RESEARCH

Toll-like receptor (TLR) signaling

Background: TLRs represent a family of receptors essential for recognizing pathogens. They initiate signaling via adaptor proteins and partially defined pathways. TLRs upregulate inflammatory genes to initiate immune responses, however, exaggerated/ prolonged TLR activation can lead to inflammatory pathology.

Our major observations: We identified/ characterized various components of these pathways, including MyD88 and TRAF6 as part of the TLR9 pathway (recognizing DNA), TRAF3 as regulator of interferons and IL-10, and ABIN1/TNIP1 as regulator of the C/EBPb pathway.

Project layout: We use primarily artificial dimerization of adaptor proteins and affinity purification to characterize transiently assembled signaling complexes by quantitative mass spectrometry. We characterize identified proteins functionally in vitro and in vivo.

Current focus: We explore the molecular mechanism of TNIP1 function, which is essential to protect us from inflammatory diseases. We also work on a ‚new‘ signaling  protein, which controls the transcription factor family‚ interferon regulatory factors (IRF)‘.

Key publications:
Zhou, PNAS, 2011 (PMID: 22011580)
Ippagunta, PNAS, 2016 (PMID: 27671649)
Kuriakose, JCI, 2019  (PMID: 31033479)

Inflammatory Diseases (Lupus, Psoriasis)

Background: We indentified ABIN1/TNIP1 as component of the TLR signaling complex, which is essential to counteract pro-inflammatory TLR signaling. Human TNIP1 is genetically linked to the inflammatory diseases “systemic lupus erythematosus (SLE)“ and “psoriasis“ (hypomorphic polymorphisms). SLE is an “autoimmune“ disease of unclear etiology characterized by auto-antibodies and inflammatory infiltration of many organ systems. Immune complex-deposits in the kidneys are believed to drive glomerulonephritis leading to kidney failure. Psoriasis is an chronic, inflammatory skin disease, characterized by proliferating epidermal cells (keratinocytes), leading to red, scaling patches.

Our major observations: TNIP1-/- mice develop constitutively the major symptoms of human SLE and, inducibly, psoriasis-like disease. Consistent with current models, SLE is driven by nucleic acid-recognizing TLRs (TLR7/9, MyD88), while psoriasis is driven by the IL-17R.

Surprisingly, genetic deletion of T- and B-cells (and thus IgG) did not provide protection from kidney disease. In contrast, we found that a monocyte subtype (Patrolling monocytes, Pmo), accumulates in kidney glomeruli and, intruigingly, that genetic deletion of PMo protected from GN. As such, innate immune cells, not B-cell-derived auto-antibodies promote GN, suggesting a shift in paradigm with important ramnifications for human disease and therapeutic approaches.

Current project: We explore the mechanism of patrolling monocyte (PMo) deregulation. We investigate why PMo are up-regulated (cell differentiation vs. survival) and study the contribution of C/EBPb to PMo deregulation and disease. We also investigate established and novel therapeutic strategies to prevent PMo- mediated disease.

Key publications:
Zhou, PNAS, 2011 (PMID: 22011580)
Ippagunta, PNAS, 2016 (PMID: 27671649)
Kuriakose, JCI, 2019  (PMID: 31033479)

Generation of conditionally immortalized hematopoietic progenitors

Background and key observations: Hox genes are developmentally important transcription factors. Constitutively active Hox-mutants are oncogenes. Estrogen-regulated Hox-genes can be used to block cell differentiation. The combination of regulated Hox-gene and specific growth factor can be used to immortalize specific progenitor cells with neutrophil potential (Hoxb8-SCF (SCF)) or multi-lineage potential (Hoxb8-FL, FLT3L)(see publication below).

Current projects:
- Conditional immortalization of an erythrocyte/ megakaryocate progenitor.
- Application of Hox-cells in various models, including inflammatory and infectious disease models to study cell differentiation and contribution of specific immune cell populations to immunity.

Key publications:
Wang, Nature Methods, 2006 (PMID: 16554834)
Redecke,  Nature Methods,  2013 (PMID: 23749299)

Drug Development of anti-inflammatory Toll-like receptor inhibitors

Background: TLR-mediated inflammation promotes a plethora of human diseases, including acute bacterial sepsis, chronic inflammatory diseases (e.g. SLE), cancer (e.g. certain lymphomas) and metabolic diseases, e.g. ischemia-reperfusion injury (cardiac infarction, stroke). Despite the obvious clinical need, no drugs are currently clinically available. This is –at least in part- due to the signaling mechanisms involved, which depend largely on protein interactions (highlighted with yellow dots in figure below). Such interactions are inherently difficult for targeted drug developmental approaches. In turn, while phenotypic approaches could be used, those have the disadvantage of the uncertainty of the drug target. To overcome this problem, we developed a novel phenotypic screening platform that relies on artificial activation of signaling proteins that act at different levels of the TLR pathway (green arrows in figure below). This allows us during the drug-screening campaign to focus on compounds that inhibit the TLR-specific signaling level (upstream of TRAF). We provided proof-of-concept for this approach in recent work.

Major observations
We used a bioactive compound library and provided proof of concept for described signaling level-specific phenotypic drug screening. Moreover, using this approach we identifed a small molecule TLR signaling inhibitor scaffold (TSI), whose more detailed analysis related to structure activity relationship and mechanism of action demostrated intruiging properties.

Current projects
We currently optimize described TSI scaffold, for further preclinical testing in in vivo inflammatory mouse models. We also initiated a more extensive HTS, in collaboration with the St. Jude Children‘s Research Hospital, to identify additional chemotypes for successful long-term drug development.

Key publications:
Ippagunta, Science Signaling, 2018 (PMID: 30108181)
Pollock, ChemMedChem,  2018 (PMID: 30117269)

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Hans Haecker MD, PhD
Professor Microbiology & Immunology

CONTACT US

Department of Pathology
Division of Microbiology and Immunology
University of Utah
Emma Eccles Jones Medical Research Building
15 N. Medical Drive East, Rm 1520 H
Salt Lake City, UT  84112
email hans.haecker@path.utah.edu
phone 801-587-1507

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