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

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
 
Final Report Year 2024

Final Report Abstract

During their lifetime, humans encounter a plethora of pathogens that are normally controlled by the host’s immune system. Invading pathogens are first detected by innate immune cells, which are triggered by the interaction of pathogen associated molecular pattern (PAMP) with so called pattern recognition receptors (PRR). The early induction of innate immune responses is particularly important to restrict pathogen propagation and spread until fully functional pathogen-specific adaptive immune cells are activated that control the infection. PRRs such as cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) with its adapter stimulator of interferon genes (STING), which build the cGAS/STING sensory pathway, play a key role for the sensing of many DNA-encoded pathogens, including intracellular bacteria and viruses. Although a great body of knowledge has been accumulated during the last years regarding the response of the cGAS/STING pathway to synthetic molecules and in representative cell types, little is known about how and in which cell types the pathway is activated by pathogens in vivo and which other signalling mechanisms interact with the cGAS/STING axis. To address these questions, we established a model to study Listeria monocytogenes (LM) and mouse cytomegalovirus (MCMV) infection of mice. We generated genetically modified mice that are devoid of either the cGAS/STING signaling axis alone or we combined the cGAS/STING deficiency with deletions in the Toll-like receptor (TLR) and RIG-I-like helicases (RLH) signaling. Furthermore, we generated a new MCMV reporter virus, that shows activation of a GFP reporter if the virus was propagated in Cre expressing cells. With these new tools we thoroughly analyzed the role of the cGAS/STING axis during the course of MCMV infection and in particular in the restriction of viral dissemination from the liver to other organs. In brief we discovered that deletion of the cGAS/STING axis alone does not affect the survival after MCMV infection, whereas in mice devoid of TLR and RLH signaling, the cGAS/STING pathway is critically needed. After MCMV infection, early IFN-beta induction in the liver is cGAS/STING dependent and Kupffer cells are the main IFN-beta producers. In presence of the cGAS/STING axis, lower virus levels were reached in the liver and lymph nodes compared to mice devoid of the cGAS/STING axis. Nevertheless, irrespective of presence or absence of the cGAS/STING axis, virus that propagated in the liver did not leave the organ to infect other tissues. Our improved understanding of the function of the cGAS/STING pathway in different cells as well as tissues was instrumental for the development of new vaccine vectors that are based on viral vaccine vectors containing the STING ligand cGAMP, which acts as an adjuvant in this context. These studies, the team of our French partner Nicolas Manel moved forward.

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