Therapeutic Strategy Targeting The Host-Pathogen Interactions Of HEV

Hepatitis E virus(HEV)is a globally prevalent pathogen,which annually results in 20 million infections,3 million hepatitis E cases,and 60,000 fatalities worldwide,endangering especially the pregnant women and immunocompromised individuals.At present,there is no HEV-specific therapeutics,and ribavirin,the broad-spectrum antiviral drug,frequently leads to treatment failure.In addition,the pregnant women are not eligible for ribavirin treatment due to fetal teratogenicity.Therefore,a safe and HEV-specific antiviral medicine is urgingly needed.Here,we performed an unbiased screening on HEV replicon,which intriguingly hit 17 compounds targeting the HSP90.Unexpectedly,we found that HEV forming a unique host-virus interaction by hijacking the host key protein HSP90 to maintain the stability of its core protein ORF1.HSP90 targeting released viral replicase(ORF1)from the ORF1-HSP90 complex,marked ORF1 for CHIP-mediated K48 ubiquitination,and triggered the unprocessed ORF1 for a unique and rapid ubiquitin-proteasomal processing to delete the putative helicase and Rd Rp domains and degradation.Notably,the anti-HEV strategy targeting the ORF1-HSP90 interaction was safe,considerably efficient,and substantially prevented the liver damage in HEV-inflicted rodents,as proofed in a preclinical trial in gerbils with chronic infection of human genotype 3 HEV.Collectively,our findings describe a critical mechanism of HEV in host-HEV interactions,and propose promising therapeutics by targeting this weakness for the treatment of deleterious hepatitis E diseases.In addition,I contributed the study to elucidate the role of a classic oncogenic pathway,i.e.HER2-AKT signaling,in innate DNA sensing mediated by the c GASSTING mechanism.Innate DNA sensing mediates host defense and plays the important roles in autoimmunity,anti-tumor immunity,and cell fate determination.We suggest at the first time in this study the key functions of HER2-AKT signlaing in host defense and anti-tumor immunity via effective control of c GAS-STING signaling,realized by an intriguing molecular mechanism.