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

Abstract

Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent1. 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 bacteria2–5. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality6. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target7. 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.

Cutting Edge: Mycobacterium tuberculosis Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication

“…IL-1b-dependent host resistance to M. tuberculosis infection was linked to production of eicosanoids through induction of the enzyme cyclooxygenase-2 (gene known as Ptgs2) (13). We confirmed that blockade or absence of IL-1R signaling in murine and human macrophages is associated with reduced PTGS2 induction (Fig.…”

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…It improves survival of Mtb-infected mice. 104 The eicosanoid pathway thus represents a complex target of TB HDT as the effect is likely dependent on infection stage, as PGE2 has protective effects early during infection but impairs anti-TB immunity during later stages. 105 …”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Because IL-10 has been known to exacerbate murine mycobacterial infections under some circumstances (84), IL-10 induction by type I IFNs could be one mechanism by which type I IFNs impair resistance to mycobacterial infection (85)(86)(87). Interestingly, a recent study suggests that M. tuberculosis-induced type I IFN production can be regulated by IL-1b through PGE 2 (88). PGE 2 administration suppresses type I IFN production and increases survival in treated mice, suggesting a cross-regulation between the IL-1b and type I IFN pathways and that antagonism of type I IFN production via PGE 2 could be used as a potential therapy for active TB.…”