The more than 40-year cessation in smallpox virus vaccinations after the eradication of variola virus
(VARV) has left a growing population in the US and globally vulnerable to orthopoxvirus infection. Concerns of
bioterrorism usage of VARV or other species of orthopoxvirus necessitate an in-depth understanding of
poxvirus immune evasion of the host. With the current immunity gap identification of new treatment targets for
development of novel therapeutics remains a critical task. On the other hand, clinical use of poxviruses to treat
cancer requires comprehensive knowledge of poxvirus-induced cellular response that can improve therapeutic
outcome. Our long-term goal is to improve understanding of the host intrinsic immunity that not only protects
the host from viral infection but also can be stimulated to facilitate the elimination of malignancy.
The goal of the proposed study is to understand how additional mechanisms enforce species barrier
that can prevent cross-species viral infection and how we discover and investigate new antiviral pathways
using poxviruses as model organisms. More importantly, sensing of cytoplasmic DNA leads to induction of type
1 interferon (IFN-I) and while we found new regulation of host DNA sensing pathway we investigate viral
strategy to evade it that affects pathogenesis. We will study species barrier function and the antiviral function of
a host protein, sterile a motif domain-containing protein 9 (SAMD9). SAMD9 plays a central role in human
health and possesses antiviral effect to a broad-spectrum of viral pathogens. However, its function is poorly
characterized. To study SAMD9's antiviral properties, we utilize myxoma virus (MYXV) as the model organism.
MYXV is a rabbit-specific poxvirus causing lethal infection in European rabbits and a candidate oncolytic virus
to treat human cancers. We previously identified MYXV M062 as the viral inhibitor of SAMD9. We thus utilize
viral M062 and M062R-null MYXV as probing tools to study SAMD9 function. Our central hypothesis is that
SAMD9 detects poxvirus infection and DNA replication, and once it binds to poxvirus DNA it inhibits DNA
replication while inducing IFN-I responses that affects viral pathogenesis. To test our hypothesis, we propose
the following studies: (1) To understand the mechanism of SAMD9 for the inhibition of viral DNA replication
and for induction of IFN-I; (2) To investigate how inhibiting SAMD9 affects pathogenesis; and (3) to study how
SAMD9 mediates the host species barrier function.
Through the completion of the proposed study, we will fill a critical gap in our knowledge of host
regulation linking the inducible antiviral response and the intrinsic immunity. This improves our understanding
of the mechanism for immunotherapeutic virotherapy using MYXV. We also characterize a novel class of viral
evasion of host immune response.