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Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.
- Source :
-
Nature [Nature] 2014 Jul 03; Vol. 511 (7507), pp. 99-103. Date of Electronic Publication: 2014 Jun 25. - Publication Year :
- 2014
-
Abstract
- Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.
- Subjects :
- Animals
Dinoprostone antagonists & inhibitors
Dinoprostone biosynthesis
Dinoprostone metabolism
Disease Models, Animal
Female
Humans
Immunity, Innate immunology
Interferon Type I antagonists & inhibitors
Interferon Type I biosynthesis
Male
Mice
Mice, Inbred C57BL
Tuberculosis, Pulmonary microbiology
Immunotherapy
Interferon Type I immunology
Interleukin-1 immunology
Mycobacterium tuberculosis immunology
Tuberculosis, Pulmonary immunology
Tuberculosis, Pulmonary therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 511
- Issue :
- 7507
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 24990750
- Full Text :
- https://doi.org/10.1038/nature13489