on understanding

  • The mechanism(s) by which E interactions with MD-2 specify activation or antagonism of TLR4;
  • What and how discrete variations in E, MD-2, or the TLR4 ectodomain affect TLR4 activation;
  • The nature of CD14-dependent vs. independent events driving the nature of TLR4 responses;
  • If and how physiologically endogenous molecules, such as hemin, interact directly with and activate (or inhibit) TLR4.

Approaches to these questions utilize metabolically radiolabeled (or [13C]-labeled) E and classical biochemical techniques, including the preparation and purification of E-binding proteins and E:protein complexes, to evaluate the nature and functional characteristics of E:protein and protein:protein interactions involved in TLR4-dependent responses. In collaboration with the NMR Facility, we have undertaken the generation of isolated E:MD-2 complexes +/- TLR4 ectodomain as a means to explore the variation in dynamics of E/MD-2/TLR4 interactions of various complexes (agonist vs. antagonist E and mutant MD-2s) by NMR

 

Selected Publications

Teghanmet, A, Weiss, JP, Gioannini, TL. (2013) Radioiodination of an endotoxin×MD-2 complex generates a novel sensitive, high affinity ligand for TLR4. Innate Immunity Epub online 2013 Feb 25.

Rallabhandi P, Phillips, RL, Boukhvalova, MS, Pletneva, LM, Shirey, KA, Gioannini, TL, Weiss, JP, Chow, JC, Hawkins, LD, Vogel, SN, Blanco, JC. (2012) Respiratory syncytial virus fusion protein-Induced Toll-Like Receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2.  MBio. 2012 published online Aug 7;3(4). doi: 10.1128/mBio.00218-12.

Wendlandt, EB, Graff, JW, Gioannini, TL, McCaffrey, AP, Wilson, ME (2012) The role of microRNAs miR-200b and miR-200c in TLR4 signaling and NF-kB activation. Innate Immunity 18:846-855.

Yu, L, Phillips, RL, Zhang, D, Teghanemt, A, Weiss, JP, Gioannini, TL. (2012) NMR studies of hexaacylated endotoxin bound to wild-type and F126A mutant MD-2 and MD-2•TLR4 ectodomain complexes. J. Biol. Chem. 287: 16346-16355.

Yang, D, Postnikov, YV, Li, Y, Tewary, P, de la Rosa, G, Wei, F, Klinman, D, Gioannini, T,Weiss, JP, Furusawa, T, Bustin, M, Oppenheim, JJ.  (2012) High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses.  J. Exp. Med. 209: 157-171.

Piazza, M, Calabrese, V, Damore, G, Cighetti, R, Gioannini, T, Weiss, J, Peri, F. (2012) A synthetic Lipid A mimetic modulates human TLR4 activity.  ChemMedChem. 7: 213-217.

Esparza, GA, Teghanemt, A, Zhang, D, Gioannini, TL,Weiss, JP (2012) Endotoxin•albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.  Innate Immunity 18:478-491.

Piazza M, Colombo M, Zanoni I, Granucci F, Tortora P, Weiss J, Gioannini, T, Prosperi D, Peri F. (2011) Uniform Lipopolysaccharide (LPS)-Loaded Magnetic Nanoparticles for the Investigation of LPS-TLR4 Signaling. Angew Chem Int Ed Engl. 50:622-626.

Piazza, M, Calabrese, V, Baruffa, C, Gioannini, T, Weiss, J and Peri, F. (2010) The cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine inhibits LPS signaling by competing with endotoxin for CD14 binding. Biochem. Pharmacol. 80:2050-2056.

Piazza, M, Damore, G, Costa, B, Gioannini, TL, Weiss, JP, and Peri, F. (2010) Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets. Innate Immunity, 17:293-301.

Prohinar, P, Rallabhandi, P, Weiss, JP, Gioannini, TL. (2010) Expression of functional D299G.T399I polymorphic variant of Toll-like receptor 4 (TLR4) depends more on co-expression of MD-2 than does wild-type TLR4. J. Immunol. 184:4362-4367.

Resman N, Vasl J, Oblak A, Pristovsek P, Gioannini TL, Weiss JP, Jerala R (2009) Essential roles of hydrophobic residues in both MD-2 and toll-like receptor 4 in activation by endotoxin. J Biol Chem 284: 15052-15060.

Trompette, A, Divanovic, S, Visintin, A, Blanchard, C, Hegde, RS, Madan, R, Thorne, PS, Wills-Karp, M, Gioannini, TL,Weiss, JP, Karp, CL.  (2009)  Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature, 457(7229):585-8.