Local pulmonary immunotherapy with siRNA targeting TGFβ1 enhances antimicrobial capacity in Mycobacterium tuberculosis infected mice

Abstract

In this study we demonstrate that it is possible to shift the immune system during a chronic infection with Mycobacterium tuberculosis. TGFβ and IL10 cytokines inhibit the Th1 response during chronic pulmonary infection with M. tuberculosis. We show that intrapulmonary delivery of siRNA targeting TGFβ1 is able to reduce the pulmonary bacillary load in mice chronically infected with M. tuberculosis: an effect that appears to be partly dependent on IL10 expression. To demonstrate this, we induced gene silencing of tgfβ1 in the lungs of wild type and IL10 knockout mice using a non-invasive aerosolized intrapulmonary delivery of siRNA targeting TGFβ1. Five days after the last treatment with siRNA, the levels of tgfb1 transcripts and TGFβ1 protein were reduced when compared with control groups treated with RNase-free water or non-targeting siRNA. Mice treated with siRNA also had increased expression of the antimicrobial mediators (NO and iNOS) which effectively reduced the bacterial load by 0.17 and 0.47 log(10) in C57BL/6 and IL-10 KO mice respectively when compared with their respective control mice. More importantly, the bacterial load in siRNA treated IL-10 KO mice four weeks after the last treatment remained 0.32 log(10) lower than in control mice.

IL12B expression is sustained by a heterogenous population of myeloid lineages during tuberculosis

“…Aerosol delivery of siRNAs can affectively alter pulomary gene expression during experimental TB. 64,65 …”

Host-directed therapy of tuberculosis: what is in it for microRNA?

“…Further studies will define the most appropriate route of delivery, kinetics of miR-mimics/ anti-miR HDT as well as pharmacovigilance issues. The encouraging results reported for intranasal administration of miRs in lung cancer and those describing modulation of TGF-b1 expression via pulmonary delivery of siRNA in the TB mouse model [25], provide a valid basis for future miR-based HDTs. Detailed mechanistic insights into the biological role of miRs remain scarce, and specifics of modeof-action of anti-miR/miR-mimics await further clarification.…”

Therapeutic face of RNAi:in vivochallenges

“…In another study, intratracheal administration of lipid complex secreted protein, acidic and rich in cysteine and connective growth factor siRNAs are followed by a reduction in collagen fabrication in fibrotic lung tissues of bleomycin-induced mice [181]. Also, administration of anti-tissue growth factor-b1 (TGFb1) and chemokine (C motif) ligand (XCL1) siRNA also enhance anti-Mycobacterium tuberculosis effects in infected mice [182,183]. Despite all accomplished studies without any side effects, it is reported that siRNA cationic lipid (AtuFECT01) lipoplexes may create an inflammatory reaction in lungs [132].…”