Abstract
Host-directed therapies have emerged as an innovative and promising approach in tuberculosis (TB) treatment due to the observed limitations of current TB regimen such as lengthy duration and emergence of drug resistance. Thus, we explored the role of curdlan (beta glucan polysaccharide) as a novel strategy to activate macrophages against Mycobacterium tuberculosis (Mtb). The aim of the study was to investigate the role of curdlan in restricting the Mtb growth both in vitro and in vivo. Further, the immunomodulatory potential of curdlan against Mtb and the underlying mechanism is largely unknown. We found that curdlan treatment enhanced the antigen presentation, pro-inflammatory cytokines, Mtb uptake and killing activity of macrophages. In vivo studies showed that curdlan therapy significantly reduced the Mtb burden in lung and spleen of mice. Administration of curdlan triggered the protective Th1 and Th17 immunity while boosting the central and effector memory response in Mtb infected mice. Curdlan mediated anti-Mtb activity is through signal transducer and activator of transcription-1 (STAT-1), which regulates nitric oxide (NO) production through inducible NO synthase (iNOS) induction; along with this activation of nuclear factor kappa B (NF-κB) was also evident in Mtb infected macrophages. Thus, we demonstrate that curdlan exerts effective anti-tuberculous activity anti-tuberculous activity. It can be used as a potential host-directed therapy against Mtb.
Highlights
Tuberculosis (TB) continues to be the devastating infectious disease with the highest mortality and morbidity after human immunodeficiency virus (HIV) (Glaziou et al, 2018)
Mycobacterium tuberculosis (Mtb) infected M s treated with curdlan in comparison to untreated control, exhibited significant (p ≤ 0.01) decrease in intracellular Mtb growth as seen in low colony forming unit (CFU) counts concomitant with the increase in IL-6 cytokine (p ≤ 0.01) release in cell SNs (Figures 1A,B)
Inhibitor of spleen tyrosine kinase (Syk), piceatannol substantially reduced the stimulatory effect of curdlan in infected M s as seen in the impaired clearance of Mtb (p ≤ 0.01) and IL-6 (p ≤ 0.001) production (Figures 1A,B)
Summary
Tuberculosis (TB) continues to be the devastating infectious disease with the highest mortality and morbidity after HIV (Glaziou et al, 2018). Among Mtb infected individuals, only 10–15% develops the disease during their lifetime, rest remains protected until the resurgence in their immunity (Alene et al, 2018). There is a need to understand the intricate interaction between pathogen and host immune factors, which regulates the disease pathogenesis and outcome. This would aid to design novel host-directed therapeutic interventions to control TB. An effective approach is to stimulate the host immune system against Mtb
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