Project 06

Glucocorticoids; hub between infection-susceptibility and inflammation treatment

• Principial Investigators:
  • TUD: Charlotte Steenblock & Stefan R. Bornstein
  • UZH: Benjamin Hale & Felix Beuschlein 
• Students:
  • TUD: Samira Kaziakhmedova (1st year-PhD student)

Background: Hypercortisolism (Cushing’s syndrome) can be either endogenous, due to pituitary or adrenal tumours, or exogenous (iatrogenic) as a consequence of long-term exposure to excessive glucocorticoids. 3% of the population in western countries receive glucocorticoid treatment for chronic diseases, such as asthma or rheumatoid arthritis. In addition to a number of comorbidities, such as hypertension, diabetes, overweight, and myopathy, patients with Cushing’s syndrome frequently suffer from multiple infections, including respiratory pathogens, that may lead to a fatal outcome if treatment is not initiated in time. Upon immune challenge, the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6, and type I interferons (e.g. IFN-α/β) are released from a variety of cell types, including activated immune cells, vascular endothelial cells, fibroblasts, and neurons. Furthermore, the T cell cytokines IL-2 
and IFN-γ (type II interferons) are important for mediating anti-viral defences. In addition to contributing to the progression of the immune response against viral infections, the cytokines can activate the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of adrenal glucocorticoids. Oppositely, glucocorticoids exhibit negative feedback onto immune cells to suppress further synthesis and release of cytokines, thereby protecting the host from the detrimental consequences of an overactive immune response (e.g., tissue damage, autoimmunity, and septic shock), as observed in the COVID-19 pandemic where glucocorticoids were used to treat COVID-19. This bidirectional relationship between the HPA axis and the immune system is not fully understood.

Aims: The overall goal is to elucidate the impact of glucocorticoids on infection susceptibility, thus evaluating why Cushing patients are more susceptible to infections. Consequently, the following aims will be addressed: 1) In vitro assessment of the impact of glucocorticoids on virus infections and innate immunity using cell culture models. 2) Assessment of the impact of chronic hypercortisolism on infection susceptibility in animal models. 3) Assessment of the effects on the immune system of chronic hypercortisolism in Cushing patients.

Added value through the collaboration between Dresden & Zurich: The Steenblock group has expertise in animal models of adrenal and metabolic diseases including also isolating, culturing and staining of cells isolated from endocrine organs. The Bornstein group has in-depth expertise in intercellular crosstalk in the endocrine system, with particular focus on the adrenal gland. The Beuschlein group has strong expertise in clinical and molecularcharacterization of various endocrine disorders, with particular focus on adrenal and pituitary gland tumours. The three groups are closely collaborating at characterizing the effect of metabolic stress on cells of the hypothalamus-pituitary-adrenocortical axis. The Hale group) has strong expertise in assessment of immune response in relation to viral infectious diseases in cell culture models.

Synergies: We plan to collaborate with projects 3, 5, and 8 on various animal models of infections (LPS, Streptococcus Pneumoniae, Escherichia coli, Trichomonas, and H1N1) associated with diet-induced metabolic disorders before or after infection. In addition, we will be working with project 8 on cell culture models for viral infections. In addition, we look forward to collaborating with project 9 to study the effects of glucocorticoid treatment in COVID-19 patients.