Study On Caveolin-1Negatively Regulates Host Responses To HSV-1Infection

Viruses coevolve with their host and exploit diverse pathways to evade host immune responses. Host also develops various immune responses to counteract viral infections. In addition, innate immunity contain DCs, macrophages and antiviral cytokines plays a key role in the initiation and modulation of antiviral innate responses. Understanding the interactions of host-virus will provide us new insight for the mechnism of viral infections, viral pathogenesis and vaccines design.Herpes simplex virus type1(HSV-1) is a dsDNA virus belongs to the a-herpesvirus family, which causes oral herpes, encephalitis, keratitis, neonatal herpes and pneumonia disease and establishes latency in the neurons after acute infection of mucosal tissues. Previous reports found that HSV-1infection led to DC accumulations and NO productions which play a role in antiviral effects. In addition, Caveolin-1(Cav-1), the principal element of caveolae structure, is implicated in the viral-host interaction. Several viruses, including SV40, exploit caveolae as a gateway to enter cell and suppress host responses to facilitate their infections.The roles of Cav-1, DCs in HSV-1infection have not been fully elucidated.Here, we identify that Cav-1KO mice are more resistant to viral infection. Compared to wild type (WT) of animals, Cav-1KO could increase the protection upon HSV-1infection, accompanied with alleviative lung injury and lower viral load. The experiment of Cav-1knockdown and Cav-1overexpression DCs intra-tracheally showed Cav-1kd DC received WT mice increased the survival, indicated that the DCs played a role in Cav-1KO mediated resistant to HSV-1infection. And HSV-1may exploit Cav-1to avoid clearance. In addition, increased survival of Cav-1-/-mice was correlated with augmented iNOS and NO production in lungs and DCs. In turns, DCs and Cav-1deficiencies (CD11c-DTR/Cav-1-1-) or Cav-1-/-mice that were treated with an iNOS inhibitor exhibited a significantly reduced protection as compared to Cav-1single deletion only. Finally, we also observed that Cav-1co-localized with iNOS and HSV-1in caveolae in the viral infected DCs by confocal microscopy and Co-IP analysis.Our findings for the first time describe a novel mechanism of interaction of HSV-1with the Cav-1protein to suppress iNOS/NO in DCs and ultimately avoiding anti-viral responses of host. In addition, the disruption of caveolae lead to the increase of iNOS and NO in DCs, resulting in the protection of Cav-1KO against HSV-1infection. Thus, Cav-1could act as a gateway for HSV-1evasion. The data also provide a valuable target for drug design and therapeutic approach against herpes virus infections.