Targeting the lung innate pathways during tuberculosis can improve vaccine-induced protection via Th17 responses in diversity outbred mice

Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against <i>Mycobacterium tuberculosis</i> (<i>Mtb)</i> challenge. This protection induced pathways associated with transforming growth factor B (TGF-β) receptor complex, genes associated with lung repair, and Toll-like receptor (TLR)-10 pathway. The enhanced protection observed in BCG-vaccinated mice correlated with improved formation of B-cell follicles and IL-17-producing CD4⁺ T-cell responses. CD4⁺ T-cell responses mediated the enhanced protection in the lungs of DO mice vaccinated with BCG + adjuvant, as depletion of CD4⁺ T-cell responses reversed the enhanced protection. The DO mouse model of tuberculosis vaccination is a highly relevant model to probe mechanisms of vaccine-induced protection and provide novel insights into lung pathways that mediate protection. The study also found that genes associated with lung repair, including TGF-β receptor complex pathways, were induced in BCG-vaccinated <i>Mtb</i>-infected DO mouse lungs. The study suggests that the activation of lung innate pathways in BCG vaccination through the use of mucosal Amph CpG delivery, CD40L activation, and IL-10 neutralization could significantly enhance protection upon <i>Mtb</i> challenge.