- Author
-
L. Guo
- Title
- The role of indoleamine 2,3-dioxygenase IDO in infectious diseases
- Subtitle
- COVID-19 and tuberculosis
- Supervisors
-
R. Lutter
- Co-supervisors
- Award date
- 9 July 2024
- Number of pages
- 194
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The studies comprised in this thesis focus on the role of indoleamine 2,3-dioxygenase (IDO) enzymes, both IDO1 and IDO2, in the pathophysiology of infectious diseases, particularly on COVID-19, long COVID, and tuberculosis. For these studies, immunohistochemistry, cell culture approaches, and ex vivo cell culture methods were employed to elucidate the expression, activity and effects of IDO1 and IDO2 in various tissues and cells.
The results show that, besides the presence of IDO1, the aryl hydrocarbon receptor (AHR)-IDO2-kynurenine pathway is active in severe/fatal COVID-19, likely contributing to cell death and cellular metabolic stress. This pathway is also induced in long COVID, where it is associated with aberrant cellular metabolism and mitochondrial activity. Inhibition of IDO2 expression and activity using an AHR antagonist attenuated cell death and cellular stress, suggesting a potential therapeutic target for long COVID.
In tuberculous meningitis, granulomatous IDO1 expression was seen, but IDO2 expression was found to be beyond in granulomas, particularly in the cerebellum, medulla oblongata, and inferior olivary nucleus. IDO1 activity was shown to reduce the sensitivity of Mycobacterium tuberculosis (M. tuberculosis) to antibiotics by depleting tryptophan in vitro. This may be an important clue for shortening the duration of antibiotic treatment. However, IDO1 activity also promoted the fusion of lysosomes to M. tuberculosis-containing phagosomes. So, inhibition of IDO activity can be both beneficial and harmful to the host.
The thesis highlights the complex roles of IDO1 and IDO2 in infectious diseases, including their potential as therapeutic targets. The findings suggest that modulation of IDO activity may be beneficial in treating long COVID and tuberculosis, but the dual effects of IDO1 in tuberculosis should be taken along with interventions. Overall, this research contributes to a better understanding of the pathophysiological mechanisms underlying (post-) infectious diseases and may lead to the development of novel therapeutic strategies. - Persistent Identifier
- https://hdl.handle.net/11245.1/7e2cd737-4f7c-4a21-8a80-0422ac406ff1
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Indoleamine 2,3-dioxygenase (IDO)1 and IDO2 activity and severe course of COVID-19
Chapter 3: Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARSCoV- 2 infection
Chapter 4: Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis
Chapter 5: Indoleamine 2,3-dioxygenase-1 activity reduces effectivity of antibiotics on intracellular Mycobacterium tuberculosis
Chapter 6: Indoleamine 2,3-dioxygenase 1 activity modulates intracellular location of Mycobacterium tuberculosis and apoptosis of Mycobacterium tuberculosis-infected macrophages
Chapter 7: General discussion
Summary; Nederlandse samenvatting; PhD portfolio; List of publication; Curriculum vitae; Acknowledgements
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.