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 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.

• 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 3rd, Alan Sher
• Journal: Nature (Nature) Vol. 511 Issue 7507 Pg. 99-103 (Jul 03 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24990750 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Interferon Type I
• Interleukin-1
• Dinoprostone

Topics

• Animals
• Dinoprostone (antagonists & inhibitors, biosynthesis, metabolism)
• Disease Models, Animal
• Female
• Humans
• Immunity, Innate (immunology)
• Immunotherapy
• Interferon Type I (antagonists & inhibitors, biosynthesis, immunology)
• Interleukin-1 (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mycobacterium tuberculosis (immunology)
• Tuberculosis, Pulmonary (immunology, microbiology, therapy)