Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection

Silva‐Gomes, Sandro; Appelberg, Rui; Larsen, Rasmus; Soares, Miguel P.; Gomes, Maria Salomé

doi:10.1128/iai.00251-13

Cited by 71 publications

(96 citation statements)

References 62 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). The regulation of HO-1 expression in macrophages was strictly required for protection against mycobacterial infection in mice, and HO-1-deficient mice were more susceptible to intravenous mycobacterium avium infections, and failed to mount a protective granulomatous response in mice lacking mature B cells (91). In a mouse model of noneosinophilic asthma, HO-1 provided anti-inflammatory effects by inhibiting the p-STAT3-RORct pathway (120).…”

Section: Ho-1 Reduces Inflammationmentioning

confidence: 99%

Heme Oxygenase in Neonatal Lung Injury and Repair

Dennery

2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Premature and sick neonates are often exposed to high concentrations of oxygen, which results in lung injury and long-term adverse consequences. Nevertheless, neonates are more tolerant to hyperoxia than are adults. This may be, in part, explained by the high lung content of heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme and an important stress protein. The abundance of HO-1 dictates its cytoprotective and deleterious effects. Interestingly, in response to hyperoxia, lung HO-1 mRNA is not further up-regulated in neonates, suggesting that lung HO-1 gene expression is tightly regulated so as to optimize cytoprotection when faced with an oxidative stress such as hyperoxia. Recent Advances: In addition to the lack of induction of HO-1 mRNA, neonatal lung HO-1 protein is observed in the nucleus in neonatal mice exposed to hyperoxia but not in adults, which is further evidence for the developmental regulation of HO-1. Nuclear HO-1 had unique properties independent of its enzymatic activity. In addition, there has been increasing evidence that nuclear HO-1 contributes to cellular proliferation and malignant transformation in several human cancers. Critical Issues: Since HO-1 has dual effects in cytoprotection and cellular proliferation, the titration of HO-1 effects is critical to ensure beneficial actions against oxidative stress. Future Directions: Much more has to be understood about the specific roles of HO-1 so as to manipulate its abundance and/or nuclear migration to maximize the therapeutic benefit of this pleiotropic protein in the neonatal lung.

show abstract

Section: Ho-1 Reduces Inflammationmentioning

confidence: 99%

Heme Oxygenase in Neonatal Lung Injury and Repair

Dennery

2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…Supernotch or long-wave pass filters (Supernotch filters, Kaiser Optics, and RazorEdge Raman filters, Semrock) were used to attenuate the Raleigh scattering. Frequencies were calibrated relative to indene and CCl 4 and are accurate to Ϯ1 cm Ϫ1 . CCl 4 was also used to check the polarization conditions.…”

Section: Site-directed Mutagenesis and Cloning Of The Doss Distalmentioning

confidence: 99%

“…Like any infection, tuberculosis leads to a host immune response resulting in recruitment of lymphocytes and macrophages (2). This process is associated with high levels of NO and CO produced by inducible nitric-oxide synthase and heme oxygenase-1 (HO-1), respectively, as part of the defense mechanism of macrophages (3)(4)(5). The ability of M. tuberculosis to successfully survive within the host for years in a clinically undetectable dormant state known as non-replicating persistence (NRP), 3 in which it is resistant to most of the currently available treatments, makes it of paramount importance to elucidate this defense strategy (6).…”

mentioning

confidence: 99%

Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS

Basudhar

Madrona

Yukl

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mycobacterium tuberculosis DosS is critical for the induction of M. tuberculosis dormancy genes in response to nitric oxide (NO), carbon monoxide (CO), or hypoxia. These environmental stimuli, which are sensed by the DosS heme group, result in autophosphorylation of a DosS His residue, followed by phosphotransfer to an Asp residue of the response regulator DosR. To clarify the mechanism of gaseous ligand recognition and signaling, we investigated the hydrogen-bonding interactions of the iron-bound CO and NO ligands by site-directed mutagenesis of Glu-87 and His-89. Autophosphorylation assays and molecular dynamics simulations suggest that Glu-87 has an important role in ligand recognition, whereas His-89 is essential for signal transduction to the kinase domain, a process for which Arg-204 is important. Mutation of Glu-87 to Ala or Gly rendered the protein constitutively active as a kinase, but with lower autophosphorylation activity than the wild-type in the Fe(II) and the Fe(II)-CO states, whereas the E87D mutant had little kinase activity except for the Fe(II)-NO complex. The H89R mutant exhibited attenuated autophosphorylation activity, although the H89A and R204A mutants were inactive as kinases, emphasizing the importance of these residues in communication to the kinase core. Resonance Raman spectroscopy of the wild-type and H89A mutant indicates the mutation does not alter the heme coordination number, spin state, or porphyrin deformation state, but it suggests that interdomain interactions are disrupted by the mutation. Overall, these results confirm the importance of the distal hydrogen-bonding network in ligand recognition and communication to the kinase domain and reveal the sensitivity of the system to subtle differences in the binding of gaseous ligands.Tuberculosis, an airborne disease caused by Mycobacterium tuberculosis, is believed to have infected nearly 1 out of 3 people worldwide (1). Like any infection, tuberculosis leads to a host immune response resulting in recruitment of lymphocytes and macrophages (2). This process is associated with high levels of NO and CO produced by inducible nitric-oxide synthase and heme oxygenase-1 (HO-1), respectively, as part of the defense mechanism of macrophages (3-5). The ability of M. tuberculosis to successfully survive within the host for years in a clinically undetectable dormant state known as non-replicating persistence (NRP), 3 in which it is resistant to most of the currently available treatments, makes it of paramount importance to elucidate this defense strategy (6). The mechanism of NRP is not fully understood; however, hypoxia (7, 8), high CO and NO levels (5, 9), nutrient deprivation (10), and the pH of the microenvironment (11) are among the factors leading to NRP. It has been shown that NRP can initiate changes in energy metabolism and cellular signaling pathways that lead to M. tuberculosis growth arrest. Decreased cellular activity is believed to be the main reason for the long term treatment protocols required to eradicate the bacteria. Mo...

show abstract

“…In severe malaria due to Plasmodium chabaudi chabaudi infection in contrast, Hmox1 −/− mice succumb to acute liver failure attributable to enhanced TNF-mediated apoptosis of hepatocytes and tissue necrosis (Seixas et al, 2009). Similarly, upon infection of Hmox1 −/− mice and macrophages with Mycobacterium (M.) avium, the cytotoxic effects of heme are detrimental to the host (Silva- Gomes et al, 2013).…”

Section: Hemolytic Anemias Challenge Macrophage Iron Recyclingmentioning

confidence: 98%