Genetic influences on viral-induced cytokine responses in the lung

Forbester, Jessica L.; Humphreys, Ian R.

doi:10.1038/s41385-020-00355-6

Cited by 36 publications

(38 citation statements)

References 187 publications

(258 reference statements)

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“…In this study, we identified that Nsp14 increases nuclear translocation of p65 and induces expression of NF-κB's downstream cytokines, such as IL-6 and IL-8, which have also been detected in lung tissues of COVID-19 patients (5,29) and animal models of SARS-CoV-2 infection (7). These cytokines are reported to play a critical role in regulating the recruitment and infiltration of immune cells (macrophages, neutrophils) during viral infection (39,40). Infiltrating immune cells may further escalate inflammatory responses leading to lung damage.…”

Section: Impdh2 Inhibition Blocks Nsp14-mediated Nf-κb Activation and Il-8 Inductionmentioning

confidence: 88%

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Kenney

Liu

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-κB activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB.

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Section: Impdh2 Inhibition Blocks Nsp14-mediated Nf-κb Activation and Il-8 Inductionmentioning

confidence: 88%

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Kenney

Liu

et al. 2021

Preprint

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“…Both types of stimuli promote release of broadly overlapping mediators, including the alarmins IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), and other DAMPs, such as receptor for advanced glycation endproducts (RAGE) ligands, including HMGB1 and S100A8/A9, by ECs (Forbester and Humphreys, 2021;Hammad and Lambrecht, 2015). The majority of data on this mediator release in response to a stimulus is derived from in vivo murine models or in vitro culture; for instance, IAV, RSV, and hRV are all potent inducers of IL-33 release in mice and from human bronchial epithelial cells (hBECs) in vitro (Josset et al, 2014;Kearley et al, 2015).…”

Section: First Immune Responders: Ecs and Am Responsesmentioning

confidence: 99%

Overlapping and distinct features of viral and allergen immunity in the human lung

Harker

Lloyd

2021

Immunity

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“…Furthermore, IAV infections are associated with strongly increased inflammatory gene expression in the respiratory tract [ 113 ]. The cytokines mainly released during IAV infection include type I and III interferons as well as pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1, and IL-6 [ 114 ].…”

Section: Neuro-immune Crosstalk In Respiratory Infection and Microbial Colonizationmentioning

confidence: 99%

Infection-Associated Mechanisms of Neuro-Inflammation and Neuro-Immune Crosstalk in Chronic Respiratory Diseases

Camp

Stegemann-Koniszewski

Schreiber

2021

IJMS

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Chronic obstructive airway diseases are characterized by airflow obstruction and airflow limitation as well as chronic airway inflammation. Especially bronchial asthma and chronic obstructive pulmonary disease (COPD) cause considerable morbidity and mortality worldwide, can be difficult to treat, and ultimately lack cures. While there are substantial knowledge gaps with respect to disease pathophysiology, our awareness of the role of neurological and neuro-immunological processes in the development of symptoms, the progression, and the outcome of these chronic obstructive respiratory diseases, is growing. Likewise, the role of pathogenic and colonizing microorganisms of the respiratory tract in the development and manifestation of asthma and COPD is increasingly appreciated. However, their role remains poorly understood with respect to the underlying mechanisms. Common bacteria and viruses causing respiratory infections and exacerbations of chronic obstructive respiratory diseases have also been implicated to affect the local neuro-immune crosstalk. In this review, we provide an overview of previously described neuro-immune interactions in asthma, COPD, and respiratory infections that support the hypothesis of a neuro-immunological component in the interplay between chronic obstructive respiratory diseases, respiratory infections, and respiratory microbial colonization.

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Genetic influences on viral-induced cytokine responses in the lung

Cited by 36 publications

References 187 publications

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Overlapping and distinct features of viral and allergen immunity in the human lung

Infection-Associated Mechanisms of Neuro-Inflammation and Neuro-Immune Crosstalk in Chronic Respiratory Diseases

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