NIH Annual Report AI000979
NIH Annual Intramural Research Report
ZIA AI000979-15
Report Title
- Poxvirus host interactions, pathogenesis and immunity
2020 Fiscal Year
- October 01, 2019 - September 30, 2020
Principal Investigator
Bernard Moss, MD, PhD
Research Organization
- Genetic Engineering Section
Lab Staff and Collaborators within the Genetic Engineering Section
Tatiana Georgia Koonin, PhD
Ruikang Liu, PhD
Patricia Earl, PhD
Jeffrey L Americo, MS
Catherine Griffin
Andrea S Weisberg, MS
Wei Xiao
External Collaborator
- There was one External Collaborator
| Paul Gershon, PhD | University of California, Irvine, Molecular Biology and Biochemistry |
Keywords
cowpox virus pathogenesis, poxvirus immunity, smallpox vaccine, monkeypox virus pathogenesis, orthopoxvirus pathogenesis, poxvirus pathogenesis, vaccinia virus pathogenesis, cell mediated immunity, cytokines, monoclonal antibodies
Goals and Objectives
The goals of this project are to increase our understanding of poxvirus host interactions, pathogenesis and the basis for immunity to poxviruses. We are particularly interested in the members of the orthopoxvirus genus, which include variola virus (the causal agent of smallpox), vaccinia virus (used as the smallpox vaccine), cowpox virus (causes zoonotic infections) and monkeypox virus (causes of human monkeypox in parts of Africa).
Summary
Poxviruses comprise a large family of complex DNA viruses that have vertebrate and invertebrate hosts. Two poxviruses, variola virus and molluscum contagiosum virus, are specific human pathogens. Variola virus was the cause of smallpox until the latter was eradicated but is still feared because of potential use a biological weapon. Molluscum contagiosum virus causes benign skin lesions in immunocompetent infants and a more severe and widespread disease in immunodeficient adults. In addition, several animal poxviruses can be transmitted to humans as zoonosis. The most serious of these is monkeypox, which has an estimated human mortality of 1 to 10%. The poxviruses express a large number of host immune evasion genes that contribute to virulence. The purpose of this project is to increase our understanding of poxvirus host interactions, pathogenesis and the basis for immunity to poxviruses. Human genome-wide RNAi screen was conducted to determine host factors that impact poxvirus replication.
The following advances were made in the current year. The wild-derived CAST mouse is an excellent small animal model for studying the pathogenicity of MPXV and related orthopoxviruses including vaccinia virus (VACV) and for evaluating therapeutics. We previously found that the susceptibility of CAST mice is correlated with low numbers of natural killer (NK) cells and a delayed interferon-gamma response. Here we showed that in vivo administration of the cytokine IL-15 transiently raised NK cell numbers and protected CAST mice from systemic infections with VACV and MPXV. CAST mouse NK cells that were purified and expanded in vitro with IL-15 also provided protection, further demonstrating the important role of NK cells. The rapid decline in NK cell numbers following cessation of IL-15 administration or NK cell transfer suggests that a low level of NK cell
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