The interplay between a pathogen and its natural host is exquisitely complex and delicate and much of this is lost when mispaired. Ectromelia virus (ECTV), the causative agent of mousepox (the smallpox of the mouse) is one of the few models available of a natural mouse pathogen that infects through the periphery and spreads through the lymphatic system to become systemic and cause disease. There are two major mechanisms that prevent mousepox. A) Natural or innate resistance, whereby some mouse strains survive a first encounter with ECTV without major symptoms of mousepox. B) Acquired resistance, whereby mousepox susceptible mice are protected by previous exposure to ECTV or vaccination. Project 2 of this U19 has two wide Aims.
In Aim 1 we will investigate the mechanisms whereby Type I IFNs (TI-IFNs) contribute to natural resistance to lethal mousepox. Completion of this Aim will give us a broad understanding about the dynamics of TI-IFN production and signaling in different organs, the importance of TI-IFN subtypes, the pathways whereby TI-IFNs are induced, the cell types that produce them, the role of local IFN signaling in the establishment of the early immune response, and the role of TI-IFNs in protecting the liver, a major target organ of the virus.
In Aim 2 we will investigate the mechanisms whereby memory CD8+ T cells and humoral immunity provide acquired resistance. For CD8+ T cells, we will characterize and compare their resting state and recall response following VACV and ECTV infection and determine their mechanisms of protection. For humoral immunity, we will determine whether memory B cells can protect and whether their role is in replenishing the plasma cell compartment to generate circulating Abs, respond rapidly to virus challenge or act as APCs. In addition, we will characterize and determine the mechanisms whereby Abs to the virion and to virulence factors protect from disease. Results from Project 2 will be integrated with those of the highly complementary Projects 1 and 3 to form a comprehensive picture of the ECTV/mouse dynamic. We expect that this picture will not only provide future directions for the program, but also insight into many other virus/host relationships including that of humans with their natural pathogens.

Public Health Relevance

Project 2 together with the other projects in this U19 should substantially contribute to understanding the immune mechanisms that control viral infections in natural hosts including those of humans with their natural pathogens such as, but not limited to, smallpox. We expect major insights about the control of periphery-tosystemic viral infections. This mechanism is used by many viruses important to human health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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Research Institute of Fox Chase Cancer Center
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Remakus, Sanda; Ma, Xueying; Tang, Lingjuan et al. (2018) Cutting Edge: Protection by Antiviral Memory CD8 T Cells Requires Rapidly Produced Antigen in Large Amounts. J Immunol 200:3347-3352
Norbury, Christopher C (2016) Defining cross presentation for a wider audience. Curr Opin Immunol 40:110-6
Sei, Janet J; Haskett, Scott; Kaminsky, Lauren W et al. (2015) Peptide-MHC-I from Endogenous Antigen Outnumber Those from Exogenous Antigen, Irrespective of APC Phenotype or Activation. PLoS Pathog 11:e1004941
Fang, Min; Remakus, Sanda; Roscoe, Felicia et al. (2015) CD4+ T cell help is dispensable for protective CD8+ T cell memory against mousepox virus following vaccinia virus immunization. J Virol 89:776-83
Xu, Ren-Huan; Wong, Eric B; Rubio, Daniel et al. (2015) Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection. Immunity 43:1148-59
Kaminsky, Lauren W; Sei, Janet J; Parekh, Nikhil J et al. (2015) Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection. J Virol 89:9974-85
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
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
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
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

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