Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection.

Mycobacterium tuberculosis (MTB) expresses a set of genes known as the dormancy regulon in vivo. These genes are expressed in vitro in response to nitric oxide (NO) or hypoxia, conditions used to model MTB persistence in latent infection. Although NO, a macrophage product that inhibits respiration, and hypoxia are likely triggers in vivo, additional cues could activate the dormancy regulon during infection. Here, we show that MTB infection stimulates expression of heme oxygenase (HO-1) by macrophages and that the gaseous product of this enzyme, carbon monoxide (CO), activates expression of the dormancy regulon. Deletion of macrophage HO-1 reduced expression of the dormancy regulon. Furthermore, we show that the MTB DosS/DosT/DosR two-component sensory relay system is required for the response to CO. Together, these findings demonstrate that MTB senses CO during macrophage infection. CO may represent a general cue used by pathogens to sense and adapt to the host environment.

[1]  M. Bolognesi,et al.  The crystal structure of FdxA, a 7Fe ferredoxin from Mycobacterium smegmatis. , 2007, Biochemical and biophysical research communications.

[2]  Yang Liu,et al.  Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages , 2003, The Journal of experimental medicine.

[3]  S. Raghavan,et al.  Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Sohaskey,et al.  Role of narK2X and narGHJI inHypoxic Upregulation of Nitrate Reduction byMycobacteriumtuberculosis , 2003, Journal of bacteriology.

[5]  Rick Lyons,et al.  The temporal expression profile of Mycobacterium tuberculosis infection in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Dirk Schnappinger,et al.  Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  T. Sjöstrand.  Endogenous formation of carbon monoxide; the CO concentration in the inspired and expired air of hospital patients. , 1951 .

[8]  F. Movahedzadeh,et al.  Deletion of the Mycobacterium tuberculosis α-Crystallin-Like hspX Gene Causes Increased Bacterial Growth In Vivo , 2006, Infection and Immunity.

[9]  S. C. Rison,et al.  A GAF domain in the hypoxia/NO-inducible Mycobacterium tuberculosis DosS protein binds haem. , 2005, Journal of molecular biology.

[10]  L. McCue,et al.  Identification and Characterization of Mycobacterial Proteins Differentially Expressed under Standing and Shaking Culture Conditions, Including Rv2623 from a Novel Class of Putative ATP-Binding Proteins , 2001, Infection and Immunity.

[11]  Tanya Parish,et al.  Deletion of Two-Component Regulatory Systems Increases the Virulence of Mycobacterium tuberculosis , 2003, Infection and Immunity.

[12]  Robert L. Kerby,et al.  CO-Sensing Mechanisms , 2004, Microbiology and Molecular Biology Reviews.

[13]  L. Kobzik,et al.  Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. , 1999, The Journal of clinical investigation.

[14]  B. Lighthart.  Survival of airborne bacteria in a high urban concentration of carbon monoxide. , 1973, Applied microbiology.

[15]  R. Kerby,et al.  Functionally Critical Elements of CooA-Related CO Sensors , 2004, Journal of bacteriology.

[16]  S. Ryter,et al.  Carbon Monoxide: To Boldly Go Where NO Has Gone Before , 2004, Science's STKE.

[17]  O. Smithies,et al.  Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Woo Kyu Jeon,et al.  Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. , 2006, Free radical biology & medicine.

[19]  Philip D. Butcher,et al.  Probing Host Pathogen Cross-Talk by Transcriptional Profiling of Both Mycobacterium tuberculosis and Infected Human Dendritic Cells and Macrophages , 2008, PloS one.

[20]  L Wernisch,et al.  The Mycobacterium tuberculosis dosRS two-component system is induced by multiple stresses. , 2004, Tuberculosis.

[21]  J. Johndrow,et al.  The Type I IFN Response to Infection with Mycobacterium tuberculosis Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis1 , 2007, The Journal of Immunology.

[22]  D. Saini,et al.  DevR-DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR. , 2004, Microbiology.

[23]  A. Lisitsa,et al.  Production of carbon monoxide by cytochrome P450 during iron-dependent lipid peroxidation. , 2002, Toxicology in vitro : an international journal published in association with BIBRA.

[24]  Gilla Kaplan,et al.  Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Chung,et al.  Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages , 2002 .

[26]  J. Pfeilschifter,et al.  Macrophage-Derived Heme-Oxygenase-1: Expression, Regulation, and Possible Functions in Skin Repair , 2001, Molecular medicine.

[27]  S. McKnight,et al.  NPAS2: A Gas-Responsive Transcription Factor , 2002, Science.

[28]  P. Brown,et al.  Yeast microarrays for genome wide parallel genetic and gene expression analysis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Thomas Dick,et al.  Mycobacterium bovis BCG Response Regulator Essential for Hypoxic Dormancy , 2002, Journal of bacteriology.

[30]  Hun-taeg Chung,et al.  Differential expressions of heme oxygenase-1 gene in CD25- and CD25+ subsets of human CD4+ T cells. , 2003, Biochemical and biophysical research communications.

[31]  P. Bardin,et al.  Localisation of mycobacterial DNA and mRNA in human tuberculous granulomas. , 2002, Journal of microbiological methods.

[32]  M. Maines.  The heme oxygenase system: past, present, and future. , 2004, Antioxidants & redox signaling.

[33]  J. Tyagi,et al.  Expression of mycobacterial cell division protein, FtsZ, and dormancy proteins, DevR and Acr, within lung granulomas throughout guinea pig infection. , 2006, FEMS immunology and medical microbiology.

[34]  J. Boreham,et al.  Carbon monoxide in breath in relation to smoking and carboxyhaemoglobin levels. , 1981, Thorax.

[35]  James E Gomez,et al.  M. tuberculosis persistence, latency, and drug tolerance. , 2004, Tuberculosis.

[36]  Carl Nathan,et al.  Role of iNOS in Human Host Defense , 2006, Science.

[37]  W. Lanzilotta,et al.  CooA: a heme-containing regulatory protein that serves as a specific sensor of both carbon monoxide and redox state. , 2001, Progress in nucleic acid research and molecular biology.

[38]  A. Ioanoviciu,et al.  DevS, a heme-containing two-component oxygen sensor of Mycobacterium tuberculosis. , 2007, Biochemistry.

[39]  G. Ronnett,et al.  The Regulation of Heme Turnover and Carbon Monoxide Biosynthesis in Cultured Primary Rat Olfactory Receptor Neurons , 1996, The Journal of Neuroscience.

[40]  G. Schoolnik,et al.  Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. , 2004, Tuberculosis.

[41]  D. Russell,et al.  Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. , 2007, Cell host & microbe.

[42]  M. Bolognesi,et al.  CO Sniffing through Heme‐based Sensor Proteins , 2004, IUBMB life.

[43]  S. Remy,et al.  Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression. , 2005, Blood.

[44]  K. Eisenach,et al.  Microaerophilic Induction of the Alpha-Crystallin Chaperone Protein Homologue (hspX) mRNA ofMycobacterium tuberculosis , 2001, Journal of bacteriology.

[45]  M. Gilles-Gonzalez,et al.  Heme-based sensors: defining characteristics, recent developments, and regulatory hypotheses. , 2005, Journal of inorganic biochemistry.

[46]  D. Sherman,et al.  Two Sensor Kinases Contribute to the Hypoxic Response of Mycobacterium tuberculosis* , 2004, Journal of Biological Chemistry.

[47]  Lingyun Wu,et al.  Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications , 2005, Pharmacological Reviews.

[48]  A. Steyn,et al.  Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor , 2007, Proceedings of the National Academy of Sciences.

[49]  Tige R. Rustad,et al.  The Enduring Hypoxic Response of Mycobacterium tuberculosis , 2008, PloS one.

[50]  Farahnaz Movahedzadeh,et al.  What do microarrays really tell us about M. tuberculosis? , 2004, Trends in microbiology.

[51]  L. M. Saraiva,et al.  Antimicrobial Action of Carbon Monoxide-Releasing Compounds , 2007, Antimicrobial Agents and Chemotherapy.

[52]  M. Alcaraz,et al.  Modulation of haem oxygenase‐1 expression by nitric oxide and leukotrienes in zymosan‐activated macrophages , 2001, British journal of pharmacology.

[53]  D. Zander,et al.  Heme oxygenase-1 expression in human lungs with cystic fibrosis and cytoprotective effects against Pseudomonas aeruginosa in vitro. , 2004, American journal of respiratory and critical care medicine.

[54]  M. Gilles-Gonzalez,et al.  DosT and DevS are oxygen‐switched kinases in Mycobacterium tuberculosis , 2007, Protein science : a publication of the Protein Society.

[55]  L. McCue,et al.  Identification of a Mycobacterium tuberculosis Putative Classical Nitroreductase Gene Whose Expression Is Coregulated with That of the acr Gene within Macrophages, in Standing versus Shaking Cultures, and under Low Oxygen Conditions , 2002, Infection and Immunity.

[56]  W. Jacobs,et al.  The effects of reactive nitrogen intermediates on gene expression in Mycobacterium tuberculosis , 2003, Cellular microbiology.

[57]  S. Ryter,et al.  The FASEB Journal • Research Communication Caveolae compartmentalization of heme oxygenase-1 in endothelial cells , 2022 .

[58]  J. Betts,et al.  In Situ Detection of Mycobacterium tuberculosis Transcripts in Human Lung Granulomas Reveals Differential Gene Expression in Necrotic Lesions , 2002, Infection and Immunity.

[59]  H. Nakajima,et al.  CO sensing and regulation of gene expression by the transcriptional activator CooA. , 2000, Journal of inorganic biochemistry.

[60]  C. Sohaskey,et al.  Nonreplicating persistence of mycobacterium tuberculosis. , 2001, Annual review of microbiology.

[61]  Dirk Schnappinger,et al.  Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program , 2003, The Journal of experimental medicine.

[62]  S. Ryter,et al.  Heme oxygenase-1 and carbon monoxide in pulmonary medicine , 2003, Respiratory research.

[63]  J. Flynn,et al.  Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension , 2006, Cellular microbiology.

[64]  D. Saini,et al.  Disruption of response regulator gene, devR, leads to attenuation in virulence of Mycobacterium tuberculosis. , 2004, FEMS microbiology letters.

[65]  M. Alcaraz,et al.  Heme oxygenase-1 induction by nitric oxide in RAW 264.7 macrophages is upregulated by a cyclo-oxygenase-2 inhibitor. , 2001, Biochimica et biophysica acta.