An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis

Abstract

Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistentMycobacterium tuberculosis(Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of therelMtbgene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of theMIP-3α/relMtb(fusion) vaccine or intranasal delivery of therelMtb(non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressingrelMtbalone in a chronic TB mouse model (absolute reduction ofMtbburden: 0.63 log10and 0.5 log10colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronouncedMtb-protective immune signatures. The combined approach involving intranasal delivery of the DNAMIP-3α/relMtbfusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction ofMtbburden: 1.13 log10, when compared to the intramuscular vaccine targetingrelMtbalone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections.