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Pharmacological modulation of the Innate Immune response

Our research interests focus in understanding the human innate immune response in inflammatory diseases, in particular the activity of phagocytes and the signaling processes involved. Toll-like receptors (TLRs) are key components of this system which recognise different molecular patterns conserved in pathogens and also some host-derived ligands that are the result of tissue damage in sterile inflammation. Therefore, TLRs play a crucial role not only in fighting infections and the host-response in sepsis, but also in many other clinical conditions including cancer. Thus, they are important therapeutic targets.

We intend to develop novel substances that may be specifically applied in the modulation of the immune activity (stimulation or down-regulation). Up to now, we discovered small-molecule agonists and antagonists of Toll-like receptor 2 (TLR2) and also we designed decoy peptides derived from the extracellular domain of TLR2 with anti-inflammatory properties (see references at the bottom). Nowadays we are testing their efficacy in different cellular and in vivo models of disease.

Alumni

• Stefanie Seidlberger, Bachelor Thesis, Master Thesis (Biotechnol.)
• Atea Shkodra, Erasmus student University of Padua (Pharmacist)
• Lisa Schütz, Bachelor Thesis (Mol. Med)
• Dorothea Malecek, Bachelor Thesis (Mol. Med)
• Alexander Moschen, Diploma-thesis (Physician)
• Sandra Renk, Diploma-thesis (Physician)
• Ramona Bruckner, Master-thesis (Biologist)

Collaborations

• Dr. M. Drexel (MUI, Innsbruck);
• Prof. S. Ebner (MUI, Innsbruck),
• Dr. J. Fuchs (LFU, Innsbruck),
• Prof. P. Henneke (CCI, Freiburg),
• Dr. P. Hörtnagl (MUI, Innsbruck),
• Prof. F Lagler (PMU, Salzburg),
• Prof. K. Liedl (LFU, Innsbruck),
• Prof. M. Schirmer (MUI, Innsbruck),
• Dr. G. Wietzorrek (MUI, Innsbruck),
• Prof. Wolber (FUB, Berlin)

Teaching

• Medicine: Module Biochemistry
• Molecular Medicine: Module Neuroscience
• PhD program "Neuroscience"

Recent publications:

Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One?
Sandra Santos-Sierr, Biomolecules. 2021 Aug 30;11(9):1291. doi: 10.3390/biom11091291. PMID: 34572504

  Developments in anticancer vaccination: budding new adjuvants.
Santos-Sierra S.; Biol Chem. 2019 Nov 1. pii: /j/bchm.just-accepted/hsz-2019-0383/hsz-2019-0383.xml. doi: 10.1515/hsz-2019-0383. [Epub ahead of print]

INH14, a small-molecule urea derivative, inhibits the IKKα/β-dependent TLR inflammatory response.
Drexel M, Kirchmair J, Santos-Sierra S.
Chembiochem. 2018 Nov 17. doi: 10.1002/cbic.201800647. PMID: 30447158

Anti-inflammatory activity of small-molecule antagonists of Toll-like receptor 2 (TLR2) in mice.Wietzorrek G, Drexel M, Trieb M, Santos-Sierra S.Immunobiology. 2019 Jan;224(1):1-9. doi: 10.1016/j.imbio.2018.11.004. Epub 2018 Nov 20.PMID:30509503

Decoy peptides derived from the extracellular domain of Toll-like receptor 2 (TLR2) show anti-inflammatory properties.
Ebner S, Trieb M, Schönfeld M, Wietzorrek G, Santos-Sierra S.
Bioorganic & Medicinal Chemistry. 2018. DOI 10.1016/j.bmc.2018.07.013

Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2).
Murgueitio MS, Ebner S, Hörtnagl P, Rakers C, Bruckner R, Henneke P, Wolber G, Santos-Sierra S.
Biochim Biophys Acta. 2017 Jul 19.

Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 antagonists.
Murgueitio MS, Henneke P, Glossmann H, Santos-Sierra S*, Wolber G*
ChemMedChem. 2014

Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase.
Kenzel S, Mergen M, von Süßkind-Schwendi J, Wennekamp J, Deshmukh SD, Haeffner M, Triantafyllopoulou A, Fuchs S, Farmand S, Santos-Sierra S, Seufert J, van den Berg TK, Kuijpers TW, Henneke P.
J Immunol. 2012

Novel pharmacological chaperones that correct phenylketonuria in mice.  
Santos-Sierra S, Kirchmair J, Perna AM, Reiss D, Kemter K, Röschinger W, Glossmann H, Gersting SW, Muntau AC, Wolber G, Lagler FB.
Hum Mol Genet. 2012

Mal connects TLR2 to PI3Kinase activation and phagocyte polarization.
Santos-Sierra S, Deshmukh SD, Kalnitski J, Küenzi P, Wymann MP, Golenbock DT, Henneke P.
EMBO J. 2009

Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus.
Kenzel S, Santos-Sierra S, Deshmukh SD, Moeller I, Ergin B, Fitzgerald KA, Lien E, Akira S, Golenbock DT, Henneke P.
Infect Immun. 2009

Lipoproteins are critical TLR2 activating toxins in group B streptococcal sepsis.
Henneke P, Dramsi S, Mancuso G, Chraibi K, Pellegrini E, Theilacker C, Hübner J, Santos-Sierra S, Teti G, Golenbock DT, Poyart C, Trieu-Cuot P.
J Immunol. 2008.

Funding:

• FWF: P22797-B13; P30779-BBL (partner); P35219-B
• EKFS: 2012_A274
• FFG Talente Entdecken: 2011/12/13/17