Abstract

Gamma interferon (IFN3) is an essential cytokine for mediation of immune functions that are critical for surveillance against infections and cancer. Important aspects of innate immunity, adaptive immunity, macrophage activation, natural killer cell activity, helper T cell responses, as well as cytotoxic T cell responses are all critically modulated by IFN3. We have developed small peptide mimetics of IFN3. The IFN3 mimetics exhibit antiviral activity against a variety of viruses including amelioration of the lethal effects of the poxvirus vaccinia in mice under conditions where intact IFN3 is ineffective because of anti- IFN proteins produced by poxviruses. The activating effects of IFN3 are suppressed by proteins called suppressors of cytokine signaling (SOCS), of which SOCS-1 is an important member. We have developed a small molecule SOCS-1 antagonist. In this renewal, we propose to study the interaction between IFN3, IFN3 mimetics, and SOCS-1 antagonist as per AIMs below to positively regulate the IFN responses of cells of the immune system and enhancement of protection of mice against vaccinia and ectromelia viruses with a view toward an IFN and SOCS-1 antagonist drug against smallpox. We hypothesize that our small peptide IFN mimetics and SOSC-1 antagonist represent novel antivirals against lethal poxvirus infections. 1. Protection of mice against lethal vaccinia virus infections by IFN mimetics. Effect of SOCS-1 antagonist on protection. 2. Compare intraperitoneal versus oral administration of IFN mimetic peptides for their relative ability to protect mice against lethal vaccinia virus infection. Effect of SOCS-1 antagonist. 3. Protection of mice against lethal ectromelia virus infection by IFN mimetics and SOCS-1 antagonist. 4. Protection of mice against superlethal ectromelia virus encoding the interleukin-4 (IL-4) gene by IFN mimetics and SOCS-1 antagonist. 5. Determine immunological aspects of treatment of mice with IFN mimetics. Effect of SOCS-1 antagonist. PUBLIC HEALTH RELEVENCE: Our interferon mimetic is a novel therapeutic for treating viral and other infectious diseases. The SOCS-1 antagonist should provide a new paradigm to boosting the immune system against infections and cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056152-07
Application #
7777372
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Leitner, Wolfgang W
Project Start
2003-09-15
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$362,588
Indirect Cost

  Institution

Name
University of Florida
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

Johnson, Howard M; Larkin 3rd, Joseph (2017) Editorial: The Dynamic Role of Suppressor of Cytokine Signaling Proteins in the Regulation of Immune and Autoimmune Responses. Front Immunol 8:825
Ahmed, Chulbul M; Dabelic, Rea; Bedoya, Simone Kennedy et al. (2015) A SOCS1/3 Antagonist Peptide Protects Mice Against Lethal Infection with Influenza A Virus. Front Immunol 6:574
Ahmed, Chulbul M; Johnson, Howard M (2014) Short peptide type I interferon mimetics: therapeutics for experimental allergic encephalomyelitis, melanoma, and viral infections. J Interferon Cytokine Res 34:802-9
Larkin 3rd, Joseph; Ahmed, Chulbul M; Wilson, Tenisha D et al. (2013) Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells. Front Immunol 4:469
Ahmed, Chulbul M; Noon-Song, Ezra N; Kemppainen, Kaisa et al. (2013) Type I IFN receptor controls activated TYK2 in the nucleus: implications for EAE therapy. J Neuroimmunol 254:101-9
Bedoya, Simone K; Wilson, Tenisha D; Collins, Erin L et al. (2013) Isolation and th17 differentiation of naïve CD4 T lymphocytes. J Vis Exp :e50765
Johnson, Howard M; Noon-Song, Ezra N; Kemppainen, Kaisa et al. (2012) Steroid-like signalling by interferons: making sense of specific gene activation by cytokines. Biochem J 443:329-38
Jager, Lindsey D; Dabelic, Rea; Waiboci, Lilian W et al. (2011) The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis. J Neuroimmunol 232:108-18
Collins, Erin L; Jager, Lindsey D; Dabelic, Rea et al. (2011) Inhibition of SOCS1-/- lethal autoinflammatory disease correlated to enhanced peripheral Foxp3+ regulatory T cell homeostasis. J Immunol 187:2666-76
Noon-Song, Ezra N; Ahmed, Chulbul M; Dabelic, Rea et al. (2011) Controlling nuclear JAKs and STATs for specific gene activation by IFN?. Biochem Biophys Res Commun 410:648-53

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