Functional analysis of the cGAS/STING axis during bacterial and viral infections and implications for the development of innovative vaccines

• Applicants: Professor Dr. Ulrich Kalinke; Dr. Zsolt Ruzsics
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Virology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406922110

The cGAS/STING innate immune sensor pathway plays a key role for the induction of protective immunity against many DNA-encoded pathogens, including intracellular bacteria and viruses. While during the last years a great body of knowledge accumulated regarding the response of the cGAS/STING pathway to synthetic molecules and representative cell types, there is much less understanding of how and where the pathway is engaged by actual pathogens in in vivo settings, and which other signaling platforms work in concert with cGAS/STING. This is a critical question, because infections involve different phases of pathogen replication and immune responses are contributed by various cell types and tissues to confer protective immunity. At the molecular level it is also unsolved, which kinds of DNAs bind to cGAS during homeostasis and infection to stimulate cGAMP formation that triggers STING and thus elicits cytokine responses. To address these questions, we will apply advanced animal models. In brief, we will study Listeria monocytogenes (LM) and mouse cytomegalovirus (MCMV) infection of mice, which are devoid of cGAS/STING signaling alone or in combination with Toll-like receptor (TLR) & RIG-I-like helicases (RLH) signaling. For MCMV, special emphasis will be laid on the role of the cGAS/STING axis in the restriction of viral dissemination from liver to other organs. Furthermore, mice that have knock-in alleles of cGAS and STING that are fused to functional protein tags will be used. These models will help to understand the function of the cGAS/STING-axis in different cells as well as tissues. We will apply these mouse models in addition to cutting edge technologies to identify DNAs binding to cGAS in the context of infections and we will study STING function on the cellular and tissue level. The newly obtained data will be exploited to develop innovative vaccine vectors containing the STING ligand cGAMP as an adjuvant. This project will be carried out by a consortium of three research teams, two from Germany and one from France, who are experts in reverse genetics of MCMV, innate immune signaling, and antiviral immunity. This project will include secondment of PhD students/postdocs to the collaborating partner laboratories and biannual retreats. By these measures plus regular video lab meetings a high degree of interaction between the involved labs and a maximal productivity will be assured.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partners: Xavier Lahaye, Ph.D.; Nicolas Manel, Ph.D.