Project 08

Dietary interventions in prevention of infectious diseases 

• Principial Investigators:
  • TUD: Hani Harb & Nikolaos Perakakis
  • UZH: Philipp Gerber & Annelies Zinkernagel
• Students:
  • TUD: Sol Seo (1st year-PhD student), Trishla Adhiraki (affiliated 2nd year-PhD student), Nadia Schlebe (Dr. med. student)

  • UZH: Leonie Mönch (2nd year-PhD student), Lorenz Klein (1st year-PhD student)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is considered the hepatic manifestation of metabolic syndrome (153). NAFLD is characterized by the accumulation of liver fat (steatosis), that can progress to liver inflammation (non-alcoholic steatohepatitis, NASH) and in later stages to liver fibrosis and cirrhosis. Recent studies have shown that NAFLD is associated with increased risk of severe infection. This risk is evident in all stages of NAFLD and increases as disease progresses. Importantly, this elevated risk remains after adjusting for all parameters of metabolic syndrome and after performing respective sensitivity analyses. The underlying mechanisms of this association remain largely unknown and it is speculated that a dysregulation of the innate and adaptive – cellular immune system may occur, which might be similar to the perturbations in immune system response observed in type 2 diabetes. Intermittent fasting (i.e. alternate-day fasting [ADF] or time restricted feeding [TRF]) has been shown to improve hepatic state and promote weight loss in adults with NAFLD. Additionally, intermittent fasting has been shown to exert beneficial 
immunomodulatory effects in healthy populations and in people with obesity. Whether 
improvement of hepatic state with intermittent fasting can restore immune system response and can reduce infection susceptibility and severity in patients with NAFLD remains a critical and yet unresolved question. Similarly, it remains unclear whether ARD or TRF might be more beneficial for immune system response to infection and whether any protective effects against severe infection are partially or exclusively dependent on concomitant weight – loss due to the diet.

Aims: 1st aim of this project is to assess whether development and progression of NAFLD due to overnutrition is associated with alterations in both innate and adaptive immune system (neutrophils, monocytes, innate lymphoid cells and T-cells) response that might increase the risk of severe infection. 2nd aim of this project is to evaluate whether intermittent fasting (ARD or TRF) is able to restore the NAFLD-related perturbations due to overnutrition in immune system, thus attenuating the risk of severe infection. 3rd aim is to assess whether the restoration of immune system response differs according to the type of intermittent fasting (ARD or TRF), as well as whether it is partially or completely weight-loss dependent.

Added value through the collaboration between Dresden & Zurich: Perakakis group has expertise in metabolism/NAFLD and Harb group in infectious immunology and they will be responsible for the NAFLD mouse models of viral infection. The Zinkernagel group has great expertise in bacterial infections and will be responsible for the Staphylococcus aureus infection model and for the ex vivo assessments after bacterial challenge. Gerber group has expertise in clinical nutrition/metabolism and will be responsible for the diet intervention in humans.

Synergies: We will collaborate with projects 5 and 7 in a clinical study that will involve lean and obese individuals at different glycemic states with or without NAFLD, to address aims of the three projects. Additionally, we will interact with project 6 to assess virus replication kinetics in airway epithelial cells of humans with vs without NAFLD and before vs after dietary interventions. We look further to collaborate with project 3 and evaluate whether late infection (planned in our project) after establishment of NAFLD (hepatic component of metabolic syndrome) may regulate adipogenesis and whether dietary interventions are capable of preventing these effects. Other interactions with projects 1, 2, 4 are also described in their respective synergy sections.