Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (751 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.

Download Full-text

Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome

Journal of Dental Research ◽

10.1177/0022034518760855 ◽

2018 ◽

Vol 97 (8) ◽

pp. 893-900 ◽

Cited By ~ 11

Author(s):

J. Papinska ◽

H. Bagavant ◽

G.B. Gmyrek ◽

M. Sroka ◽

S. Tummala ◽

...

Keyword(s):

Gene Expression ◽

Viral Infections ◽

Critical Role ◽

Autoimmune Disorder ◽

Sjögren Syndrome ◽

Lymphoid Cells ◽

Type I Interferons ◽

Sjogren Syndrome ◽

Type I ◽

Type I Ifns

Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

Download Full-text

CD8, FoxP3, and CD45RO+ Lymphocytic Infiltrates in Type I and Type II Endometrial Cancers in African American and European American Females

International Journal of Gynecological Pathology ◽

10.1097/pgp.0000000000000359 ◽

2017 ◽

Vol 36 (6) ◽

pp. 540-549 ◽

Cited By ~ 1

Author(s):

Tariq Rashid ◽

Jennifer L. Young-Pierce ◽

Elizabeth Garrett-Mayer ◽

Whitney Graybill ◽

Shelby Neal ◽

...

Keyword(s):

African American ◽

European American ◽

Type I ◽

Type Ii ◽

Endometrial Cancers ◽

Lymphocytic Infiltrates

Download Full-text

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials

Lupus ◽

10.1177/0961203320959702 ◽

2020 ◽

Vol 29 (14) ◽

pp. 1845-1853

Author(s):

Jeffery Wei Heng Koh ◽

Cheng Han Ng ◽

Sen Hee Tay

Keyword(s):

Systematic Review ◽

Herpes Zoster ◽

Lupus Erythematosus ◽

Viral Infections ◽

Meta Analysis ◽

Type I Interferons ◽

Type I ◽

Upper Respiratory Tract ◽

Type I Ifn ◽

Tract Infections

Objective The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. Methods A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Results Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88–7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. Conclusion This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

Download Full-text

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

Viruses ◽

10.3390/v11080762 ◽

2019 ◽

Vol 11 (8) ◽

pp. 762 ◽

Cited By ~ 38

Author(s):

Maria K. Smatti ◽

Farhan S. Cyprian ◽

Gheyath K. Nasrallah ◽

Asmaa A. Al Thani ◽

Ruba O. Almishal ◽

...

Keyword(s):

Immune Responses ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Influenza A ◽

Molecular Mechanisms ◽

Viral Infections ◽

Molecular Mimicry ◽

Experimental Studies ◽

Onset Time ◽

Protective Effects

For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

Download Full-text

Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma

Frontiers in Immunology ◽

10.3389/fimmu.2021.743890 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juan José Nieto-Fontarigo ◽

Sofia Tillgren ◽

Samuel Cerps ◽

Asger Sverrild ◽

Morten Hvidtfeldt ◽

...

Keyword(s):

Viral Infections ◽

Ex Vivo ◽

Bronchial Epithelium ◽

Poly I:C ◽

Interferon Response ◽

Cytokine Signaling ◽

Type I ◽

Protective Effects ◽

Bronchial Epithelial ◽

Proteomic Analyses

BackgroundBoth anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity.ObjectiveTo investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients.MethodsEffects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses.ResultsImiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections.ConclusionImiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.

Download Full-text

IFN-β signalling regulates RAW 264.7 macrophage activation, cytokine production, and killing activity

Innate Immunity ◽

10.1177/1753425919878839 ◽

2019 ◽

Vol 26 (3) ◽

pp. 172-182

Author(s):

Yalda Karimi ◽

Elizabeth C Giles ◽

Fatemeh Vahedi ◽

Marianne V Chew ◽

Tina Nham ◽

...

Keyword(s):

Inflammatory Response ◽

Bacterial Infections ◽

Viral Infections ◽

Critical Role ◽

Raw 264.7 ◽

Type I ◽

Type I Ifn ◽

Killing Activity ◽

Raw 264.7 Macrophage

Type I IFN holds a critical role in host defence, providing protection against pathogenic organisms through coordinating a pro-inflammatory response. Type I IFN provides additional protection through mitigating this inflammatory response, preventing immunopathology. Within the context of viral infections, type I IFN signalling commonly results in successful viral clearance. Conversely, during bacterial infections, the role of type I IFN is less predictable, leading to either detrimental or beneficial outcomes. The factors responsible for the variability in the role of type I IFN remain unclear. Here, we aimed to elucidate differences in the effect of type I IFN signalling on macrophage functioning in the context of TLR activation. Using RAW 264.7 macrophages, we observed the influence of type I IFN to be dependent on the type of TLR ligand, length of TLR exposure and the timing of IFN-β signalling. However, in all conditions, IFN-β increased the production of the anti-inflammatory cytokine IL-10. Examination of RAW 264.7 macrophage function showed type I IFN to induce an activated phenotype by up-regulating MHC II expression and enhancing killing activity. Our results support a context-dependent role for type I IFN in regulating RAW 264.7 macrophage activity.

Download Full-text

Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

Nature Communications ◽

10.1038/s41467-021-23003-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Junji Xing ◽

Ao Zhang ◽

Yong Du ◽

Mingli Fang ◽

Laurie J. Minze ◽

...

Keyword(s):

Dendritic Cells ◽

Protective Immunity ◽

Viral Infections ◽

Rna Virus ◽

Critical Role ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Mitochondrial Antiviral Signaling ◽

Phosphoinositide 3 Kinase

AbstractInnate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9.

Download Full-text

Alphaherpesvirus-induced activation of plasmacytoid dendritic cells depends on the viral glycoprotein gD and is inhibited by non-infectious light particles

PLoS Pathogens ◽

10.1371/journal.ppat.1010117 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1010117

Author(s):

Jonas L. Delva ◽

Cliff Van Waesberghe ◽

Barbara G. Klupp ◽

Thomas C. Mettenleiter ◽

Herman W. Favoreel

Keyword(s):

Dendritic Cells ◽

Pseudorabies Virus ◽

Viral Infections ◽

Critical Role ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Viral Glycoprotein ◽

Dna Viruses ◽

Endosomal Acidification ◽

Simplex Virus

Plasmacytoid dendritic cells (pDC) are important innate immune cells during the onset of viral infections as they are specialized in the production of massive amounts of antiviral type I interferon (IFN). Alphaherpesviruses such as herpes simplex virus (HSV) or pseudorabies virus (PRV) are double stranded DNA viruses and potent stimulators of pDC. Detailed information on how PRV activates porcine pDC is lacking. Using PRV and porcine primary pDC, we report here that PRV virions, so-called heavy (H-)particles, trigger IFNα production by pDC, whereas light (L-) particles that lack viral DNA and capsid do not. Activation of pDC requires endosomal acidification and, importantly, depends on the PRV gD envelope glycoprotein and O-glycosylations. Intriguingly, both for PRV and HSV-1, we found that L-particles suppress H-particle-mediated activation of pDC, a process which again depends on viral gD. This is the first report describing that gD plays a critical role in alphaherpesvirus-induced pDC activation and that L-particles directly interfere with alphaherpesvirus-induced IFNα production by pDC.

Download Full-text

TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation

Life Science Alliance ◽

10.26508/lsa.202101067 ◽

2021 ◽

Vol 5 (2) ◽

pp. e202101067

Author(s):

Atsuko Wakabayashi ◽

Masanori Yoshinaga ◽

Osamu Takeuchi

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Critical Role ◽

Vascular Endothelial Cell ◽

Diffuse Alveolar Hemorrhage ◽

Negative Regulator ◽

Alveolar Hemorrhage ◽

Type I ◽

Systemic Lupus ◽

Cytoplasmic Dna

Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is mediated by type I IFN signaling, but not IL-6. We further uncover that STING, an adaptor essential for the signaling of cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), plays a critical role in DAH under Tank deficiency. TANK controls cGAS-mediated cGAMP production and suppresses DNA-mediated induction of IFN-stimulated genes in macrophages by inhibiting the formation of DNA-cGAS aggregates containing ubiquitin. Collectively, TANK inhibits the cGAS-dependent recognition of cytoplasmic DNA to prevent fatal DAH in the murine lupus model.

Download Full-text

PINK1 Mediates the Protective Effects of Thyroid Hormone T3 in Hyperoxia-induced Lung Injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00598.2020 ◽

2021 ◽

Author(s):

Yi Zhang ◽

Guoying Yu ◽

Naftali Kaminski ◽

Patty Lee

Keyword(s):

Thyroid Hormone ◽

Lung Injury ◽

Critical Role ◽

Protective Role ◽

Type I ◽

Dependent Manner ◽

Protective Effects ◽

Cell Counts ◽

Hyperoxia Exposure ◽

Cellular Bioenergetics

Introduction: Hyperoxia can lead to respiratory failure and death. Our previous work demonstrates that oxidant and mitochondrial injury plays a critical role in hyperoxia-induced acute lung injury (HALI). Recently, thyroid hormone has been demonstrated to promote mitochondrial survival in other models of lung injury, but its role in hyperoxia is unknown. Methods: Adult WT mice were pretreated with nebulized triiodothyronine (T3, 40 μg/kg) for 1 or 3 days, or with propylthiouracil (PTU, 100 μg/kg), for 3 days. Following pretreatment, WT mice underwent 72 hours of hyperoxia exposure. WT and PINK1-/- mice were pretreated with nebulized T3 (40 μg/kg) for 3 days or no pretreatment prior to 72h continuous hyperoxia exposure. Bronchoalveolar lavage (BAL), histological changes in cellular composition, and type I cytokine induction were assessed. Lung lysates for mitochondrial cellular bioenergetics markers were analyzed by Western blot. Results: Hyperoxia caused a significant increase in BAL total cell counts and lung cellular infiltrates. Administration of PTU enhanced HALI, while T3 attenuated HALI, inflammation, and oxidants in WT mice. T3 pretreatment increased mitochondrial biogenesis/fusion/mitophagy and decreased ER stress and apoptosis. PINK1-/- mice were more susceptible to hyperoxia than WT mice. Notably, pretreatment with T3 did not attenuate HALI in PINK1-/- mice. T3 pretreatment also increased mitochondrial anti-ROS potential, improved mitochondrial bioenergetics and mitophagy, and attenuated mitochondria-regulated apoptosis, all in a PINK1-dependent manner. Conclusions: Our results highlight a novel protective role for PINK1 in mediating the cytoprotective effects of thyroid hormone in HALI. Therefore, thyroid hormone may represent a potential therapy for ALI.

Download Full-text