Drug analog inhibition of indoleamine 2,3-dioxygenase (IDO) activity modifies pattern recognition receptor expression and proinflammatory cytokine responses early during influenza virus infection

Fox, Julie M.; Sage, Leo K.; Poore, Spencer; Johnson, Scott K.; Tompkins, S. Mark; Tripp, Ralph A.

doi:10.1189/jlb.3ab0114-046rr

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…The expression of IDO1 was shown to be upregulated in response to IAV infection through interferon (IFN) pathway . Moreover, the overexpression of IDO1 was associated with cytokine overproduction, suppression of T‐cell response, pain hypersensitivity and behavioural disturbances . The neurological symptoms were linked to high levels of kynurenine, the product of IDO1 catalysis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of kynurenine biosynthesis during influenza virus infection

et al. 2016

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Influenza A viruses (IAVs) remain serious threats to public health because of the shortage of effective means of control. Developing more effective virus control modalities requires better understanding of virus-host interactions. It has previously been shown that IAV induces the production of kynurenine, which suppresses T-cell responses, enhances pain hypersensitivity and disturbs behaviour in infected animals. However, the regulation of kynurenine biosynthesis during IAV infection remains elusive. Here we showed that IAV infection induced expression of interferons (IFNs), which upregulated production of indoleamine-2,3-dioxygenase (IDO1), which catalysed the kynurenine biosynthesis. Furthermore, IAV attenuated the IDO1 expression and the production of kynurenine through its NS1 protein. Interestingly, inhibition of viral replication prior to IFN induction limited IDO1 expression, while inhibition after did not. Finally, we showed that kynurenine biosynthesis was activated in macrophages in response to other stimuli, such as influenza B virus, herpes simplex virus 1 and 2 as well as bacterial lipopolysaccharides. Thus, the tight regulation of the kynurenine biosynthesis by host cell and, perhaps, pathogen might be a basic signature of a wide range of host-pathogen interactions, which should be taken into account during development of novel antiviral and antibacterial drugs.

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Section: Introductionmentioning

confidence: 99%

Regulation of kynurenine biosynthesis during influenza virus infection

et al. 2016

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“…However, this idea needs further empirical confirmation. New therapeutic strategies, as the use of complementary anti‐IDO treatment, could improve both, the immunological memory and the cytokine profile of the host during viral infection. Thus, it would be interesting to assess if 1MT can work as an “adjuvant push” for emerging vaccines, such as vaccines against hRSV and hMPV, which are currently under development .…”

Section: Discussionmentioning

confidence: 99%

“…Because IDO up‐regulation occurs immediately after infection (24 h p.i. ), as determined in an in vivo model of infection with influenza virus, it is likely that this enzyme is similarly induced shortly after hRSV infection and that it may be able to promptly shift the immune response toward a Th2 response (IL‐4, IL‐13), altogether down‐regulating IDO expression (Fig. ).…”

Section: Hrsv‐infection and Ido Activitymentioning

confidence: 99%

“…These data suggest an essential role for IDO during the initial response of the host against the pathogen. This finding could be exploited for the development of vaccines or act as a stimulus for vaccines with weak immune activation to improve T memory responses and reduce disease‐associated morbidity …”

Section: Inhibition Of Ido Activity During Viral Infectionsmentioning

confidence: 99%

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Contribution of IDO to human respiratory syncytial virus infection

Benavente

Soto

Pizarro-Ortega

et al. 2019

Journal of Leukocyte Biology

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IDO is an enzyme that participates in the degradation of tryptophan (Trp), which is an essential amino acid necessary for vital cellular processes. The degradation of Trp and the metabolites generated by the enzymatic activity of IDO can have immunomodulating effects, notably over T cells, which are particularly sensitive to the absence of Trp and leads to the inhibition of T cell activation, cell death, and the suppression of T cell effector functions. Noteworthy, T cells participate in the cellular immune response against the human respiratory syncytial virus (hRSV) and are essential for viral clearance, as well as the total recovery of the host. Furthermore, inadequate or non-optimal polarization of T cells is often seen during the acute phase of the disease caused by this pathogen. Here, we discuss the capacity of hRSV to exploit the immunosuppressive features of IDO to reduce T cell function, thus acquiring relevant aspects during the biology of the virus.Additionally, we review studies on the influence of IDO over T cell activation and its relationship with hRSV infection. K E Y W O R D Sindoleamine-2,3-dioxygenase, tryptophan (Trp), hRSV, T cells J Leukoc Biol. 2019;106:933-942.

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“…IFN-β, and/or IL-1β production in the presence of 1-methyltryptophan another IDO pharmacological competitive inhibitor, following influenza infection [67]. On the other hand, overexpression of IDO enzyme in the murine macrophage cell line RAW264.7 suppressed IL-6, G-CSF, MCP-1, and MIP-1β production [68] while treatment of these cells with the metabolites indole-3-acetate and tryptamine significantly attenuates the expression of TNF-α, IL-1β, and MCP-1 [69].…”

Section: Plos Onementioning

confidence: 99%

Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

et al. 2020

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Lung macrophages (LM) are in the first line of defense against inhaled pathogens and can undergo phenotypic polarization to the proinflammatory M1 after stimulation with Toll-like receptor agonists. The objective of the present work was to characterize the metabolic alterations occurring during the experimental M1 LM polarization. Human LM were obtained from resected lungs and cultured for 24 hrs in medium alone or with 10 ng.mL -1 lipopolysaccharide. Cells and culture supernatants were subjected to extraction for metabolomic analysis with high-resolution LC-MS (HILIC and reverse phase -RP-chromatography in both negative and positive ionization modes) and GC-MS. The data were analyzed with R and the Worklow4Metabolomics and MetaboAnalyst online infrastructures. A total of 8,741 and 4,356 features were detected in the intracellular and extracellular content, respectively, after the filtering steps. Pathway analysis showed involvement of arachidonic acid metabolism, tryptophan metabolism and Krebs cycle in the response of LM to LPS, which was confirmed by the specific quantitation of selected compounds. This refined analysis highlighted a regulation of the kynurenin pathway as well as the serotonin biosynthesis pathway, and an involvement of aspartate-arginosuccinate shunt in the malate production. Macrophages M1 polarization is accompanied by changes in the cell metabolome, with the differential expression of metabolites involved in the promotion and regulation of inflammation and antimicrobial activity. The analysis of this macrophage immunometabolome may be of interest for the understanding of the pathophysiology of lung inflammatory disesases.

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Drug analog inhibition of indoleamine 2,3-dioxygenase (IDO) activity modifies pattern recognition receptor expression and proinflammatory cytokine responses early during influenza virus infection

Cited by 18 publications

References 33 publications

Regulation of kynurenine biosynthesis during influenza virus infection

Regulation of kynurenine biosynthesis during influenza virus infection

Contribution of IDO to human respiratory syncytial virus infection

Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

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