Our lab is interested in the underlying mechanisms of the sensing of viral DNA in the nucleus of the infected cell and how this sensing results in a response to restrict virus replication and future infectious virion production. It is known that sensing of the viral DNA in the nucleus elicits a type-I interferon response to induce a cellular antiviral state, but the pathways behind this phenomenon are poorly understood. Our lab has observed that the nuclear envelope proteins Sun1, Sun2, Nesprin-1, and TorsinA appear to play a role in the induction of the interferon response as their knockdown results in decreased transcription of a type-I interferon, interferon-?. Our lab is also interested in the epigenetic dynamics of the viral genome over the course of infection. Within the virion, the viral DNA is not associated with histones, but rapidly becomes chromatinized upon introduction of the viral DNA into the nucleus of the host cell. In addition, transcriptionally repressive chromatic marks, termed heterochromatin, are placed on the histones of the viral genome. This silences transcription from the viral genome and therefore restricts virus replication.
The aims of this proposal are: 1) to investigate the role of the nuclear envelope in antiviral type-I interferon signaling, 2) to investigate the role of the nuclear envelope in the restriction of viral replication and heterochromatin formation on the viral genome, and 3) to investigate the association patterns of Sun1, Sun2, Nesprin-1, TorsinA, and IFI16 over the course of viral infection. Based on previously published studies along with data from our lab, we hypothesize the formation of an antiviral protein signaling complex in the envelope of the nucleus, an antiviral phenomenon not previously reported or explored.
Our lab has observed that certain nuclear envelope proteins appear to be involved in the antiviral response to herpes simplex virus-1 infection, proteins previously undescribed to be involved in the response. This project will investigate the mechanisms of, and association patterns between, these envelope proteins in conjunction with the viral DNA that culminate in the antiviral response.