The synergy between Streptococcus pneumoniae and influenza during co-infection has long been recognized. Our data indicate that this synergy is operative on a physical level, as we provide evidence of influenza A virus (IAV) binding to the surface of S. pneumoniae, providing fitness benefits to both pathogens. We have strong experimental evidence that IAV directly binds to S. pneumoniae, facilitating enhanced bacterial adhesion in vitro and enhanced colonization and dissemination in vivo. This intimate interaction between virus and the bacterial surface is not limited to S. pneumoniae, as binding was observed with multiple bacterial inhabitants of the human respiratory tract including species of Staphylococcus, Moraxella, and Haemophilus. The relationship between IAV and the bacterial surface is mutually beneficial, as IAV bound to specific bacterial species demonstrate dramatically enhanced environmental stability, with IAV retaining infectivity during desiccation only when in complex with bacteria. Our long-term goal is to gain a greater understanding of the synergies operative during IAV-bacterial co- infections during both invasive disease and transmission. The overall objective of this proposal is to gain a mechanistic understanding of how direct IAV-pneumococcal binding occurs and the impact of these interactions on host-pathogen interactions. We hypothesize that the direct interactions between IAV and bacteria are mediated by specific factors of both pathogens and that the direct interactions between bacteria and IAV impact respiratory infection. The interkingdom interplay between respiratory pathogens may be underappreciated as a mechanism underlying viral–bacterial synergy during respiratory infection.