A potential role for indoleamine 2,3-dioxygenase (IDO) in Rhodococcus equi infection.
Abstract: Rhodococcus equi is a facultative intracellular bacterial pathogen of foals and immunocompromised humans that infects and proliferates within host macrophages and dendritic cells (DC). Indoleamine 2,3-dioxygenase (IDO), the initial enzyme in the tryptophan catabolism pathway, is upregulated in R. equi infected equine monocyte-derived DC and alveolar macrophages. Tryptophan requirement of R. equi for extracellular and intracellular growth was assessed. Growth of R. equi in minimal media did not require tryptophan and pharmacologic inhibition of IDO had no effect on intracellular proliferation of R. equi in equine alveolar macrophages. To investigate an immune-regulatory role for INDO in R. equi infection, IDO(-/-) (B6.129-(Indotm1Alm)/J) (n=22) and strain matched control (C57BL/6J) (n=20) mice were infected with R. equi by intraperitoneal injection, for 3 and 6 days. There was no difference in bacterial counts in liver or spleen between the two groups. Histological sections of liver and spleen were assigned inflammation scores and RT-PCR for interferon-gamma (IFNγ), tumor necrosis factor-alpha (TNFα), IL-4, IL-6, IL-10, IL-12, IL-23, forkhead box P3 (FoxP3), and transforming growth factor-beta (TGFβ) was performed on liver and spleen. Liver tissue of IDO(-/-) had higher inflammation scores at 6 days post-infection (PI) (P=0.05) and had decreased expression of TGFβ at 3 days PI (P=0.01), and FOXP3 at 3 days (P=0.02) and 6 days (P=0.03) compared to control mice. Immunostaining for FOXP3 showed lower numbers of FOXP3+ regulatory T cells in liver of IDO(-/-) mice 6 days PI. Prolonged inflammation in the liver tissue of IDO(-/-) mice corresponded with lower expression of FOXP3 and TGFβ in that tissue, and also with lower numbers of FOXP3+ regulatory T cells. We conclude that IDO expression by activated macrophages and DC plays a role in dampening the inflammatory response to R. equi infection in mice.
Copyright © 2010 Elsevier B.V. All rights reserved.
Publication Date: 2010-07-22 PubMed ID: 20739070DOI: 10.1016/j.vetimm.2010.07.013Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates the role of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in body’s metabolism, on the proliferation of Rhodococcus equi, an intracellular bacterial pathogen which affect horses and humans with compromised immunity. The findings suggest that IDO may moderate the body’s inflammatory response to the pathogen.
Explaining the Research
- Initial part of the research focuses on Rhodococcus equi, a bacterial pathogen known to affect young horses (foals) and humans with less effective immune systems. This bacterium provokes an infection within certain immune cells (macrophages and dendritic cells) of the host organism.
- It has been indicated in this study that the up-regulation of IDO in equine-derived dendritic cells and alveolar macrophages post Rhodococcus equi infection might signify its potential role in the process.
- The researchers examined the necessity of tryptophan (a crucial element in the IDO pathway) for the growth of the pathogen, concluding there was no discernible requirement of it.
- Additionally, they found inhibiting IDO had no effect on the proliferation of the pathogen inside these immune cells.
Experimenting with Mouse Models
- Continuing the research, the team tested the role of IDO in mice with inoculated Rhodococcus equi. The experiment included both normal mice and those with genetically knocked-out IDO, running for 3 and 6 days.
- The animals were observed for bacterial count, immune cell reaction in the spleen and liver, alongside tissue inflammation level, and relative expressions of several immune-related genes like IFNγ, TNFα, IL-4, IL-6, IL-10, IL-12, IL-23, FoxP3, and TGFβ.
Results and Conclusion
- There was no difference observed in bacterial count among two mouse groups, but the liver tissues in mice without active IDO showed higher inflammation at the 6-day mark post-infection.
- Genes TGFβ and FoxP3, which code for immune-regulating proteins, showed decreased expression levels at 3-day (both) and 6-day (FoxP3) mark, along with fewer regulatory T cells.
- These results led the team to suggest the role of IDO in potentially subduing the inflammatory response to Rhodococcus equi.
Cite This Article
APA
Heller MC, Drew CP, Jackson KA, Griffey S, Watson JL.
(2010).
A potential role for indoleamine 2,3-dioxygenase (IDO) in Rhodococcus equi infection.
Vet Immunol Immunopathol, 138(3), 174-182.
https://doi.org/10.1016/j.vetimm.2010.07.013 Publication
Researcher Affiliations
- Dept. of Veterinary Medicine and Epidemiology, University of California Davis, One Shields Ave., Davis, CA 95616, USA. mcheller@ucdavis.edu
MeSH Terms
- Actinomycetales Infections / enzymology
- Actinomycetales Infections / immunology
- Actinomycetales Infections / veterinary
- Animals
- Cytokines / metabolism
- Dendritic Cells / enzymology
- Dendritic Cells / immunology
- Female
- Horse Diseases / enzymology
- Horse Diseases / immunology
- Horses
- In Vitro Techniques
- Indoleamine-Pyrrole 2,3,-Dioxygenase / deficiency
- Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
- Liver / immunology
- Macrophages, Alveolar / enzymology
- Macrophages, Alveolar / immunology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Rhodococcus equi
- Spleen / immunology
- T-Lymphocytes, Regulatory / immunology
Citations
This article has been cited 9 times.- Liu X, Liu X, Wang X, Shang K, Li J, Lan Y, Wang J, Li J, Yue B, He M, Fan Z. Multi-omics analysis reveals changes in tryptophan and cholesterol metabolism before and after sexual maturation in captive macaques.. BMC Genomics 2023 Jun 7;24(1):308.
- Crociati M, Capomaccio S, Mandara MT, Stradaioli G, Sylla L, Monaci M, Cappelli K. Different expression of Defensin-B gene in the endometrium of mares of different age during the breeding season.. BMC Vet Res 2019 Dec 21;15(1):465.
- Boros FA, Vécsei L. Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway.. Front Immunol 2019;10:2570.
- Karagianni AE, Kapetanovic R, Summers KM, McGorum BC, Hume DA, Pirie RS. Comparative transcriptome analysis of equine alveolar macrophages.. Equine Vet J 2017 May;49(3):375-382.
- Karagianni AE, Kapetanovic R, McGorum BC, Hume DA, Pirie SR. The equine alveolar macrophage: functional and phenotypic comparisons with peritoneal macrophages.. Vet Immunol Immunopathol 2013 Oct 1;155(4):219-28.
- Kachroo P, Ivanov I, Seabury AG, Liu M, Chowdhary BP, Cohen ND. Age-related changes following in vitro stimulation with Rhodococcus equi of peripheral blood leukocytes from neonatal foals.. PLoS One 2013;8(5):e62879.
- Harden JL, Egilmez NK. Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity.. Immunol Invest 2012;41(6-7):738-64.
- Sumpter TL, Dangi A, Matta BM, Huang C, Stolz DB, Vodovotz Y, Thomson AW, Gandhi CR. Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO.. J Immunol 2012 Oct 15;189(8):3848-58.
- Blumenthal A, Nagalingam G, Huch JH, Walker L, Guillemin GJ, Smythe GA, Ehrt S, Britton WJ, Saunders BM. M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection.. PLoS One 2012;7(5):e37314.
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