Page:Interim Staff Report on Investigation into Risky MPXV Experiment at the National Institute of Allergy and Infectious Diseases.pdf/67



Report Title
 * Poxvirus host interactions, pathogenesis and immunity

2020 Fiscal Year
 * October 01, 2019 - September 30, 2020

Principal Investigator

&ensp;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

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 1/2