The interplay between autophagy and S. aureus infection

• Applicant: Professor Dr. Ingo Schmitz
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Immunology
• Term: from 2012 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213312245

Final Report Abstract

Autophagy is a catabolic mechanism that is important for many biological processes such as cell homeostasis, development and immunity. On the molecular level, it is executed by so-called AuTophaGy-related (ATG) proteins. At the center of the autophagy pathway and crucial for efficient autophagic flux are two ubiquitin conjugation systems including the ATG5- conjugation system. Staphylococcus aureus, is a Gram-positive opportunistic pathogen that can cause diseases such as skin infections, pneumonia, endocarditis and sepsis. Previously, we showed that infection with S. aureus induces selective autophagy. However, S. aureus evades autophagic degradation by activating the host mitogen-activated protein kinase (MAPK) p38, degradation of the autophagosomal membranes, and escape into the cytoplasm. In order to understand the interplay between intracellular S. aureus and the host cell, we followed a genomics approach at the global level. To this end, we performed next-generation sequencing of infected cells and analyzed the transcriptomes of the infected host cells as well as of the intracellular bacteria in parallel. This was done with autophagy-proficient and -deficient host cells. Surprisingly, the ability of the host cell to perform autophagy had little effect on the gene expression profile of intracellular S. aureus. On the host cell side, we detected upregulation of genes of the Nod-like receptor and inflammasome pathways including the intracellular pattern recognition receptor NOD2. In line, NOD2 was required for induction of autophagy and p38 MAPK activation. In contrast, TLR2, a cell surface receptor that recognizes S. aureus, was required for early p38 MAPK activation, but not for autophagy induction. p38 MAPK activation at late time points post infection was independent of TLR2. Moreover, PknB, a S. aureus kinase with MAPK-like activity, was not required for p38 MAPK activation. Taken together, our results provide a framework for further investigations of the interplay between host innate immune signaling pathways such as Nod-like receptors, autophagy and S. aureus infection.

Publications

• STS Meeting on Signal Transduction, Weimar, 2018, A battle for survival – the interplay between autophagy and S. aureus infection
  Riebisch, Anna
  
• STS Meeting on Signal Transduction, Weimar, 2019, The Interplay between autophagy and S. aureus infection; 2nd poster prize
  Riebisch, Anna
  
• Attaching and Effacing Pathogens: The Effector ABC of Immune Subversion. Future Microbiology, 15(10), 945-958.
  Riebisch, Anna Katharina & Mühlen, Sabrina
  
• Controlled Functional Zonation of Hepatocytes In Vitro by Engineering of Wnt Signaling. ACS Synthetic Biology, 9(7), 1638-1649.
  Wahlicht, Tom; Vièyres, Gabrielle; Bruns, Svenja A.; Meumann, Nadja; Büning, Hildegard; Hauser, Hansjörg; Schmitz, Ingo; Pietschmann, Thomas & Wirth, Dagmar
  
• Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses. Frontiers in Immunology, 11(2020, 8, 7).
  Bonifacius, Agnes; Goldmann, Oliver; Floess, Stefan; Holtfreter, Silva; Robert, Philippe A.; Nordengrün, Maria; Kruse, Friederike; Lochner, Matthias; Falk, Christine S.; Schmitz, Ingo; Bröker, Barbara M.; Medina, Eva & Huehn, Jochen
  
• A Central Role for Atg5 in Microbiota-Dependent Foxp3+ RORγt+ Treg Cell Preservation to Maintain Intestinal Immune Homeostasis. Frontiers in Immunology, 12(2021, 8, 26).
  Plaza-Sirvent, Carlos; Zhao, Bei; Bronietzki, Alisha W.; Pils, Marina C.; Tafrishi, Neda; Schuster, Marc; Strowig, Till & Schmitz, Ingo
  
• Autophagy—A Story of Bacteria Interfering with the Host Cell Degradation Machinery. Pathogens, 10(2), 110.
  Riebisch, Anna K.; Mühlen, Sabrina; Beer, Yan Yan & Schmitz, Ingo
  
• Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy, 17(1), 1-382.
  Klionsky, Daniel J.; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud; Abdoli, Asghar; Abel, Steffen; Abeliovich, Hagai; Abildgaard, Marie H.; Abudu, Yakubu Princely; Acevedo-Arozena, Abraham; Adamopoulos, Iannis E.; Adeli, Khosrow; Adolph, Timon E.; Adornetto, Annagrazia; Aflaki, Elma; Agam, Galila; Agarwal, Anupam; Aggarwal, Bharat B.; Agnello, Maria; ... & Tong, Chun-Kit
  
• Regulating T-cell differentiation through the polyamine spermidine. Journal of Allergy and Clinical Immunology, 147(1), 335-348.e11.
  Carriche, Guilhermina M.; Almeida, Luís; Stüve, Philipp; Velasquez, Lis; Dhillon-LaBrooy, Ayesha; Roy, Urmi; Lindenberg, Marc; Strowig, Till; Plaza-Sirvent, Carlos; Schmitz, Ingo; Lochner, Matthias; Simon, Anna Katharina & Sparwasser, Tim
  
• Gadd45 Proteins in Immunity 2.0. Advances in Experimental Medicine and Biology (2022), 69-86. Springer International Publishing.
  Schmitz, Ingo
  
• In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo. iScience, 25(12), 105522.
  Papaxenopoulou, Lito A.; Zhao, Gang; Khailaie, Sahamoddin; Katsoulis-Dimitriou, Konstantinos; Schmitz, Ingo; Medina, Eva; Hatzikirou, Haralampos & Meyer-Hermann, Michael
  
• Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems. Frontiers in Cellular and Infection Microbiology, 12(2023, 1, 10).
  Blasey, Nadja; Rehrmann, Daria; Riebisch, Anna Katharina & Mühlen, Sabrina