The Two-Component System YesMN Promotes Pneumococcal Host-to-Host Transmission and Regulates Genes Involved in Zinc Homeostasis.

The ability to sense and respond rapidly to the dynamic environment of the upper respiratory tract (URT) makes Streptococcus pneumoniae () a highly successful human pathogen. Two-component systems (TCSs) of sense and respond to multiple signals it encounters allowing to adapt and thrive in various host sites. TCS have been implicated in their ability to promote pneumococcal colonization of the URT and virulence. As the disease state can be a dead-end for a pathogen, we considered whether TCS would contribute to pneumococcal transmission. Herein, we determined the role of YesMN, an understudied TCS of , and observe that YesMN contributes toward pneumococcal shedding and transmission but is not essential for colonization. The YesMN regulon includes genes involved in zinc homeostasis and glycan metabolism, which are upregulated during reduced zinc availability in a YesMN-dependent fashion. Thus, we identified the YesMN regulon and a potential molecular signal it senses that lead to the activation of genes involved in zinc homeostasis and glycan metabolism. Furthermore, in contrast to monoinfection, we demonstrate that YesMN is critical for high pneumococcal density in the URT during influenza A virus (IAV) coinfection. We attribute reduced colonization of the mutant possibly due to increased association with and clearance by the mucus covering the URT epithelial surface. Thus, our results highlight the dynamic interactions that occur between and IAV in the URT, and the role that TCSs play in modulation of these interactions.