Page:Interim Staff Report on Investigation into Risky MPXV Experiment at the National Institute of Allergy and Infectious Diseases.pdf/71



Report Title
 * Poxvirus host interactions, pathogenesis and immunity

2022 Fiscal Year
 * October 01, 2021 - September 30, 2022

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
 * Patricia Earl, PhD
 * Jeffrey L Americo, MS
 * Catherine Griffin
 * Wei Xiao
 * Andrea S Weisberg, MS
 * Huibin Yu, PhD

Collaborators from other NIH organizations

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.

During the past year we took advantage of the 235 available unique complete genome sequences of Orthopoxviruses (ORPV) and reannotated the approximately 200 genes of each to provide the first uniform gene nomenclature. We focused on the approximately 100 accessory genes, predicting the functions of uncharacterized genes, and reconstructed the history of their gain and loss during the evolution of ORPV. Most of the accessory genes were acquired in three major waves antedating the origin of ORPV from chordopoxviruses. The evolution of ORPV themselves was dominated by gene loss, with numerous genes lost at the base of each major group of ORPV. Examination of pairs of ORPV accessory genes that were either often or rarely lost concurrently 1/2