Viruses and their hosts have co-evolved an intricate interplay that is delicately balanced during the course of infection. The value of exploring such a natural relationship, rather than the mismatched experimental systems that currently prevail, is becoming increasingly clear. This program will focus squarely upon ectromelia virus (ECTV), a genuine mouse pathogen with several attractive properties. First, routes of transmission are similar to those of other orthopoxviridae in their natural hosts. Second, mousepox disease is remarkably similar to that of human monkeypox and smallpox. Third, some mouse strains are resistant to ECTV while others are highly susceptible, analogous to natural variations within human populations. None of this is true for vaccinia virus (VACV), an orthopoxvirus of unknown origin, frequently used in mouse models of immunity, and made all the more suspect by preliminary results presented below. Headed by three PIs with extensive experience in host defense against poxviruses, the program will comprehensively dissect the interplay between ECTV and resistant/susceptible strains of mice, referencing to VACV when appropriate. Project 1 will examine the cells and cytokines of the innate system that play critical roles in keeping the virus in check at the site of infection. Project 2 continues inspection of innate/natural immunity by examining the mechanisms by which type 1 interferons limit spread of the virus beyond the draining lymph node. Finally, Projects 2 and 3 will investigate all three major arms of the adaptive immune system to understand how they defend against primary infection and establish protection from subsequent challenge. All three projects will examine strategies by ECTV to thwart these different levels of host defense. Administrative, Biological Reagent, and Imaging Core Components will provide a wide range of support to the program, with the latter two carrying out their own exploratory projects. Our goal with this hypothesis-driven, highly interactive program is to develop an understanding of virus-host relationships that provides a framework for many other natural virus infections. PROJECT 1: THE INNATE IMMUNE RESPONSE TO MOUSEPOX AT THE SITE OF INFECTION (Norbury, C) PROJECT 1 DESCRIPTION (provided by applicant): During a natural virus infection small doses of infectious virus are deposited at a peripheral infection site and then a "race" ensues, in which the replicating virus attempts to "outpace" the host's immune system. In the early phases of infection, the innate immune system must contain the infection prior to the development of an adaptive response. In Project 1 we will examine the mechanisms that are used by the innate immune system to contain infection with mousepox, a lethal mouse disease caused by ectromelia virus (ECTV), an exclusive mouse pathogen. This system is unique because it allows us to examine the innate response in susceptible and resistant mouse strains. The three Specific Aims will examine the cells that are required to slow the systemic spread of ECTV at the site of infection, the chemoattractants that mediate their migration to the site of infection and the cell biological mechanisms that are used by both the virus and the immune system during virus-cell interaction.
In Aim 1 we will characterize the cellular infiltrate to the site of ECTV infection in resistant or susceptible mice and identify the innate immune effector cell types that are required to slow the systemic spread of ECTV and allow the development of an adaptive response that can clear the infection. In this aim we will also examine the effector functions that are required by innate immune cells to retard ECTV infection.
In Aim 2 we will determine the chemokines and chemokine receptors expressed at the site of ECTV infection in resistant or susceptible mice, and the chemokines that are essential to attract innate effector cells that slow replication and spread of the virus. We will also study the role of immune modifiers of cellular migration encoded by ECTV in the innate response to the virus, and will identify the targets of these genes in vivo.
In Aim 3 we will study the interaction of ECTV and innate immune cells in vitro, focusing primarily upon macropinocytosis, which has recently been described as the mode of infection of orthopoxviruses. Macropinocytosis has an important role in the sampling of extracellular solute for initiation of an adaptive immune response and we will examine its contribution to sampling of the environment for initiation of an innate response. We will also examine the trafficking to macropinosomes of TLR9, an innate receptor that is required for survival from ECTV challenge. The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection.

Public Health Relevance

This U19 will impact our understanding on the immune mechanisms controlling viral infections in natural hosts, in particular, the control of periphery-to-systemic viral infections. This is the mechanism used by a large number of viruses important to human health such as those that produce smallpox, monkeypox, rubella, measles, chickenpox, West Nile encephalitis and many others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083008-04
Application #
8259476
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J3))
Program Officer
Miller, Lara R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$1,779,931
Indirect Cost
$335,231
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Davies, Michael L; Sei, Janet J; Siciliano, Nicholas A et al. (2014) MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. J Virol 88:3557-67
Heipertz, Erica L; Davies, Michael L; Lin, Eugene et al. (2014) Prolonged antigen presentation following an acute virus infection requires direct and then cross-presentation. J Immunol 193:4169-77
Siciliano, Nicholas A; Hersperger, Adam R; Lacuanan, Aimee M et al. (2014) Impact of distinct poxvirus infections on the specificities and functionalities of CD4+ T cell responses. J Virol 88:10078-91
Hersperger, Adam R; Siciliano, Nicholas A; DeHaven, Brian C et al. (2014) Epithelial immunization induces polyfunctional CD8+ T cells and optimal mousepox protection. J Virol 88:9472-5
Remakus, Sanda; Rubio, Daniel; Lev, Avital et al. (2013) Memory CD8? T cells can outsource IFN-? production but not cytolytic killing for antiviral protection. Cell Host Microbe 13:546-57
Eisenlohr, Laurence C (2013) Alternative generation of MHC class II-restricted epitopes: not so exceptional? Mol Immunol 55:169-71
Rubio, Daniel; Xu, Ren-Huan; Remakus, Sanda et al. (2013) Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection. Cell Host Microbe 13:701-10
Remakus, Sanda; Sigal, Luis J (2013) Memory CD8? T cell protection. Adv Exp Med Biol 785:77-86
Ma, Xueying; Xu, Ren-Huan; Roscoe, Felicia et al. (2013) The mature virion of ectromelia virus, a pathogenic poxvirus, is capable of intrahepatic spread and can serve as a target for delayed therapy. J Virol 87:7046-53
Xu, Ren-Huan; Rubio, Daniel; Roscoe, Felicia et al. (2012) Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver. PLoS Pathog 8:e1002475

Showing the most recent 10 out of 13 publications