Title |
Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk
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Published in |
Nature, June 2014
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DOI | 10.1038/nature13489 |
Pubmed ID | |
Authors |
Katrin D. Mayer-Barber, Bruno B. Andrade, Sandra D. Oland, Eduardo P. Amaral, Daniel L. Barber, Jacqueline Gonzales, Steven C. Derrick, Ruiru Shi, Nathella Pavan Kumar, Wang Wei, Xing Yuan, Guolong Zhang, Ying Cai, Subash Babu, Marta Catalfamo, Andres M. Salazar, Laura E. Via, Clifton E. Barry III, Alan Sher |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 11% |
Italy | 2 | 11% |
India | 1 | 5% |
Curaçao | 1 | 5% |
Netherlands | 1 | 5% |
United States | 1 | 5% |
Portugal | 1 | 5% |
South Africa | 1 | 5% |
Unknown | 9 | 47% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 14 | 74% |
Scientists | 4 | 21% |
Science communicators (journalists, bloggers, editors) | 1 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | <1% |
Norway | 2 | <1% |
Brazil | 2 | <1% |
Netherlands | 1 | <1% |
Korea, Republic of | 1 | <1% |
Germany | 1 | <1% |
Australia | 1 | <1% |
Japan | 1 | <1% |
Argentina | 1 | <1% |
Other | 0 | 0% |
Unknown | 537 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 129 | 23% |
Researcher | 83 | 15% |
Student > Master | 69 | 13% |
Student > Bachelor | 46 | 8% |
Student > Doctoral Student | 32 | 6% |
Other | 87 | 16% |
Unknown | 104 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 140 | 25% |
Immunology and Microbiology | 107 | 19% |
Medicine and Dentistry | 65 | 12% |
Biochemistry, Genetics and Molecular Biology | 59 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 9 | 2% |
Other | 46 | 8% |
Unknown | 124 | 23% |