The MUC5B Promoter Polymorphism Associates With Severe COVID-19 in the European Population

Background: Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 may be related to the innate immune response in the elderly. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele is a risk allele for the non-infectious aging lung disease idiopathic pulmonary fibrosis (IPF). We investigated if MUC5B rs35705950 associates with severe COVID-19.Methods: In this retrospective candidate gene case-control study we recruited 108 Dutch patients (69% male, median age 66 years, 77% white) requiring hospitalization for COVID-19 (22% ICU stay, 24% died). For validation, genotypes were obtained from the UK-Biobank (n = 436, 57% male, median age 70 years, 27% died), for replication data from the severe COVID-19 GWAS group from Italy (n = 835) and Spain (n = 775) was used, each with a control cohort (n = 356,735, n = 1,255, n = 950, respectively). MUC5B association analysis was performed including adjustment for age and sex.Results: The rs35705950 T-allele frequency was significantly lower in Dutch white patients (n = 83) than in controls (0.04 vs. 0.10; p = 0.02). This was validated in the UK biobank cohort (0.08 vs. 0.11; p = 0.001). While age and sex differed significantly between cases and control, comparable results were obtained with age and sex as confounding variables in a multivariate analysis. The association was replicated in the Italian (p = 0.04), and Spanish (p = 0.03) case-control cohorts. Meta-analysis showed a negative association for the T-allele with COVID-19 (OR = 0.75 (CI: 0.67–0.85); p = 6.63 × 10−6).Conclusions: This study shows that carriage of the T-allele of MUC5B rs35705950 confers protection from development of severe COVID-19. Because the T-allele is a known risk allele for IPF, this study provides further evidence for the existence of trade-offs between optimal mucin expression levels in the aging lung.

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THE MUC5B PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19

10.1101/2020.05.12.20099333 ◽

2020 ◽

Cited By ~ 1

Author(s):

Coline H.M. van Moorsel ◽

Joanne J van der Vis ◽

Claudia Benschop ◽

Henk J.T. Ruven ◽

Marian Quanjel ◽

...

Keyword(s):

Immune Response ◽

Lung Disease ◽

Innate Immune Response ◽

Survival Data ◽

Risk Allele ◽

Promoter Polymorphism ◽

Innate Immune ◽

Allele Frequencies ◽

Expression Levels ◽

Trade Offs

Background Diversity in response to exposition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and may be related to the innate immune response. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele of rs35705950 is an accepted risk allele for a non-infectious aging lung disease called idiopathic pulmonary fibrosis (IPF). However, given the theory of trade-offs in aging lung disease and the importance of high expression for an adequate immune response, we hypothesize that the T-allele is protective against severe coronavirus disease 2019 (COVID-19). Methods We collected demographics, radiology, survival data and MUC5B rs35705950 allele status for 108 patients requiring hospitalisation for COVID-19 at St Antonius Hospital in The Netherlands. For comparison of allele frequencies and allele carriership with a white control cohort, the patient cohort was divided in a white (n=83) and non-white cohort. Results The patients had a median age of 66 years and consisted predominantly of males (74%) and 23 patients (21%) died. The T-allele frequencies of rs35705950 in white patients was 0.04 which was significantly lower than the T-allele frequency of 0.10 in white controls (p= 0.02). Moreover, comparison of the number of carriers and non-carriers of the T allele showed that only 8.4% of patients carried the T-allele versus 18% of controls (p=0.029; OR= 0.41, CI=0.19-0.94). Conclusions The MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for IPF is protective against the development of severe COVID-19 disease. This is a further example of a trade-off between optimal expression levels in the respiratory system which associates with aging diseases. However, these results require further investigation.

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Abstract A31: The two most potent PARP inhibitors increase expression levels of innate immune response genes in BRCA wild-type HGSC tumors

10.1158/1557-3265.ovca19-a31 ◽

2020 ◽

Author(s):

Monica Wielgos-Bonvallet ◽

Danhui Weng ◽

Petar Jelinic ◽

Douglas A. Levine

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Parp Inhibitors ◽

Innate Immune ◽

Wild Type ◽

Expression Levels ◽

Immune Response Genes

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The SIRT3 and SIRT6 Promote Prostate Cancer Progression by Inhibiting Necroptosis-Mediated Innate Immune Response

Journal of Immunology Research ◽

10.1155/2020/8820355 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Weiwei Fu ◽

Hong Li ◽

Haiyang Fu ◽

Shuchao Zhao ◽

Weiping Shi ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

Innate Immune Response ◽

Cancer Progression ◽

Nodal Metastasis ◽

Innate Immune ◽

Prostate Cancer Progression ◽

Class Iii ◽

Expression Levels ◽

Mrna And Protein Expression

The sirtuins (SIRTs), including seven family members, belong to class III histone deacetylase (HDAC) enzymes, which have been intensively investigated in cancers. Although the function of SIRTs in the cancer immunology is explored, SIRT-specific mechanisms regulating necroptosis-related innate immune response are not clear. In our present study, we found that both the mRNA and protein expression levels of SIRT3 and SIRT6 are significantly increased in the PCa tissues (HR, CI P = 3.30 E − 03 ; HR, CI P = 2.35 E − 08 ; and HR, CI P = 9.20 E − 08 ) and were associated with patients’ Gleason score and nodal metastasis. Furthermore, multivariate analysis showed that the PCa patients with higher expression levels of SIRT3 and SIRT6 had shorter overall survival (OS). Mechanistically, we found that SIRT3 and SIRT6 promote prostate cancer progress by inhibiting RIPK3-mediated necroptosis and innate immune response. Knockdown of both SIRT3 and SIRT6 not only activates TNF-induced necroptosis but also refreshes the corresponding recruitment of macrophages and neutrophils. Overall, our study identified that SIRT3 and SIRT6 are key regulators of necroptosis during prostate cancer progression.

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Differential Susceptibility and Innate Immune Response of Aedes aegypti and Aedes albopictus to the Haitian Strain of the Mayaro Virus

Viruses ◽

10.3390/v11100924 ◽

2019 ◽

Vol 11 (10) ◽

pp. 924 ◽

Cited By ~ 5

Author(s):

Diop ◽

Alout ◽

Diagne ◽

Bengue ◽

Baronti ◽

...

Keyword(s):

Immune Response ◽

Aedes Aegypti ◽

Innate Immune Response ◽

Aedes Albopictus ◽

Serine Proteases ◽

Early Stage ◽

Mosquito Species ◽

Innate Immune ◽

Expression Levels ◽

Npc1 Gene

Mayaro (MAYV) is an emerging arthropod-borne virus belonging to the Alphavirus genus of the Togaviridae family. Although forest-dwelling Haemagogus mosquitoes have been considered as its main vector, the virus has also been detected in circulating Aedes ssp mosquitoes. Here we assess the susceptibility of Aedes aegypti and Aedes albopictus to infection with MAYV and their innate immune response at an early stage of infection. Aedes albopictus was more susceptible to infection with MAYV than Ae. aegypti. Analysis of transcript levels of twenty immunity-related genes by real-time PCR in the midgut of both mosquitoes infected with MAYV revealed increased expression of several immune genes, including CLIP-domain serine proteases, the anti-microbial peptides defensin A, E, cecropin E, and the virus inducible gene. The regulation of certain genes appeared to be Aedes species-dependent. Infection of Ae. aegypti with MAYV resulted in increased levels of myeloid differentiation2-related lipid recognition protein (ML26A) transcripts, as compared to Ae. albopictus. Increased expression levels of thio-ester-containing protein 22 (TEP22) and Niemann–Pick type C1 (NPC1) gene transcripts were observed in infected Ae. albopictus, but not Ae. aegypti. The differences in these gene expression levels during MAYV infection could explain the variation in susceptibility observed in both mosquito species.

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DIFFERENCES IN THE EXPRESSION OF INNATE IMMUNE RESPONSE-MODULATING GENES IN BLOOD MONOCYTES BETWEEN SUBCLINICALLY PORCINE CIRCOVIRUS TYPE 2 (PCV2)-INFECTED AND PCV2-FREE PIGS PRIOR TO AND AFTER LIPOPOLYSACCHARIDE STIMULATIONIN VITRO

Taiwan Veterinary Journal ◽

10.1142/s168264851450005x ◽

2014 ◽

Vol 40 (01) ◽

pp. 37-48

Author(s):

Yi-Chieh Tsai ◽

Chian-Ren Jeng ◽

Chih-Cheng Chang ◽

Shih-Hsuan Hsiao ◽

Hui-Wen Chang ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Secondary Infection ◽

Porcine Circovirus Type ◽

Innate Immune ◽

Porcine Circovirus ◽

Blood Monocytes ◽

Expression Levels ◽

Tnf Α

The objective of the present study was to characterize and compare the differences in gene expression associated with innate immune response of blood monocytes (Mos) between healthy subclinically PCV2-infected and PCV2-free pigs prior to and after lipopolysaccharide (LPS) stimulation in vitro by relative quantitative real-time PCR (q-rt-PCR). Genes coding for 24 innate molecules, including toll-like receptors (TLRs), interferon-regulatory factors (IRFs), nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) and pro-inflammatory cytokines were evaluated. When compared with PCV2-free pigs, Mos from subclinically PCV2-infected pigs showed significantly lower mRNA expression levels in TLR-9, IRF-3, IRF-6, IRF-7, IL-6, IL-12p35, IL-12p40 and IFN-α under no further stimulation. Following LPS stimulation in vitro, a broad and/or obvious reduction in TLRs, IRFs, IL-12 and IFN-α along with increase in IL-1α, IL-6, IL-8, IL-10 and/or TNF-α were seen in both PCV2-free and subclinically PCV2-infected pigs; when compared with PCV2-free pigs, the subclinically PCV2-infected pigs had significantly higher expression levels in TLR-10 and IRF-1 but lower expression levels in IRF-6, IL-1α and IL-12p40. On the contrary, the expression level of NF-κB was consistently higher in subclinically PCV2-infected pigs than in PCV2-free pigs with or without LPS stimulation. The changes seen in the present study suggest that the subclinically PCV2-infected pigs may look healthy clinically, but their innate immunity has become dis-regulated or is in an improper status. The adverse condition may become even worse when exposed to certain bacterial products such as endotoxin. Such alterations in the innate immune system may make the subclinically PCV2-infected pigs more vulnerable to the secondary infection and subsequent PCV2-associated disease development.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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