When AHR signaling pathways meet viral infections

Hu, Jieke; Ding, Yuan; Li, Wen; Liu, Shuzhen

doi:10.1186/s12964-023-01058-8

Cited by 9 publications

(3 citation statements)

References 101 publications

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“…In particular, AHR has been identified as a host dependency factor for a few enveloped viruses such as Dengue virus and Zika virus [ 53 ] – reviewed comprehensively in Hu et al . [ 54 ]. Moreover, Giovannoni et al have recently reported that AHR is transcriptionally upregulated upon SARS-CoV-2 infection both in vitro and in patients samples [ 37 ], speculating that SARS-CoV-2 requires AHR to evade cellular antiviral responses, as previously reported for flaviviruses [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor

Yousefi,

Lee,

Chan

et al. 2023

Emerging Microbes & Infections

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The emergence of novel betacoronaviruses has posed significant financial and human health burdens, necessitating the development of appropriate tools to combat future outbreaks. In this study, we have characterized a human cell line, IGROV-1, as a robust tool to detect, propagate, and titrate betacoronaviruses SARS-CoV-2 and HCoV-OC43. IGROV-1 cells can be used for serological assays, antiviral drug testing, and isolating SARS-CoV-2 variants from patient samples. Using time-course transcriptomics, we confirmed that IGROV-1 cells exhibit a robust innate immune response upon SARS-CoV-2 infection, recapitulating the response previously observed in primary human nasal epithelial cells. We performed genome-wide CRISPR knockout genetic screens in IGROV-1 cells and identified Aryl hydrocarbon receptor (AHR) as a critical host dependency factor for both SARS-CoV-2 and HCoV-OC43. Using DiMNF, a small molecule inhibitor of AHR, we observed that the drug selectively inhibits HCoV-OC43 infection but not SARS-CoV-2. Transcriptomic analysis in primary normal human bronchial epithelial cells revealed that DiMNF blocks HCoV-OC43 infection via basal activation of innate immune responses. Our findings highlight the potential of IGROV-1 cells as a valuable diagnostic and research tool to combat betacoronavirus diseases.

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Section: Discussionmentioning

confidence: 99%

Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor

Yousefi,

Lee,

Chan

et al. 2023

Emerging Microbes & Infections

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“…This transcription factor activates the expression of the mentioned proteins and also cytochromes P450 [ 43 ]. Besides regulating xenobiotics metabolism, Ahr has many functions and is considered a signaling protein [ 44 ]. There is also evidence that the interaction between Ahr and the antioxidant response element (ARE) via the nuclear factor E2-related factor 2 (Nrf2) can change the expression of antioxidant and xenobiotic metabolizing enzymes, including GST and NQO1 [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Redox Proteomic Profile of Tirapazamine-Resistant Murine Hepatoma Cells

Nemeikaitė-Čėnienė

Haberkant

Kučiauskas

et al. 2023

IJMS

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3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities. Their action is attributed to the enzymatic single-electron reduction to free radicals that initiate the prooxidant processes. In order to clarify the mechanisms of aerobic mammalian cytotoxicity of ArN→O, we derived a TPZ-resistant subline of murine hepatoma MH22a cells (resistance index, 5.64). The quantitative proteomic of wild-type and TPZ-resistant cells revealed 5818 proteins, of which 237 were up- and 184 down-regulated. The expression of the antioxidant enzymes aldehyde- and alcohol dehydrogenases, carbonyl reductases, catalase, and glutathione reductase was increased 1.6–5.2 times, whereas the changes in the expression of glutathione peroxidase, superoxide dismutase, thioredoxin reductase, and peroxiredoxins were less pronounced. The expression of xenobiotics conjugating glutathione-S-transferases was increased by 1.6–2.6 times. On the other hand, the expression of NADPH:cytochrome P450 reductase was responsible for the single-electron reduction in TPZ and for the 2.1-fold decrease. These data support the fact that the main mechanism of action of TPZ under aerobic conditions is oxidative stress. The unchanged expression of intranuclear antioxidant proteins peroxiredoxin, glutaredoxin, and glutathione peroxidase, and a modest increase in the expression of DNA damage repair proteins, tend to support non-site-specific but not intranuclear oxidative stress as a main factor of TPZ aerobic cytotoxicity.

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“…For example, chlorpromazine exerts antiviral properties against SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, and is currently in clinical trials (NCT04366739) for this viral infection [252]. Other viruses enter host cells via clathrin-dependent endocytosis (CDE) and are inhibited by several neuroleptics, including chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine, emphasizing an alternative, DA-independent mechanisms of action, likely mediated by AhR (functioning as an E3 ubiquitin ligase) [253][254][255].…”

Section: Antipsychotics As Antiviralsmentioning

confidence: 99%

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

Sfera

2023

Reports

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In 1957, Arvid Carlsson discovered that dopamine, at the time believed to be nothing more than a norepinephrine precursor, was a brain neurotransmitter in and of itself. By 1963, postsynaptic dopamine blockade had become the cornerstone of psychiatric treatment as it appeared to have deciphered the “chlorpromazine enigma”, a 1950s term, denoting the action mechanism of antipsychotic drugs. The same year, Carlsson and Lindqvist launched the dopamine hypothesis of schizophrenia, ushering in the era of psychopharmacology. At present, six decades later, although watered down by three consecutive revisions, the dopamine model remains in vogue. The latest emendation of this paradigm proposes that “environmental and genetic factors” converge on the dopaminergic pathways, upregulating postsynaptic transmission. Aryl hydrocarbon receptors, expressed by the gut and blood–brain barrier, respond to a variety of endogenous and exogenous ligands, including dopamine, probably participating in interoceptive awareness, a feed-back loop, conveying intestinal barrier status to the insular cortex. The conceptualization of aryl hydrocarbon receptor as a bridge, connecting vagal terminals with the microbiome, may elucidate the aspects of schizophrenia seemingly incongruous with the dopamine hypothesis, such as increased prevalence in urban areas, distance from the equator, autoantibodies, or comorbidity with inflammatory bowel disease and human immunodeficiency 1 virus. In this review article, after a short discussion of schizophrenia outcome studies and insight, we take a closer look at the action mechanism of antipsychotic drugs, attempting to answer the question: do these agents exert their beneficial effects via both dopaminergic and nondopaminergic mechanisms? Finally, we discuss potential new therapies, including transcutaneous vagal stimulation, aryl hydrocarbon receptor ligands, and restoring the homeostasis of the gut barrier.

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When AHR signaling pathways meet viral infections

Cited by 9 publications

References 101 publications

Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor

Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor

Redox Proteomic Profile of Tirapazamine-Resistant Murine Hepatoma Cells

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

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