Targeting Mycobacterium Tuberculosis Persisters by Enhancing Stringent Response-specific Cellular Immunity

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This study is being led by Dr. Petros Karakousis of Johns Hopkins Medicine, and is using stored samples from the Cohort for Tuberculosis Research by the Indo-US Medical Partnership (C-TRIUMPH), under the Regional Prospective Observational Research for Tuberculosis (RePORT) Network, an international TB consortium.

Despite the high efficacy of the current 6-month “short-course” combination regimen and efforts to implement it throughout the world, the long duration of treatment and emerging drug resistance resulting from medical non-adherence pose significant challenges for global TB eradication efforts, especially in HIV/TB co-infected patients. Therefore, shorter TB treatment regimens are urgently needed.

The prolonged duration of TB treatment is believed to reflect the unique ability of a subpopulation of bacteria to remain in a non-replicating, persistent state in the infected host. These “persister” bacteria evade immune-based clearance mechanisms and become tolerant to first-line anti-TB drugs, which more effectively target actively dividing bacteria.

One of the important mechanisms by which persisters acquire this phenotype is through induction of the stringent response. Hyperphosphorylated guanosine ((p)ppGpp), which is synthesized by the stringent response enzyme RelMtb, is required for bacterial growth restriction and antibiotic tolerance. RelMtb is essential for long-term Mtb survival during various in vitro and in vivo stress conditions. Deficiency of relMtb renders Mtb more sensitive to isoniazid in various models.

We have generated a therapeutic DNA vaccine targeting the Mtb stringent response gene, which induces antigen-specific cellular immunity, and, when combined with the first-line drug isoniazid, exhibits significantly greater activity against Mtb in the lungs of chronically infected mice relative to isoniazid alone. Although genes of the stringent response are known to be upregulated during Mtb persistence in mice, it remains to be determined whether continued presentation of Mtb stringent response antigens occurs in human subjects during TB treatment.

In the current proposal, we will directly address the knowledge gaps by testing the novel hypothesis that stringent response antigen is enhanced during treatment of drug-susceptible TB cases using the first-line anti-TB regimen.