Type II interferon-dependent antibacterial defense in the lungs is compromised in diabetes

Diabetes mellitus is associated with an increased risk of pneumonia, which is often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a varity of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with Streptoccocus pneumoniae or Legionella pneumphila, type 2 diabetic and prediabetic mice had higher bacterial loads in their lungs as compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised type II IFN (IFNg) production by natural killer cells in diabetic and prediabetic mice, which was linked to reduced IL-12 production by CD103+ dendritic cells. Treatment with IFNg rescued antibacterial defense against L. pneumophila but not against S. pneumoniae in diabetic animals, although impaired production of IFNg also contributed to the compromised anti-pneumococcal resistance in diabetic mice. These findings uncover a mechanism that could help to explain why type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNg-mediated antibacterial defense against atypical lung pathogens.