Slc2a6 in Kupffer cells shapes host recognition of Streptococcus pneumoniae

The interaction between Kupffer cells (KCs) and Streptococcus pneumoniae is crucial for bacterial clearance, yet the host factors that regulate this interplay remain elusive. Here, we investigate the role of the solute carrier protein Slc2a6 in antibacterial immunity of KCs during S. pneumoniae bacteremia and find that Slc2a6 significantly compromises host defense by attenuating bacterial capture by KCs at the early stages of infection. Mechanistically, Slc2a6 downregulates anti-phosphorylcholine natural antibodies in the serum, which are crucial for the opsonization of the S. pneumoniae D39 strain via cross-reactivity with the serotype 2 capsule. Thus, Slc2a6 inhibits complement activation by attenuating the natural-antibody-mediated classical pathway during D39 infection. In conclusion, our results highlight a key role for Slc2a6 in macrophages in modulating pathogen recognition through regulation of natural antibody repertoire.