Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients

Zhang, Hongliang; Tang, Yujie; Tao, Jin‐Hui

doi:10.3389/fmolb.2021.671363

Cited by 17 publications

(22 citation statements)

References 114 publications

(117 reference statements)

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“…Previously, it was shown that the male sex predicts death with an OR = 1.46 (95% CI 1.31–1.62) [ 41 ]. It is important to note that in male COVID-19 patients overactivation of the NLRP3 inflammasome is accompanied by increased lethality [ 43 ]. Higher plasma levels of IL-8 and IL-18 as well as stronger induction of non-classical monocytes are seen in male COVID-19 patients [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), 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 and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, 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 elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…Previously, it was shown that male sex predicts death with an OR=1.46 (95% CI 1.31-1.62) [38]. It is important to note that in male COVID-19 patients overactivation of the NLRP3 inflammasome is accompanied by increased lethality [40]. Higher plasma levels of IL-8 and IL-18 as well as stronger induction of non-classical monocytes are seen in male COVID-19 patients [41].…”

Section: Discussionmentioning

confidence: 99%

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

Maes

Tedesco

Lozovoy

et al. 2021

Preprint

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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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“…Ratajczak et al demonstrated in human cells that Ang II ameliorated the activation of the NLRP3 inflammasome after interaction with SARS‐CoV‐2 S protein 55 . These features are summarized concisely by Zhang et al and include a SARS‐CoV‐2‐mediated decrease in Ang‐(1‐7), weakening the inhibition of the NLRP3 inflammasome and concurrently Ang II by way of AT 1 R activating the NLRP3 inflammasome 57 …”

Section: The Migration Of Sars‐cov‐2 To Vectors and To The Humanmentioning

confidence: 99%

“…In lung fibroblasts, Ang-( 1-7) has an inhibitory effect on the Ang II-induced NLRP3 inflammasome through intermediates. 54 57 In summary, it is the dampening of primary immune cells involving the inflammasome in asymptomatic viral reservoirs that is like the initial upper airway infection in COVID-19 disease in the human and this contrasts vividly with the hyper inflammatory state induced in the human lower respiratory tract with SARS-CoV-2.…”

Section: Thus Host Regulation Of the Physiological Consequences Of Vi...mentioning

confidence: 99%

Systems analysis shows that thermodynamic physiological and pharmacological fundamentals drive COVID‐19 and response to treatment

Head

Lumbers

Jarrott

et al. 2022

Pharmacology Res & Perspec

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Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID‐19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID‐19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID‐19 in an individual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID‐19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS‐CoV‐2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS‐CoV‐2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS‐CoV‐2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS‐CoV‐2 infection.

show abstract

Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients

Cited by 17 publications

References 114 publications

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

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

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

Systems analysis shows that thermodynamic physiological and pharmacological fundamentals drive COVID‐19 and response to treatment

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