Influenza A virus infection induces indoleamine 2,3-dioxygenase (IDO) expression and modulates subsequent inflammatory mediators in nasal epithelial cells

Lin, Young-Tso; Lin, Chih‐Feng; Yeh, Te‐Huei

doi:10.1080/00016489.2019.1700304

Cited by 10 publications

(13 citation statements)

References 18 publications

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“…Given the unique in-line two-column method of the approach presented in this study, comprehensive comparative test performance datapoints for metabolomics applications are lacking. Nonetheless, several published studies have described similar potential applications, mostly from cell culture or animal models [ 13 – 16 ]. However, this approach compared favorably to a previous study using unbiased proteomics from nasopharyngeal lavage sampling with normal saline from 15 previously healthy hosts experimentally infected with influenza A H3N2 or human rhinovirus [12] .…”

Section: Discussionmentioning

confidence: 99%

“…These viruses infect respiratory epithelial cells, where they may induce metabolite alterations in the host [ 8 , 9 ]. The ‘-omics’ field, including genomics, proteomics, and metabolomics, has been studied for the diagnosis of influenza with variable success [ [10] , [11] , [12] , [13] , [14] , [15] – 16 ]. Of the three fields, genomics has been the most utilized for clinical virology purposes; however, there is significant interest in leveraging alternative approaches such as metabolomics and proteomics to address remaining gaps.…”

Section: Introductionmentioning

confidence: 99%

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Nasopharyngeal metabolomics and machine learning approach for the diagnosis of influenza

et al. 2021

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Background Respiratory virus infections are significant causes of morbidity and mortality, and may induce host metabolite alterations by infecting respiratory epithelial cells. We investigated the use of liquid chromatography quadrupole time-of-flight mass spectrometry (LC/Q-TOF) combined with machine learning for the diagnosis of influenza infection. Methods We analyzed nasopharyngeal swab samples by LC/Q-TOF to identify distinct metabolic signatures for diagnosis of acute illness. Machine learning models were performed for classification, followed by Shapley additive explanation (SHAP) analysis to analyze feature importance and for biomarker discovery. Findings A total of 236 samples were tested in the discovery phase by LC/Q-TOF, including 118 positive samples (40 influenza A 2009 H1N1, 39 influenza H3 and 39 influenza B) as well as 118 age and sex-matched negative controls with acute respiratory illness. Analysis showed an area under the receiver operating characteristic curve (AUC) of 1.00 (95% confidence interval [95% CI] 0.99, 1.00), sensitivity of 1.00 (95% CI 0.86, 1.00) and specificity of 0.96 (95% CI 0.81, 0.99). The metabolite most strongly associated with differential classification was pyroglutamic acid. Independent validation of a biomarker signature based on the top 20 differentiating ion features was performed in a prospective cohort of 96 symptomatic individuals including 48 positive samples (24 influenza A 2009 H1N1, 5 influenza H3 and 19 influenza B) and 48 negative samples. Testing performed using a clinically-applicable targeted approach, liquid chromatography triple quadrupole mass spectrometry, showed an AUC of 1.00 (95% CI 0.998, 1.00), sensitivity of 0.94 (95% CI 0.83, 0.98), and specificity of 1.00 (95% CI 0.93, 1.00). Limitations include lack of sample suitability assessment, and need to validate these findings in additional patient populations. Interpretation This metabolomic approach has potential for diagnostic applications in infectious diseases testing, including other respiratory viruses, and may eventually be adapted for point-of-care testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nasopharyngeal metabolomics and machine learning approach for the diagnosis of influenza

et al. 2021

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“…In pathological processes, pro-inflammatory cytokines and chemokines are robustly induced and can lead IDO-1 activity and tryptophan associated metabolites (39,41,42). IDO-1 inhibition in Influenza virus infection does not affect leukocyte infiltration or viral clearance, thus, blockade of IDO-1 could play a beneficial role in host protection (43)(44)(45). These data show that pharmacological inhibition or genetic ablation of IDO-1 did not completely prevent brain inflammation, but reduced brain damage and cell death.…”

Section: Discussionmentioning

confidence: 79%

Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection

et al. 2021

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Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment.

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“…It should also be noted that raised IDO levels are evident in epithelial cells and may modulate SARS-CoV-2 entry and consequences, as has been shown for increased IDO in nasal epithelial cells to influeza infection (70). The relevance of the cytokine-IDO/TDOkynurenine-AhR pathway in pulmonary epithelial cells in response to SARS-CoV-2 will be important to determine.…”

Section: Pro-inflammatory Cytokines and Kynureninementioning

confidence: 98%

COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

Anderson¹,

Reíter²

2020

Melatonin Res.

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As data emerges on the pathophysiological underpinnings of severe acute respiratory syndrome coronavirus (SARS-CoV)-2, it is clear that there are considerable variations in its susceptibility and severity/fatality, which give indications as to its pathophysiology and treatment. SARS-CoV-2 modulatory factors include age, vitamin D levels, cigarette smoking, gender and ethnicity as well as premorbid medical conditions, including diabetes, cancer, obesity, cardiovascular disease, and immune-compromised conditions. A complex picture is emerging, with an array of systemic physiological processes interacting including circadian, immune, intestinal, CNS and coagulation factors. This article reviews data on SARS-CoV-2 pathoetiology and pathophysiology. It is proposed that a decrease in pineal and systemic melatonin is an important driver of SARS-CoV-2 susceptibility and severity, with the loss of pineal melatonin's induction of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) in pulmonary epithelial cells and immune cells being a powerful regulator of susceptibility and severity, respectively. Stress, including discrimination stress, and decreased vitamin D also regulate SARS-CoV-2, including via gut dysbiosis and permeability, with a resultant decrease in the short-chain fatty acid, butyrate, and increase in circulating lipopolysaccharide. Stress and cytokine induction of the kynurenine pathways, leads to aryl hydrocarbon receptor activation, which primes platelets for heightened activity, coagulation and thrombin production, thereby driving elevations in thrombin that underpin many SARS-CoV-2 fatalities. On the basis of these pathophysiological changes, prophylactic and symptomatic treatments are proposed, including the use of melatonin and α7nAChR agonism.

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Influenza A virus infection induces indoleamine 2,3-dioxygenase (IDO) expression and modulates subsequent inflammatory mediators in nasal epithelial cells

Cited by 10 publications

References 18 publications

Nasopharyngeal metabolomics and machine learning approach for the diagnosis of influenza

Nasopharyngeal metabolomics and machine learning approach for the diagnosis of influenza

Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection

COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

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