In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach

Abstract Background COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic to mild or moderate symptoms, reaching the most severe forms and death. The mechanisms underlying the SARS-CoV-2 infection and its clinical evolution are still unclear. Once SARS-CoV-2 infects individuals, host factors are activated by the presence of the virus inside the cells, such as the inflammasome system. The search of risk factors for COVID-19 is of relevance for clinical management. In this study, we investigated the impact of 11 single-base polymorphisms (SNPs) in the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1β inflammasome genes in SARS-CoV-2 infected individuals with distinct disease outcomes. Methods Patients were divided into two groups: (1) inpatients, with severe/critical disease (Hospitalized group, n=451), and (2) convalescent volunteers with prior SARS-CoV-2 infection and a history of asymptomatic to mild symptoms (Mild group, n=43). Patients hospitalized were followed up at a Hospital Center for COVID-19 Pandemic – National Institute of Infectology (INI)/FIOCRUZ, Rio de Janeiro, Brazil, from June 2020 to March 2021. The Mild group was recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, Rio de Janeiro, Brazil, in 2020. Genotyping of the SNPs was determined by Real-Time PCR. Protection and risk estimations were performed by unconditional logistic regression models. Results Among the genotyped SNPs, significant differences in the NLRP3 rs1539019 and rs10754558 frequencies were observed between the groups. The C/C genotype (ORadj=6.31; Padj=0.026) or allele C (ORadj=1.05; Padj=0.002) in rs1539019 polymorphism were associated with the risk for hospitalization, while the C/G genotype (ORadj=0.16; Padj=0.016) or carrier-G (ORadj=0.2; Padj=0.028) in rs10754558 polymorphism were associated with protection for hospitalization. Regarding the NLRP3 genetic variants, the A-C-G-C-G haplotype (ORadj=0.14; Padj= 0.030) was associated with protection for hospitalization. No significant association was observed for the other polymorphisms. Conclusions As of our knowledge, this is the first study demonstrating the association of inflammasome NLRP3 variants with risk and/or protection for hospitalization in COVID-19. Studies linking the NLRP3 inflammasome and SARS-CoV-2 infection are still scarce due to the recent emergence of this pathogen. Our results contribute to the discussion of the impact of inflammasomes in the clinical evolution of COVID-19.

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Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.141529 ◽

2015 ◽

Vol 42 (10) ◽

pp. 1740-1745 ◽

Cited By ~ 9

Author(s):

Alf Kastbom ◽

Lisbeth Ärlestig ◽

Solbritt Rantapää-Dahlqvist

Keyword(s):

Rheumatoid Arthritis ◽

Angina Pectoris ◽

Nlrp3 Inflammasome ◽

Genetic Variants ◽

Protein Complexes ◽

Increased Risk ◽

Variant Alleles ◽

Traditional Risk Factors ◽

Cv Disease ◽

Ischemic Attack

Objective.Inflammasomes are intracellular protein complexes important for the production of pro-inflammatory cytokines. Studies have suggested that the NLRP3 inflammasome influences both the severity of rheumatoid arthritis (RA) and development of atherosclerosis. Therefore, we investigated whether functional genetic variants related to the NLRP3 inflammasome influence the risk of cardiovascular (CV) disease (CVD) in patients with RA.Methods.The incidence of CVD was assessed in 522 patients with established RA by a retrospective survey of medical records in combination with a 6-year prospective followup. NLRP3-Q705K and CARD8-C10X genotypes were analyzed in relation to CVD by logistic regression, adjusting for traditional risk factors, antirheumatic treatment, and age at the onset of RA.Results.Carriage of the NLRP3-Q705K minor allele was associated with an increased risk of stroke/transient ischemic attack (TIA; OR 2.01, 95% CI 1.0–4.1, p = 0.05), while CARD8-C10X was not associated with any type of CV event. Patients with ≥ 1 variant allele in both polymorphisms had an increased risk of CVD when compared with patients without variant alleles present in both polymorphisms (adjusted OR 3.05, 95% CI 1.42–6.54, p = 0.004). Stratification showed that this risk was confined to stroke/TIA (adjusted OR 5.09, 95% CI 2.27–11.44, p < 0.0001) and not to myocardial infarction (MI)/angina pectoris (adjusted OR 1.58, 95% CI 0.67–3.73). Risk estimates were consistently higher among female patients.Conclusion.Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in Swedish patients with established RA.

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In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

10.1101/2021.09.26.21264127 ◽

2021 ◽

Author(s):

Michael Maes ◽

Walton Luiz Del Tedesco Junior ◽

Marcell Lozovoy ◽

Mayara Mori ◽

Tiago Danelli ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Gastrointestinal Symptoms ◽

Diabetes Type 2 ◽

Protective Role ◽

Partial Least Squares Analysis ◽

Mild Disease ◽

Increase Risk ◽

Symptom Complex

Background: In COVID-19, the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is a highly conserved symptom complex that protects against infections and hyperinflammation. Aims: To examine the associations of COVID-19, SSC and the NLPR3 rs10157379 T>C and NLPR3 rs10754558 C>G SNV variants; and the protective role of SSC in severe acute respiratory syndrome (SARS)-CoV-2 infection. Methods: We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Results: Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly predict reduced SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows a) that 41.8% of the variance in critical COVID-19 symptoms could be explained by SSC and oxygen saturation (inversely associated), and inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia, dysgeusia and gastrointestinal symptoms. Conclusions: Intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in individuals with reduced SSC, elderly people, and those with increased BMI, hypertension, and diabetes type 2. SSC is a new drug target to combat acute COVID-19.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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The Collaborative Network Approach: a model for advancing patient-centric research for Castleman disease and other rare diseases

Emerging Topics in Life Sciences ◽

10.1042/etls20180178 ◽

2019 ◽

Vol 3 (1) ◽

pp. 97-105

Author(s):

Mary Zuccato ◽

Dustin Shilling ◽

David C. Fajgenbaum

Keyword(s):

Rare Diseases ◽

Treatment Options ◽

Castleman Disease ◽

High Impact ◽

Collaborative Network ◽

Network Approach ◽

Grant Applications ◽

Research Questions ◽

Novel Strategy ◽

Patient Centric

Abstract There are ∼7000 rare diseases affecting 30 000 000 individuals in the U.S.A. 95% of these rare diseases do not have a single Food and Drug Administration-approved therapy. Relatively, limited progress has been made to develop new or repurpose existing therapies for these disorders, in part because traditional funding models are not as effective when applied to rare diseases. Due to the suboptimal research infrastructure and treatment options for Castleman disease, the Castleman Disease Collaborative Network (CDCN), founded in 2012, spearheaded a novel strategy for advancing biomedical research, the ‘Collaborative Network Approach’. At its heart, the Collaborative Network Approach leverages and integrates the entire community of stakeholders — patients, physicians and researchers — to identify and prioritize high-impact research questions. It then recruits the most qualified researchers to conduct these studies. In parallel, patients are empowered to fight back by supporting research through fundraising and providing their biospecimens and clinical data. This approach democratizes research, allowing the entire community to identify the most clinically relevant and pressing questions; any idea can be translated into a study rather than limiting research to the ideas proposed by researchers in grant applications. Preliminary results from the CDCN and other organizations that have followed its Collaborative Network Approach suggest that this model is generalizable across rare diseases.

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