Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk

By K. Mayer-Barber, B. Andrade, Sandra D. Oland, Eduardo P. Amaral, Daniel L. Barber, Jacqueline Gonzales, S. Derrick, Rui-ru Shi, N. P. Kumar, Wang Wei and 9 more. Nature, 2014

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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.

Subfields: Immunology, Infectious Diseases, Oncology

View Paper: https://www.semanticscholar.org/paper/2dcae24a98ebd1b47df79a9e68bbbd9173e7a154

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