Bhattacharya, BidishaChatterjee, SujoyDevine, William G.Kobzik, LesterBeeler, Aaron B.Porco, John A.Kramnik, Igor2016-05-022016Bhattacharya, Bidisha, Sujoy Chatterjee, William G. Devine, Lester Kobzik, Aaron B. Beeler, John A. Porco, and Igor Kramnik. 2016. “Fine-tuning of macrophage activation using synthetic rocaglate derivatives.” Scientific Reports 6 (1): 24409. doi:10.1038/srep24409. http://dx.doi.org/10.1038/srep24409.2045-2322http://nrs.harvard.edu/urn-3:HUL.InstRepos:26860285Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource.en-USJournal Article2016-05-0210.1038/srep24409