Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes

Significance Tuberculosis (TB) susceptibility and disease are significantly exacerbated in people with type 2 diabetes. The underlying mechanisms are incompletely understood, and it is not known if new TB vaccine candidates will be safe and provide protection in the context of diabetes. Using a long-term diet-induced murine model of type 2 diabetes, we demonstrate that increased susceptibility to TB is caused by impaired mycobacterial recognition and killing in the diabetic lung. Importantly, we show that mucosal vaccination of diabetic mice with Bacillus Calmette–Guérin (BCG) strains expressing the ESX-1 secretion system from Mycobacterium tuberculosis can overcome this defect and provide superior immunity against TB. Our data warrant a consideration of ESX-1–containing BCG strains as effective TB vaccines in older individuals and diabetics.