Characterization Of Small Molecules That Enhance Macrophage Activation For Host-Directed Therapy Of Tuberculosis
Tuberculosis (TB) is a disease of global concern. Mycobacterium tuberculosis (Mtb), the causative agent of TB, has evolved to survive in its human host, and it frequently develops resistance to current antibiotics targeted against it with the emergence of multi drug-resistant and extensively drug-resistant strains on the rise. Furthermore, current therapeutic interventions for treatment of TB are limited in efficacy due to lengthy duration of therapy and severe lung damage. Hence, efforts are required to improve TB treatment. Host-directed therapy (HDT) might be used as an adjunctive treatment for TB along with anti-mycobacterials. Here, we characterize small molecules as potential candidates for HDT that boost immune response by enhancing macrophage activation in the presence of interferon gamma (IFN?) in vitro and in vivo. For the purpose of our study, we define macrophage activation as an increase in production of pro-inflammatory mediators such as tumor necrosis factor alpha (TNF) and reactive nitrogen intermediates (RNI) and a decrease in the production of the anti-inflammatory cytokine – Interleukin 10 (IL-10). We also report that protein kinase R (PKR) does not mediate the IFN?–dependent production of IL-10 and does not restrain the IFN?–dependent production of RNI and TNF. PKR is dispensable for host control of TB in mice. We show that a small molecule C2062 that enhances macrophage activation in vitro, also does so in a mouse model of Mtb infection. The phenotype of increased TNF and RNI directly correlates with reduction in bacterial burden, suggesting that enhancement of macrophage activation can lead to improved control of TB. In addition, C2062 did not exacerbate immunopathology in the lung. We further show in Mtb-infected macrophages and a mouse model of Mtb infection, that C2062 modestly augments the impact of rifampicin, an antibiotic active against Mtb. Thus, targeting the pathways leading to enhancement of macrophage activation can be used to identify new HDTs that can help the immune system control TB in conjunction with anti-mycobacterial drugs.
cytokine; iNOS; macrophage; PKR; small molecules; tuberculosis
Immunology & Microbial Pathogenesis
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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