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

Nature (2014-07-06)
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, 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Prostaglandin E2, synthetic, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Prostaglandin E2, ≥93% (HPLC), synthetic
Sigma-Aldrich
Prostaglandin E2, γ-irradiated, powder, BioXtra, suitable for cell culture
Dinoprostone, European Pharmacopoeia (EP) Reference Standard