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Differential use of cellular and molecular components shapes immune responses, but understanding of how these are regulated to promote defense and health during infections is still incomplete. Examples include signaling from members of the Janus activated kinase-signal transducer and activator of transcription (JAK-STAT) cytokine family. Following receptor stimulation, individual JAK-STAT cytokines have preferences for particular key STAT molecules to lead to specific cellular responses. Certain of these cytokines, however, can conditionally activate alternative STATs as well as elicit pleiotropic and paradoxical effects. Studies examining basal and infection conditions are revealing intrinsic and induced cellular differences in various intracellular STAT concentrations to control the biological consequences of cytokine exposure. The system can be likened to changing partners at a dance based on competition and relative availability, and sets a framework for understanding the particular conditions promoting subset biological functions of cytokines as needed during evolving immune responses to infections. [ABSTRACT FROM AUTHOR]

In recent years members of the tripartite motif-containing (TRIM) family of E3 ubiquitin ligases have been shown to both positively and negatively regulate viral defence and as such are emerging as compelling targets for modulating the anti-viral immune response. In this study we identify TRIM68, a close homologue of TRIM21, as a novel regulator of Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I IFN production. Proteomic analysis of TRIM68-containing complexes identified TRK-fused gene (TFG) as a potential TRIM68 target. Overexpression of TRIM68 and TFG confirmed their ability to associate, with TLR3 stimulation appearing to enhance the interaction. TFG is a known activator of NF-κB via its ability to interact with inhibitor of NF-κB kinase subunit gamma (IKK-γ) and TRAF family member-associated NF-κB activator (TANK). Our data identifies a novel role for TFG as a positive regulator of type I IFN production and suggests that TRIM68 targets TFG for lysosomal degradation, thus turning off TFG-mediated IFN-β production. Knockdown of TRIM68 in primary human monocytes resulted in enhanced levels of type I IFN and TFG following poly(I:C) treatment. Thus TRIM68 targets TFG, a novel regulator of IFN production, and in doing so turns off and limits type I IFN production in response to anti-viral detection systems. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations Principal Findings: In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsionadjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSVspecific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines. Conclusions: These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology. [ABSTRACT FROM AUTHOR]

Electrophilic trisubstituted ethylene monomers, ring-substituted methyl 2-cyano-3-phenyl2-propenoates, RC6H4CH=C(CN)CO2 CH3 (where R = H, 2-CH3, 3-CH3, 4-CH3, 2-C2H5, 4-C2H5, 4-iC3H7, 4-C4H9 and 2,4,6-(CH3)3), were synthesized by the piperidine-catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and methyl cyanoacetate, and characterized by CHN elemental analysis, IR, 1H- and 13C-NMR. Co-polymerization of the propenoates and vinyl acetate in solution with radical initiation (AIBN) at 70°C yielded equimolar alternating co-polymers. The composition of the co-polymers was calculated from nitrogen analysis and the structures were analyzed by IR, 1H- and 13C-NMR, GPC, DSC and TGA. The high Tg of the co-polymers in comparison with that of polyvinyl acetate indicates a substantial decrease in chain mobility of the co-polymer due to the high dipolar character of the trisubstituted ethylene monomer unit. The gravimetric analysis indicated that the co-polymers decompose in the 214–400°C range. [ABSTRACT FROM AUTHOR]