AUTHOR=Karanika Styliani , Gordy James T. , Neupane Pranita , Karantanos Theodoros , Ruelas Castillo Jennie , Quijada Darla , Comstock Kaitlyn , Sandhu Avinaash K. , Kapoor Aakanksha R. , Hui Yinan , Ayeh Samuel K. , Tasneen Rokeya , Krug Stefanie , Danchik Carina , Wang Tianyin , Schill Courtney , Markham Richard B. , Karakousis Petros C. 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.972266

DOI=10.3389/fimmu.2022.972266

ISSN=1664-3224

ABSTRACT=<p>Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the Rel<sub>Mtb</sub>-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the <italic>rel<sub>Mtb</sub></italic> gene 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 the <italic>MIP-3α</italic>/<italic>rel<sub>Mtb</sub></italic> (fusion) vaccine or intranasal delivery of the <italic>rel<sub>Mtb</sub></italic> (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing <italic>rel<sub>Mtb</sub></italic> alone in a chronic TB mouse model (absolute reduction of <italic>Mtb</italic> burden: 0.63 log<sub>10</sub> and 0.5 log<sub>10</sub> colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced <italic>Mtb</italic>-protective immune signatures. The combined approach involving intranasal delivery of the DNA <italic>MIP-3α</italic>/<italic>rel<sub>Mtb</sub></italic> fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of <italic>Mtb</italic> burden: 1.13 log<sub>10</sub>, when compared to the intramuscular vaccine targeting <italic>rel<sub>Mtb</sub></italic> alone; P&lt;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.</p>