Interferons in immunity to peripheral vaccinia virus infection
Open Access
- Author:
- Parekh, Nikhil
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 24, 2019
- Committee Members:
- Christopher Charles Norbury, Dissertation Advisor/Co-Advisor
Christopher Charles Norbury, Committee Chair/Co-Chair
Aron Eliot Lukacher, Committee Member
Todd Schell, Committee Member
Ian Alexander Simpson, Outside Member
Ziaur Rahman, Committee Member - Keywords:
- Immunology
Virology
Innate Immunity
Interferon
Poxvirus - Abstract:
- The prototypic Orthopoxvirus, vaccinia virus (VACV), is capable of establishing a localized skin infection in a wide range of mammals. VACV infection stimulates a robust immune response, making it a widely used vector. As a vaccine, VACV is most effective at generating tissue-resident memory CD8+ T cells when delivered via damage to the epidermis, but can result in severe complications in some individuals. Despite extensive studies, little is known about the initial actions of the innate immune response following dermal VACV infection. VACV encodes numerous proteins that block pathogen recognition and subsequent activation of type-I interferon. Infection of primary cells and cell lines with VACV fail to produce type-I interferon in vitro. However, mice lacking components of type-I interferon signaling are more susceptible to VACV infection than wild-type mice, indicating the importance of this antiviral pathway. We found evidence that a specialized cell population in vivo is able to bypass viral evasion strategies employed by VACV to produce type-I interferon and mediate a protective response in infected tissue. Signal transducer and activator of transcription 1 (STAT1) is a critical effector in mediating the biological effects of many cytokines, including interferons. As such, humans and mice are acutely sensitive to infection in the absence of STAT1, which is often attributed to a lack of interferon signaling. We found that STAT1-/- mice succumb to intradermal infection with VACV, with a high, systemic viral burden. To equate our findings in STAT1-/- mice with a defect in interferon signaling, we generated mice that lack functional receptors for all three interferon-signaling pathways. However, mice with a complete lack of interferon signaling remain resistant to VACV infection, and do not recapitulate the systemic viral burden of STAT1-/- mice. This infection model is uniquely positioned to investigate the interferon-independent mechanisms of STAT1-mediated antiviral immunity.