Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus

Multiple domains of TonEBP cooperate to stimulate transcription in response to hypertonicity.

Tonicity-responsive enhancer binding protein (TonEBP), also known as NFAT5, belongs to the Rel family of transcriptional activators. In the kidney medulla and thymus, TonEBP plays a major role in protecting renal cells and T cells from the deleterious effects of ambient hypertonicity. TonEBP is stimulated by hypertonicity via several pathways: increased expression of protein, nuclear translocation, and increased transactivation. In this study, we identified five domains of TonEBP involved in transactivation. The two conserved glutamine repeats were not involved in transactivation. There were three activation domains that could stimulate transcription independently. In addition, there were two modulation domains that potentiated the activity of the activation domains. One of the activation domains is unique to a splice isoform that is more active than others, indicating that alternative splicing can affect the activity of TonEBP. Another activation domain and one of the modulation domains were stimulated by hypertonicity. All the five domains acted in synergy in every combination. Although overall phosphorylation of TonEBP increased in response to hypertonicity, phosphorylation of the activation and modulation domains did not increase in isolation. In sum, TonEBP possesses far more elaborate domains involved in transactivation compared with other Rel proteins