MTOR regulates protection against a lethal H5N1 influenza infection by modulating the antibody response (P6184)

Abstract

Abstract Highly pathogenic H5N1 avian influenza A viruses pose a serious threat for global catastrophe. Due to frequent mutations in the influenza genome, current vaccination protocols promote only strain-specific responses, and therefore fail to provide protection against novel pandemic strains. Antibodies that protect against multiple subtypes of influenza have been identified, however, these antibodies are extremely rare, and the immunological mechanisms that lead to their development are not clear. We show here that rapamycin, an immunosuppressive drug that inhibits mTOR, promoted cross-strain protection against lethal H5N1 infection when administered during H3N2 vaccination. Surprisingly, this protection did not require memory CD8 T cells, but rather required CD4 T cells and B cells, suggesting the protection was antibody-mediated. In support of this, serum from rapamycin-treated mice immunized with a H3N2 strain protected naïve mice from a lethal H5N1 infection. Our data further reveal that rapamycin reduced germinal center formation and B cell class-switching, yielding a unique repertoire of antibodies that was more protective against a lethal, heterosubtypic influenza infection. These data not only reveal a requirement for mTOR in B cell class-switching, but also indicate that a broader antibody repertoire, which provides better protection against multiple strains of influenza, can be achieved by reducing germinal center formation during the primary infection.