Antibiotic treatment shapes antigen presentation during chronic TB infection, offering novel targets for therapeutic vaccination

Abstract

The lengthy and complicated current regimen required to treat drug-susceptible tuberculosis (TB) reflects the ability of Mycobacterium tuberculosis (Mtb) to persist in host tissues. The stringent response pathway, governed by the dual (p)ppGpp synthetase/hydrolase, RelMtb, is a major mechanism underlying Mtb persistence and antibiotic tolerance. In the current study, we addressed the hypothesis that RelMtb is a \"persistence antigen\" presented during TB chemotherapy and that enhanced T-cell immunity to RelMtb can enhance the tuberculocidal activity of the first-line anti-TB drug, isoniazid, which has reduced efficacy against Mtb persisters, C57BL/6 mice and Hartley guinea pigs were aerosol-infected with Mycobacterium tuberculosis (Mtb) and, 4 weeks later, received either human-equivalent daily doses of isoniazid alone, or isoniazid in combination with a DNA vaccine targeting relMtb. After isoniazid treatment, the total number of Mtb antigen-specific CD4+ T cells remained stable in mouse lungs and spleens, as did the number of RelMtb-specific T cells, although there was a significant reduction in dominant antigen ESAT6-specific CD4+ or TB10.4-specific CD8+ T cells in the lungs and spleens of mice, Therapeutic vaccination enhanced the activity of isoniazid in Mtb-infected C57BL/6 mice and guinea pigs. When treatment with isoniazid was discontinued, mice immunized with the relMtb DNA vaccine showed a lower mean lung bacterial burden at relapse compared to the control group. Our work shows that antitubercular treatment shapes antigen presentation and antigen-specific T-cell responses, and that therapeutic vaccination targeting the Mtb stringent response may represent a novel approach to enhance immunity against Mtb persisters, with the ultimate goal of shortening curative TB treatment.