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- Title
Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.
- Authors
Mayer-Barber, Katrin D.; Andrade, Bruno B.; Oland, Sandra D.; Amaral, Eduardo P.; Barber, Daniel L.; Gonzales, Jacqueline; Derrick, Steven C.; Shi, Ruiru; Kumar, Nathella Pavan; Wei, Wang; Yuan, Xing; Zhang, Guolong; Cai, Ying; Babu, Subash; Catalfamo, Marta; Salazar, Andres M.; Via, Laura E.; Barry III, Clifton E.; Sher, Alan
- 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
TUBERCULOSIS treatment; INTERLEUKIN-1; INTERFERONS; EICOSANOIDS; ANTIBODY-directed enzyme prodrug therapy; DRUG resistance in bacteria; DINOPROSTONE; THERAPEUTICS
- Publication
Nature, 2014, Vol 511, Issue 7507, p99
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13489