Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Aerosol of siRNA Targeting the STAT3 Pathway

In this study is shown that host directed therapy [HDT] targeting IL-10 and STAT3 during chronic pulmonary infection with Mycobactrium tuberculosis has bactericidal effect against drug tolerant bacilli.  When chronically Mtb infected C57BL/6 mice received two weeks of standard TB chemotherapy consisting of isoniazid and rifampin (HR) as expected the pulmonary bacterial load decreased significantly and a population of drug tolerant bacilli remained after therapy. When compared to infected animal controls not receiving chemotherapy, the lungs of mice receiving HR had higher concentrations of IL-10 and STAT3 whereas the concentration of antimicrobial end effector products were decreased. On the other hand if chronically Mtb infected mice received combined therapy regimens (HR-HDT) of HR chemotherapy followed by HDT consisting of intrapulmonary aerosols of siRNAs targeting il-10 and stat3 the pulmonary drug tolerant bacterial load was significantly reduced by more than 90% when compared to control mice receiving HR but not HDT. Furthermore, mice receiving HR-HDT have incresased pulmonary antimicrobial capacity as evidenced by higher expression of antimicrobial end effector molecules and decreased arginase activity. Moreover, important checkpoints regulating cell apoptosis-autophagy were also affected by HR-HDT therapy. As a proof of concept, here, it is  shown that a successful targeting of the host IL-10-STAT3 pathway via aerosol delivery of siRNAs can modulate the lung immunity to enhance its own antimicrobial capacity and can reduce the pulmonary drug tolerant bacterial burden.