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

Mayer-Barber K.D .; Andrade, B.B .; Oland, S.D.; Amaral, E.P .; Barber, D.L .; Gonzales, J.; Derrick, S.C .; Shi, R.; Kumar, N.P .; Wei, W .; Yuan, X .; Zhang, G .; Cai, Y .; Babu, S .; Catalfamo, M.; Salazar, A.M .; Via, L.E . Barry, C.E .; Sher, A .

Nature; 2014; 511; 99-103.

Abstract: Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to 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.

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