This project deals with immune control of cowpox virus (CPXV), a member ofthe medically important orthopoxvirus genus. CPXV causes zoonotic infections, is endemic in rodent populations, and has the largest repertoire of immune evasion genes. The project is based on published work and preliminary data from the applicant's laboratory on CD8+ T and natural killer (NK) cell control of CPXV infections in mice. The applicant's laboratory showed that CPXV encodes two open reading frames (ORFs) that inhibit major histocompatibility complex (MHC) class I (MHC-I) expression on infected cells. Deletion of these ORFs resulted in attenuated CPXV virulence due to CD8+ T cell control, the first clear-cut example of the role of viral MHC-I inhibition in in vivo infections. T cell priming is not affected but virus-specific CD8+ T cell effector responses are blocked by MHC-I inhibition, providing opportunities for further study of virus-specific CD8+ T cell responses. In addition, the applicant's lab showed that NK cells are recruited to the draining LN following CPXV infection. They showed this was dependent on interferon-gamma which induces the chemokines CXCL9 and CXCL10 and CXCR3-expressing NK cells. However, NK cells are inhibited by CPXV from producing interferon-gamma. In this project, they plan to address the following Specific Aims to further study: 1) CD8+ T cell responses to CPXV;2) CPXV-dependent recruitment of NK cells;and 3) Novel . immunomodulatory CPXV ORFs. Ongoing and planned experiments will be done in collaboration with other principal investigators in this U19 application. In addition, human transiational studies are planned. Thus, these studies will provide new insight into how the innate and adaptive immune systems control viruses, such as CPXV.

Public Health Relevance

The overall goal of this project is to understand how the immune system controls viruses, like cowpox virus, a virus which infects humans and is related to other viruses that infect humans. The project focuses on trying to understand how immune cells respond to and control cowpox virus which in turn makes molecules to block immune system function. A better understanding of this attack/counter-attack will provide new information on how to control viruses

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-ZL-I (J1))
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Washington University
Saint Louis
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Gilchuk, Iuliia; Gilchuk, Pavlo; Sapparapu, Gopal et al. (2016) Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections. Cell 167:684-694.e9
Ghasemi, Reza; Lazear, Eric; Wang, Xiaoli et al. (2016) Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy. Nat Commun 7:12878
Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69
Nelson, Christopher A; Epperson, Megan L; Singh, Sukrit et al. (2015) Structural Conservation and Functional Diversity of the Poxvirus Immune Evasion (PIE) Domain Superfamily. Viruses 7:4878-98
Nelson, Christopher A; Lee, Chung A; Fremont, Daved H (2014) Oxidative refolding from inclusion bodies. Methods Mol Biol 1140:145-57
Alzhanova, Dina; Hammarlund, Erika; Reed, Jason et al. (2014) T cell inactivation by poxviral B22 family proteins increases viral virulence. PLoS Pathog 10:e1004123
Luteijn, Rutger D; Hoelen, Hanneke; Kruse, Elisabeth et al. (2014) Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. J Immunol 193:1578-89
Nelson, Christopher A; McCoy, William H; Fremont, Daved H (2014) Eukaryotic expression systems for structural studies. Methods Mol Biol 1140:107-16