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

Abstract

UNLABELLED: Tuberculosis (TB), caused by the bacterium(), infects approximately one-fourth of the world's population. Inbred mouse models of TB do not reflect the pathological states and heterogeneity seen in human TB disease. Thus, we recently established a model of TB in diversity outbred (DO) mice, which displayed heterogeneity in inflammatory and protective responses following aerosolinfection. In the current study, we show that DO mice vaccinated withBacille Calmette Guerin (BCG) are significantly protected uponHN878 infection, and protection is associated with the induction of transcriptional pathways involved in transforming growth factor B (TGF-β) and Toll-like receptor (TLR)-10 signaling. Targeting lung innate pathways in BCG-vaccinated DO mice using adjuvants also further improved protection uponinfection by inducing genes associated with cellular responses to external stimuli, B-cell responses, as well as IL-17-producing CD4T-cell responses. Depletion of CD4T cells resulted in loss of vaccine-induced protection in DO BCG-vaccinated and adjuvant-treated-infected mice. Together, our new results show that innate targeting of the lung by activating TLR pathways could induce protective pathways in T cells that significantly improve upon the protection induced by BCG vaccination. Additionally, the DO mouse model of vaccination andinfection can provide novel insights into immune pathways that are important for improving vaccine-induced protection against TB. IMPORTANCE: Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against(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 CD4T-cell responses. CD4T-cell responses mediated the enhanced protection in the lungs of DO mice vaccinated with BCG + adjuvant, as depletion of CD4T-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-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 uponchallenge.