Institute of Anatomy

Research

Immunobiology

Research

Bacterial pore-forming toxins: Indirect and direct effects on immune cells

Pore-forming toxins are produced by many pathogenic bacteria and are important virulence factors. These toxins bind as monomers to receptors in the plasma membrane (e.g. cholesterol or a surface receptor) and form a transmembrane pore, which leads to the death of the affected cells. However, our cells possess plasma membrane repair mechanisms that enable them to survive these detrimental attacks.

Indirect effects of pore-forming toxins on immune cells: polarization of macrophages

In a prominent membrane repair process, induced by annexin-protein family members, parts of the toxin-damaged plasma membrane are pinched off in the form of repair-microvesicles. We investigate the effects of these repair-microvesicles on different immune cell types.

We were able to show that repair-microvesicles are recognized by macrophages. The repair-microvesicles induce a strong immune response against toxin-producing bacteria by polarizing macrophages to a novel pro-inflammatory phenotype (Köffel et al., 2018).

Direct effects of pore-forming toxins on immune cells: plasma membrane damage and -repair mechanisms

In bacterial infections, pore-forming toxins also kill primarily immune cells, which migrate infection sites to fight the bacteria. We investigate the resistance of different immune cell types to pore-forming toxins from different pathogens.

We were able to show that in lymphocytes and macrophages resistance to e.g. pneumolysin (from Streptococcus pneumoniae) differs as a direct result of distinct plasma membrane repair efficiency and lipid architecture of the plasma membrane (Schoenauer et al., 2019; Larpin et al., 2020).

Dendritic cell biology and annexins

Dendritic cells (DCs) are a heterogeneous population of specialized antigen presenting cells that are located at the outmost barriers of our human body. They have critical functions in orchestrating immune responses and act as immune guardians. Langerhans dendritic cells (LCs) represent a highly abundant subtype of DCs, residing in epithelial tissues (epidermis/mucosae), where they build a cell network. Epidermal LCs are suggested to be important in the local control of T cells and tissue responses. Thus, disturbances of the epidermal LCs network or function could therefore play a role in inflammatory skin disorders.

The annexin family consists of 12 structurally related Ca2+ and phospholipid-sensing proteins, which exert various functions, ranging from membrane repair to more physiological roles in apoptosis and inflammation homeostasis. We find annexin family members expressed in skin tissue and in DCs subsets in mouse and human.

We investigate the function of annexins in inflammatory skin diseases f.e. psoriasis, with special focus on LCs function.

Epidermal Langerhans dendritic cells.
Immunofluorescence staining of LCs (red, Langerin+) in human skin biopsies (blue, nuclei; size bar 50µm).

Current projects

  • Effects of repair-microvesicles (triggered by distinct pore-forming toxins, e.g. streptolysin O) on myeloid immune cells, e.g. macrophages and granulocytes.
  • Correlation between toxin pore structure (e.g. pore size) and mode of membrane repair.
  • Annexin-mediated repair mechanisms in different immune cells.
  • Functions of AnnexinA1 in skin diseases and dendritic cells.

Collaborations

  • Prof. Thomas Pabst, Department of Medical Oncology, Inselspital, Bern
  • Prof. Benoît Zuber, Institute for Anatomy, University of Bern
  • Prof. Horst Posthaus, Vetsuisse Faculty, University of Bern
  • Prof. Nikhil Yawalkar, Department of Dermatology, Inselspital, Bern
  • Prof. Ursula Rescher, University of Münster, Germany