title: Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes.
abstract: Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function.
  
  
  
  There is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB.
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Diego L
authors: DL
authors: Costa
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Sivaranjani
authors: S
authors: Namasivayam
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Eduardo P
authors: EP
authors: Amaral
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Kriti
authors: K
authors: Arora
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA.
authors: Alex
authors: A
authors: Chao
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Lara R
authors: LR
authors: Mittereder
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Mamoudou
authors: M
authors: Maiga
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Helena I
authors: HI
authors: Boshoff
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Clifton E
authors: CE
authors: Barry
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA.|Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, California, USA.
authors: Celia W
authors: CW
authors: Goulding
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA.|Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Instituto Pesquisas Gonçalo Moniz, Fiocruz, Salvador, Bahia, Brazil.|Multinational Organization Network Sponsoring Translational and Epidemiological Research, Instituto Brasileiro para a Investigação da Tuberculose, Fundação José Silveira, Salvador, Bahia, Brazil.
authors: Bruno B
authors: BB
authors: Andrade
authors: Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA asher@niaid.nih.gov.
authors: Alan
authors: A
authors: Sher
mesh_terms: D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D007155:Immunologic Factors / Q000008:administration & dosage*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008665:Metalloporphyrins / Q000008:administration & dosage*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011524:Protoporphyrins / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D008665:Metalloporphyrins; D011524:Protoporphyrins; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1