Cell-specific inhibition of SMAD2/3 restores lymph node cellularity and germinal center function in aged mice responding to acute chikungunya virus (CHIKV) infection

Abstract

Abstract Targeted delivery of small-molecule inhibitors increases drug efficacy by focusing its action upon specific cell-types without global disruption of signaling pathways. TGFβ is a pleotropic cytokine involved in many cellular processes, including specific regulatory functions during anti-viral immune responses. Previously, we have shown that in aged mice, over-production of TGFβ correlates with decreased immune function. TGFβ neutralization during acute chikungunya virus (CHIKV) infection decreases acute- and chronic- disease severity and improves neutralizing antibody titers. Herein, we selectively interrupted TGFβ signaling during acute CHIKV infection via the delivery of lymph node (LN)-targeting nanoparticles coupled to a small-molecule inhibitor of SMAD2/3 phosphorylation. We show that LN-targeted inhibition of SMAD phosphorylation during the initiation of a viral immune response can restore – to the levels measured in adult mice - the cellular content of the draining lymph node. We further demonstrate that inhibition of TGFβ signaling decreases LN fibrosis and improves the germinal center reaction in aged mice.