Targeting immunophilin- and MAPK-associated pathways to inhibit MERS-CoV replication and prevent inflammatory lung injury
Coronaviruses (CoV) are causative agents of acute lung injury, and it is expected that novel highly pathogenic CoV will infect humans in future. However, drugs providing protection against emerging human CoV (such as MERS-CoV), are lacking. By use of a novel MERS-CoV mouse infection model and primary human lung cells, we aim to define the antiviral and lung injury-attenuating properties of compounds known to block CoV-host interactions by targeting immunophilin and downstream MAPK pathways in vitro and in vivo to establish readily-available treatment strategies for ongoing and future emerging severe human CoV infections.
Combining knowledge in the fields of molecular pathogenesis of acute lung injury gained in animal models and in patients suffering from severe respiratory virus infections, and virology expertise in research of highly pathogenic viruses under BSL4 conditions, the project aims at i) defining in detail the molecular host-virus interactions related to immunophilin-mediated blockade of MERS-CoV replication, ii) characterizing how MERS-CoV viral replication results in loss of barrier integrity and lung injury, and how these processes can be targeted to attenuate the disease progression in vivo, and iii) evaluating the role of transcriptional programs downstream of immunophilins (e.g. NFAT- and AP-1-dependent programs), in MERS-CoV-induced immunopathology, and their exploitation as therapeutic targets to decrease damaging hyperinflammation. To achieve this, we will use complementary murine and human in vitro, ex vivo and in vivo MERS-CoV infection models, using both inhibitory compounds affecting immunophilin-dependent signaling, and transgenic mice lacking crucial signaling components of these pathways. These studies will be complemented by NGS analyses of FACS-separated and infected lung cell subsets, for novel target identification.
The obtained data are expected to ultimately pave the way for development of novel antiviral and lung injury-attenuating compounds for treatment of MERS-CoV and, putatively, a broad range of human-pathogenic CoV.