title: Enhancement of antiviral immunity by small molecule antagonist of suppressor of cytokine signaling.
abstract: Suppressors of cytokine signaling (SOCSs) are negative regulators of both innate and adaptive immunity via inhibition of signaling by cytokines such as type I and type II IFNs. We have developed a small peptide antagonist of SOCS-1 that corresponds to the activation loop of JAK2. SOCS-1 inhibits both type I and type II IFN activities by binding to the kinase activation loop via the kinase inhibitory region of the SOCS. The antagonist, pJAK2(1001-1013), inhibited the replication of vaccinia virus and encephalomyocarditis virus in cell culture, suggesting that it possesses broad antiviral activity. In addition, pJAK2(1001-1013) protected mice against lethal vaccinia and encephalomyocarditis virus infection. pJAK2(1001-1013) increased the intracellular level of the constitutive IFN-beta, which may play a role in the antagonist antiviral effect at the cellular level. Ab neutralization suggests that constitutive IFN-beta may act intracellularly, consistent with recent findings on IFN-gamma intracellular signaling. pJAK2(1001-1013) also synergizes with IFNs as per IFN-gamma mimetic to exert a multiplicative antiviral effect at the level of transcription, the cell, and protection of mice against lethal viral infection. pJAK2(1001-1013) binds to the kinase inhibitory region of both SOCS-1 and SOCS-3 and blocks their inhibitory effects on the IFN-gamma activation site promoter. In addition to a direct antiviral effect and synergism with IFN, the SOCS antagonist also exhibits adjuvant effects on humoral and cellular immunity as well as an enhancement of polyinosinic-polycytidylic acid activation of TLR3. The SOCS antagonist thus presents a novel and effective approach to enhancement of host defense against viruses.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA. ahmed1@ufl.edu
authors.forename: Chulbul M I
authors.initials: CM
authors.lastname: Ahmed
authors.forename: Rea
authors.initials: R
authors.lastname: Dabelic
authors.forename: James P
authors.initials: JP
authors.lastname: Martin
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Jager
authors.forename: S Mohammad
authors.initials: SM
authors.lastname: Haider
authors.forename: Howard M
authors.initials: HM
authors.lastname: Johnson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D016899:Interferon-beta / Q000378:metabolism; D007371:Interferon-gamma / Q000737:chemistry; D053614:Janus Kinase 2 / Q000737:chemistry; D053208:Kaplan-Meier Estimate; D007739:L Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010849:Picornaviridae / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D010850:Picornaviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D050826:Suppressor of Cytokine Signaling Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; D053614:Janus Kinase 2