Susanna Zierler is the head of the Institute of Pharmacology at the JKU Linz and group leader at the Walther Straub Institute of Pharmacology and Toxicology, LMU Munich. She holds a PhD from the University of Salzburg and completed her postdoctoral training at The Queen’s Medical Center, in Honolulu. Her research expertise spans pharmacology, immunology, and cell biology. She focuses with her team on immune cell signaling at the smallest level of ions. Herein they investigate the transport of ions across cell membranes and between organelles. This aims at a better understanding of the regulation of ion channels at the cellular level and in the context of in vivo immune reactions.

TRPM7 channel-kinase function – from cellular signaling to immune system homeostasis

The immune system protects our body against pathogens. However, if it overshoots, proinflammatory or autoimmune diseases may develop. Therefore, respective mechanisms are in place to ensure a suitable immune response at the right time. Using different mouse models as well as primary human immune cells, we deciphered an essential role for the transient-receptor-potential melastatin-like 7 channel-kinase, TRPM7, in cellular signaling and in vivo immune reactions. TRPM7 comprises a cation channel fused with a serine/threonine kinase. We found that its genetic disruption in mice affects innate as well as adaptive immune system responses. Using a homozygous TRPM7-kinase-dead mouse model with a single point mutation at the active site of the kinase, Trpm7^R/R, we demonstrated that TRPM7-kinase activity controls proinflammatory T_H17 cell differentiation, but is dispensable for anti-inflammatory, regulatory T cell (T_reg) differentiation. We identified SMAD2 as native substrate of the TRPM7-kinase. Notably, genetic disruption of the TRPM7-kinase activity prevented the development of acute graft-versus-host-disease in an established mouse model. Similarly, TRPM7 kinase-activity seems essential for the development of autoimmune diseases, such as Multiple Sclerosis. In a murine model of experimental autoimmune encephalomyelitis (EAE) we could demonstrate a protective effect of genetic TRPM7-kinase disruption on incidence and severity, in an adoptive transfer EAE model. This further highlights the need for good pharmacologic modulators of channel and kinase function. Using novel tools, our translational results imply that TRPM7 is similarly important for the activation and differentiation of primary human T cells. Our results unravel a fundamental role of the TRPM7-kinase in immune cell function and suggest a therapeutic potential of TRPM7 kinase inhibition in averting proinflammatory diseases.

Regulation of innate immunity by ion channels

Nicolas Demaurex's lab focuses on the mechanisms controlling the ionic homeostasis of innate immune cells, in particular the mechanisms regulating calcium channels activated by a decrease in calcium concentration in the endoplasmic reticulum. These so-called store-operated channels generate signals controlling gene expression, cell proliferation and the secretion of inflammatory mediators by immune cells.

His laboratory has helped establish the molecular basis of membrane contact sites in the activation of store-operated calcium channels and the physiological significance of these channels in the regulation of neutrophil and dendritic cell functions. Work in progress in the laboratory is focused on understanding the role of the proteins STIM, ORAI, and Hv1 in leukocyte trafficking and in regulating the bactericidal activity of neutrophils.

T regulatory cell therapy for treating autoimmune diseases

Yannick Muller is interested in the development of adoptive cell therapy based on regulatory T lymphocytes (a subpopulation of white blood cells) for autoimmune diseases, allergies and transplantation. Adoptive cell therapy involves isolating specialised lymphocytes from blood and then artificially stimulating them to multiply ex-vivo before reinjecting them via the vein as an immunomodulating biological treatment.

Yannick Muller's research focuses on genetic engineering and the use of CRISPR-Cas9 technology, a molecular scissors that can surgically cut the DNA of cells in order to remove, repair or insert new genes. His team is working on the possibility of redirecting the specificity of regulatory lymphocytes against peptides or antigens specific to certain diseases and/or tissues in the context of adoptive cell therapy. He has particular interest and expertise in the use of chimeric antigenic receptors, synthetic molecules that target soluble or membrane proteins. Yannick Muller's research therefore aims to be translational, ‘from bench to clinic’, with the medium-term development of new targeted and personalised therapeutic approaches that restore or induce immune tolerance.