A potential role for AHR in SARS-CoV-2 pathology

Giovannoni, Federico; Li, Zhaorong; Quintana, Francisco J.

doi:10.21203/rs.3.rs-25639/v1

Cited by 22 publications

(26 citation statements)

References 45 publications

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“…The MAFB/MAF ratio-AHR expression link is of special relevance because AhR is activated during coronavirus infection and the constitutive AhR activation constrains type I IFN-mediated antiviral innate defense (44,45). In fact, a role for AhR in SARS-CoV-2 pathology has been recently proposed (46), and AhR antagonists have been propositioned as potential therapy for coronavirus-infected patients (46). Therefore, considering the link between MAFB/ MAF ratio and AHR expression, the proposed involvement of AhR in COVID-19 pathogenesis is well in agreement with our hypothesis on the contribution of MAFB and MAF to severe COVID-19.…”

Section: Mafb and Maf Control Gene Expression In Pulmonary Macrophagementioning

confidence: 99%

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

et al. 2020

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Section: Mafb and Maf Control Gene Expression In Pulmonary Macrophagementioning

confidence: 99%

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

et al. 2020

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“…Other aspects of immune function emerge from studies with a range of coronaviruses, the RSV pneumovirus and from those in COPD patients. Thus, activation of the AhR was demonstrated with SARS, MERS, COVID-19 [ 14 ], with the mouse hepatitis virus (MHV) model [ 15 ] and the pneumovirus RSV [ 16 ]. MHV activates the AhR independently of the extrahepatic tryptophan (Trp)-degrading enzyme indoleamine 2,3-dioxygenase (IDO) [ 15 ], causing cytokine modulation and inducing expression of PARP, and RSV-infected mesenchymal stem cells regulate immunity via IFN-β and IDO [ 16 ].…”

Section: Previous Findings With Coronaviruses and A Pneumovirusmentioning

confidence: 99%

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

Badawy

2020

Bioscience Reports

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COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is over-expressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and ATP, especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide, which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines, and is effective against HIV infection. These properties qualify nicotinamide for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.

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“…A similar activity in the respiratory tract would be beneficial to protect from mucosal damage and re-establish protection against infection [64]. Although a recent report has associated AhR activation with lung pathogenesis in COVID-19 [65], the multiplicity of ligands and the different effects upon AhR binding do not allow definitive conclusions on the role of AhR and further studies will be required to determine whether activation is protective against COVID-19 and potential secondary infections, such as with Aspergillus.…”

Section: Restoring Immune Homeostasis In Covid-19 To Prevent Capamentioning

confidence: 99%

Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin

2020

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The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a critical factor in the clinical presentation of COVID-19, which may range from asymptomatic to a fatal, multi-organ disease. A dysregulated immune response not only compromises the ability of the host to resolve the viral infection, but may also predispose the individual to secondary bacterial and fungal infections, a risk to which the current therapeutic immunomodulatory approaches significantly contribute. Among the secondary infections that may occur in COVID-19 patients, coronavirus-associated pulmonary aspergillosis (CAPA) is emerging as a potential cause of morbidity and mortality, although many aspects of the disease still remain unresolved. With this opinion, we present the current view of CAPA and discuss how the same mechanisms that underlie the dysregulated immune response in COVID-19 increase susceptibility to Aspergillus infection. Likewise, resorting to endogenous pathways of immunomodulation may not only restore immune homeostasis in COVID-19 patients, but also reduce the risk for aspergillosis. Therefore, CAPA represents the other side of the coin in COVID-19 and our advances in the understanding and treatment of the immune response in COVID-19 should represent the framework for the study of CAPA.

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A potential role for AHR in SARS-CoV-2 pathology

Cited by 22 publications

References 45 publications

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin

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