Unraveling the role of α-(1,2)-fucosylation in bacterial pneumonia

<bold>Background:</bold> Mucosal surfaces are rich in <italic>N</italic>- and <italic>O</italic>-glycans containing terminal sugars such as fucose. A frequency of individuals have a mutation in the <italic>FUT2</italic> gene, resulting in the inability to secrete α-(1,2)-fucosylated glycans. Such mutations render these individuals susceptible or resistant to certain infections. <bold>Aim:</bold> Investigation of how α-(1,2)-fucosylated glycans influence <italic>Streptococcus pneumoniae</italic> (<italic>Spn</italic>) infection. <bold>Methods:</bold> We developed a murine model of pneumococcal pneumonia using mice systemically treated with 2-deoxy-D-galactose (2-DGal), a biochemical inhibitor of fucosylation. We evaluated the murine glycome using LC-MS/MS. Lung immune cell recruitment was analyzed via flow cytometry. <bold>Findings:</bold> Fucose utilization genes are upregulated in <italic>Spn</italic> upon interaction with fucosylated MUC5AC <italic>in vitro</italic>. Fucosylated glycans are shed into the bronchoalveolar lavage (BAL) during <italic>Spn</italic> infection. Systemic treatment of mice with 2-DGal resulted in incorporation of 2-DGal into the murine glycome and inhibition of fucosylation <italic>in vivo</italic>. Mice treated with 2-DGal displayed improved physiological parameters such as infection-induced body weight and temperature loss. Treatment with 2-DGal led to reduced bacterial burden in BAL and spleen following <italic>Spn</italic> infection. Flow cytometry revealed that 2-DGal treatment enabled quicker resolution of neutrophilic inflammation following infection. 2-DGal treatment led to reduced lung permeability and lower IL-6 and TNF-α levels in infected mice. <bold>Conclusion:</bold> Our findings reveal that 2-DGal treatment prevents the establishment of pneumococcal infection in mice. Inhibiting pulmonary fucosylation could limit <italic>Spn</italic> virulence and pneumonia pathogenesis.