title: 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.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Katrin D
authors.initials: KD
authors.lastname: Mayer-Barber
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Oland
authors.affiliation: 1] Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Department of Immunology, Biomedical Sciences Institutes, University of Sao Paulo, 05508-900 Sao Paulo, Brazil.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Amaral
authors.affiliation: T Lymphocyte Biology Unit, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gonzales
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Derrick
authors.affiliation: Henan Chest Hospital, 450003 Zhengzhou, China.
authors.forename: Ruiru
authors.initials: R
authors.lastname: Shi
authors.affiliation: 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] National Institute for Research in Tuberculosis (NIRT), 600 031 Chennai, India.
authors.forename: Nathella Pavan
authors.initials: NP
authors.lastname: Kumar
authors.affiliation: Henan Chest Hospital, 450003 Zhengzhou, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Wei
authors.affiliation: Henan Chest Hospital, 450003 Zhengzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Sino-US International Research Center for Tuberculosis, and Henan Public Health Center, 450003 Zhengzhou, China.
authors.forename: Guolong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] Helminth Immunology Section, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Subash
authors.initials: S
authors.lastname: Babu
authors.affiliation: Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Catalfamo
authors.affiliation: Oncovir Inc., Washington, Washington DC 20008, USA.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007167:Immunotherapy; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000628:therapy*
chemical_list: D007370:Interferon Type I; D007375:Interleukin-1; D015232:Dinoprostone