期刊
IMMUNOLOGICAL REVIEWS
卷 264, 期 1, 页码 344-362出版社
WILEY
DOI: 10.1111/imr.12255
关键词
tuberculosis; macrophage; drug; innate immunity
类别
资金
- National Institute of Allergy and Infectious Diseases at the National Institutes of Health [K24AI089794, K08-AI102971, R01A107246201-A2, R01-AI056067-01]
- Burroughs Wellcome Foundation
- Bio-Merieux Foundation
Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. One solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. Here, we discuss recent progress in so-called host-directed therapeutics' (HDTs), focusing on two general mechanistic strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii) immunomodulatory HDTs that facilitate protective immune responses that kill Mtb or reduce deleterious responses that exacerbate disease. HDTs hold significant promise as adjunctive therapies in that they are less likely to engender resistance, will likely have efficacy against antibiotic-resistant strains, and may have activity against non-replicating Mtb. However, TB is a complex and variegated disease, and human populations exhibit significant diversity in their immune responses to it, which presents a complicated landscape for HDTs to navigate. Nevertheless, we suggest that a detailed mechanistic understanding of drug action, together with careful selection of disease stage targetsand dosing strategies may overcome such limitations and allow the development of HDTs as effective adjunctive treatment options forTB.
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