Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host? Thomas R. Hawn,a Alastair I. Matheson,b Stephen N. Maley,b Omar Vandalc Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USAa; Department of Epidemiology, University of Washington, Seattle, Washington, USAb; The Bill & Melinda Gates Foundation, Seattle, Washington, USAc SUMMARY ..................................................................................................................................................608 INTRODUCTION ............................................................................................................................................608 OVERVIEW OF IMMUNE RESPONSE TO M. TUBERCULOSIS AND POTENTIAL HDT TARGETS..............................................................609 HDTs AND MACROPHAGE FUNCTION ....................................................................................................................609 Binding and M. tuberculosis Uptake.......................................................................................................................609 Phagosome Maturation and Function....................................................................................................................610 Phagosome acidification ..............................................................................................................................611 GTPases and phagosome maturation .................................................................................................................611 Effector Function .........................................................................................................................................611 Autophagy.............................................................................................................................................611 Vitamin D ..............................................................................................................................................612 Lipid Metabolism ........................................................................................................................................614 Lipid bodies and foamy macrophages ................................................................................................................614 Lipid-sensing nuclear receptors: PPAR␥, LXR␣,␤,andTR4.............................................................................................614 (i) PPAR␥ ............................................................................................................................................614 (ii) LXR␣,␤ andTR4..................................................................................................................................614 (iii) HDTs for lipid-sensing nuclear receptors ........................................................................................................614 Phospholipases...........................................................................................................................................614 Eicosanoids, Inflammation, and Mechanisms of Cell Death ..............................................................................................616 Protein Kinase R ..........................................................................................................................................617 Siderophores and Iron Sequestration ....................................................................................................................617 HDTs AND THE PULMONARY IMMUNE RESPONSE........................................................................................................617 Cytokine Modulation .....................................................................................................................................618 IFN-␥...................................................................................................................................................618 TNF....................................................................................................................................................618 (i) cAMP and phosphodiesterase inhibitors .........................................................................................................619 (ii) ROS and mechanisms of cell death ..............................................................................................................619 HDTs, PATHOLOGY, AND TISSUE HOMEOSTASIS .........................................................................................................620 Matrix Metalloproteinases ................................................................................................................................620 Neutrophils...............................................................................................................................................620 Antifibrotics ..............................................................................................................................................621 CONCLUSIONS .............................................................................................................................................621 ACKNOWLEDGMENTS......................................................................................................................................622 REFERENCES ................................................................................................................................................622 SUMMARY been proposed, only a few have been explored in detail or ad- Treatment of tuberculosis (TB) remains challenging, with lengthy vanced to preclinical and clinical studies. Our review focuses on treatment durations and complex drug regimens that are toxic molecular targets and inhibitory small molecules that function and difficult to administer. Similar to the vast majority of antibi- within the macrophage or other myeloid cells, on host inflamma- otics, drugs for Mycobacterium tuberculosis are directed against tory pathways, or at the level of TB-induced lung pathology. microbial targets. Although more effective drugs that target the INTRODUCTION bacterium may lead to faster cure of patients, it is possible that a biological limit will be reached that can be overcome only by he effective treatment of tuberculosis (TB) using current anti- adopting a fundamentally new treatment approach. TB regimens Tbiotics faces obstacles that include a lengthy duration of treat- might be improved by including agents that target host pathways. ment, potential drug toxicity, drug interactions with HIV medi- Recent work on host-pathogen interactions, host immunity, and cations, and rising rates of drug resistance. Efforts to develop new host-directed interventions suggests that supplementing anti-TB TB drugs have focused on mechanisms that target the bacillus. therapy with host modulators may lead to shorter treatment times, a reduction in lung damage caused by the disease, and a lower risk of relapse or reinfection. We undertook this review to Address correspondence to Thomas R. Hawn, [email protected] identify molecular pathways of the host that may be amenable to Copyright © 2013, American Society for Microbiology. All Rights Reserved. modulation by small molecules for the treatment of TB. Although doi:10.1128/MMBR.00032-13 several approaches to augmenting standard TB treatment have 608 mmbr.asm.org Microbiology and Molecular Biology Reviews p. 608–627 December 2013 Volume 77 Number 4 Host-Directed Therapeutics for TB Recently, attention has turned to potential host-directed thera- IFN-␥ and B cell production of antibodies (10, 11). The classical peutics (HDTs) in the hope that novel treatment strategies might model of a successful immune response to M. tuberculosis includes overcome many of the obstacles faced by antibiotic therapies for secretion of IFN-␥ by T cells, which activates macrophages to kill TB. The goal of HDTs might be to shorten the course of treatment, M. tuberculosis. When this is unsuccessful, M. tuberculosis contin- reduce the number of agents required in combination drug ther- ues to grow intracellularly until it lyses the cell and either reinfects apy, simplify treatment of drug-resistant TB by improving the new cells or replicates extracellularly. Extracellular TB can be as- efficacy of second-line therapy, and/or preserve lung function of sociated with high numbers of bacteria (e.g., in lung cavities), TB patients. The goal of treatment would determine the host tar- which, due to their growth rate and metabolic state, likely have get selected for intervention. HDTs that manipulate immune re- varying susceptibilities to TB drugs in comparison with intracel- sponses or the metabolic state of the bacteria to enhance host cell lular bacilli. In addition, the extracellular niche can be a source of function, optimize inflammatory responses at the cell and organ drug-resistant organisms due to the high bacterial burden and level, or modify lung pathology might be employed during treat- known ability of M. tuberculosis to develop drug resistance. When ment. To identify pathways involved in the host response to TB the immune response is partially successful, activated macro- and compounds that modulate these pathways, we searched phages and other host cells (T cells, B cells, and fibroblasts) sur- PubMed for papers published from 2000 onwards and, with a few round the M. tuberculosis-infected