Iota-Carrageenan Is a Potent Inhibitor of Influenza A Virus Infection

The 2009 flu pandemic and the appearance of oseltamivir-resistant H1N1 influenza strains highlight the need for treatment alternatives. One such option is the creation of a protective physical barrier in the nasal cavity. In vitro tests demonstrated that iota-carrageenan is a potent inhibitor of influenza A virus infection, most importantly also of pandemic H1N1/2009 in vitro. Consequently, we tested a commercially available nasal spray containing iota-carrageenan in an influenza A mouse infection model. Treatment of mice infected with a lethal dose of influenza A PR8/34 H1N1 virus with iota-carrageenan starting up to 48 hours post infection resulted in a strong protection of mice similar to mice treated with oseltamivir. Since alternative treatment options for influenza are rare, we conclude that the nasal spray containing iota-carrageenan is an alternative to neuraminidase inhibitors and should be tested for prevention and treatment of influenza A in clinical trials in humans

Suppression of early T-cell-receptor-triggered cellular activation by the Janus kinase 3 inhibitor WHI-P-154

BACKGROUND: Therapeutic targeting of Janus kinase 3 (JAK3) has received particular attention, because it is associated with the common gamma signaling of cytokine receptors and thus vitally influences T-cell growth and survival. Recent evidence, however, indicates a critical role for JAK3 in signaling linked to the T-cell antigen receptor. METHODS: In this study we investigated whether targeting JAK3 with a rationally designed inhibitor affects early T-cell activation events. T cells were stimulated by CD3 and CD28 cross-linking, and interleukin (IL)-2 production, activation marker expression, increase of free intracellular Ca2+ concentration, activation of the extracellular-related kinase, and nuclear translocation of transcription factors were evaluated. RESULTS: We found that JAK3 inhibitor treatment dramatically impaired T-cell-receptor (TCR)-induced IL-2 production, surface activation marker expression (CD69, CD154), and homotypic T-cell aggregation. Accordingly, mRNA production of IL-2, interferon-gamma, and IL-10 was profoundly inhibited. Molecular analysis revealed that TCR-triggered phosphorylation of phospholipase C-gamma1, increase in cytoplasmic Ca2+ concentration, and activation of extracellular-related kinase were markedly reduced by the JAK3 inhibitor, resulting in substantially decreased DNA binding of nuclear factor of activated T cells and alkaline phosphatase-1 and subsequent IL-2 promoter activation. Remarkably, on TCR-independent stimulation, IL-2 production, CD69 expression, and blast formation were completely insensitive to JAK3 inhibitor treatment. CONCLUSION: These data indicate that pharmacologic targeting of JAK3 uncouples early TCR-triggered signaling from essential downstream events, which may have important implications for the use of such compounds in T-cell-mediated disorders such as allograft rejection or graft-versus-host disease