Caspases and therapeutic potential of caspase inhibitors in moderate–severe SARS‐CoV‐2 infection and long COVID

Plassmeyer, Matthew; Alpan, Oral; Corley, Michael J.; Premeaux, Thomas A.; Lillard, Kimberleigh; Coatney, Paige; Vaziri, Tina; Michalsky, Suzan; Pang, Alina P.S.; Bukhari, Zaheer; Yeung, Stephen T.; Evering, Teresa H.; Naughton, Gail K.; Latterich, Martin; Mudd, Philip A.; Spada, Alfred P.; Rindone, Nicole; Loizou, Denise; Sønder, Søren Ulrik; Ndhlovu, Lishomwa C.; Gupta, Raavi

doi:10.1111/all.14907

Cited by 45 publications

(51 citation statements)

References 86 publications

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“…Among the top Δβ-value methylation changes comparing pre- and post-COVID-19 timepoints, we observed two differentially methylated loci (cg02037503 and cg23712970) in a gene promoter transcription start site regulatory region of the apoptotic chromatin condensation inducer 1 ( ACIN1 ) gene Supplementary Figure S2 that decreased in DNA methylation following COVID-19 by approximately 15% for both CpG sites ( Fig.1d,e ). This gene codes a nuclear protein that induces apoptotic chromatin condensation after activation by caspase-3 (Sahara et al, 1999), which we previously reported was increased in red blood cells of hospitalized COVID-19 participants (Plassmeyer et al, 2021). We also observed differential methylation at cg10846936 related to the caspase recruitment domain family member 14 ( CARD14 ) gene that is involved in activating nuclear factor-kappa-B involved in immune inflammation.…”

Section: Resultsmentioning

confidence: 99%

Longitudinal study of DNA methylation and epigenetic clocks prior to and following test-confirmed COVID-19 and mRNA vaccination

Pang

Higgins‐Chen

Comite

et al. 2021

Preprint

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The host epigenetic landscape is rapidly changed during SARS-CoV-2 infection and evidence suggests that severe COVID-19 is associated with durable scars to the epigenome. Specifically, aberrant DNA methylation changes in immune cells and alterations to epigenetic clocks in blood relate to severe COVID-19. However, a longitudinal assessment of DNA methylation states and epigenetic clocks in blood from healthy individuals prior to and following test-confirmed non-hospitalized COVID-19 has not been performed. Moreover, the impact of mRNA COVID-19 vaccines upon the host epigenome remains understudied. Here, we first examined DNA methylation states in blood of 21 participants prior to and following test confirmed COVID-19 diagnosis at a median timeframe of 8.35 weeks. 261 CpGs were identified as differentially methylated following COVID-19 diagnosis in blood at an FDR adjusted P value <0.05. These CpGs were enriched in gene body and northern and southern shelf regions of genes involved in metabolic pathways. Integrative analysis revealed overlap among genes identified in transcriptional SARS-CoV-2 infection datasets. Principal component-based epigenetic clock estimates of PhenoAge and GrimAge significantly increased in people over 50 following infection by an average of 2.1 and 0.84 years. In contrast, PCPhenoAge significantly decreased in people under 50 following infection by an average of 2.06 years. This observed divergence in epigenetic clocks following COVID-19 was related to age and immune cell-type compositional changes in CD4+ T cells, B cells, granulocytes, plasmablasts, exhausted T cells, and naïve T cells. Complementary longitudinal epigenetic clock analyses of 36 participants prior to and following Pfizer and Moderna mRNA-based COVID-19 vaccination revealed vaccination significantly reduced principal component-based Horvath epigenetic clock estimates in people over 50 by an average of 3.91 years for those that received Moderna. This reduction in epigenetic clock estimates was significantly related to chronological age and immune cell-type compositional changes in B cells and plasmablasts pre- and post-vaccination. These findings suggest the potential utility of epigenetic clocks as a biomarker of COVID-19 vaccine responses. Future research will need to unravel the significance and durability of short-term changes in epigenetic age related to COVID-19 exposure and mRNA vaccination.

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Section: Resultsmentioning

confidence: 99%

Longitudinal study of DNA methylation and epigenetic clocks prior to and following test-confirmed COVID-19 and mRNA vaccination

Pang

Higgins‐Chen

Comite

et al. 2021

Preprint

Self Cite

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“…These observations point out to an immunological basis in the different course of the disease according to gender [37], and it could be theorized that these characteristics -the strong CD8 T-cell response, as well as the activation of TLRs and the inflammasome [39]-, are likely involved in the differences by sex observed in PCS.…”

Section: Pcs and Gendermentioning

confidence: 97%

Post-Covid-19 Syndrome, Inflammatory Markers and Sex Differences

Maamar

Artime²,

Rodrigo

et al. 2021

Preprint

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INTRODUCTION AND OBJECTIVEPost-COVID syndrome (PCS) is a poorly-known entity. Underlying low-grade inflammation (LGI) has been theorized as one of its pathophysiological mechanisms. We aimed to investigate a possible relationship between PCS and an increase in inflammation markers, in a sex-stratified analysis.PARTICIPANTS AND METHODSMild cases of COVID-19 according to the WHO classification followed-up in a Primary Care Center, were included. We collected epidemiological data (age, sex, body mass index -BMI-, smoking, and comorbidities -Charlson index-), variables of the acute COVID-19 episode, and data at 3 months of follow-up (clinical manifestations and inflammatory markers). Serum C-reactive protein (CRP), neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), ferritin, fibrinogen, and D-dimer levels were analyzed. Low-grade inflammation (LGI) was defined as serum CRP between >0.3 and <1.0 mg/dL. Five composite indices were built combining the upper ranges of 4 markers. Bivariate and multivariate analyses (logistic regression and general linear models) were performed, stratified by sex.RESULTSWe analyzed 121 subjects with mild COVID-19 (56.2% women; mean age 46 years). The most common symptom in the acute episode was fever (60.3%), while it was fatigue in PCS (42.8%). Prevalence of PCS was 35.8% in women and 20.8% in men (p = 0.07).In women, after controlling for age, BMI, smoking, and comorbidities, the D1, D3, and D4 indices were consistently associated with PCS, with ORs of 5.14 (95% CI, 1.6-16.4), 4.20 (95% CI, 1.3-13.3), and 4.12 (95% CI, 1.3-13.1), respectively; in patients with post-COVID anosmia and ageusia, neutrophils were significantly elevated (3.43±0.3 vs 2.58±0.1; p = 0.014, and 3.89±0.3 vs 2.59±0.1; p = 0.002,respectively), after adjusting for confounders.In men, the D2 and D5 indices were associated with PCS, with adjusted ORs of 10.1 (95% CI, 1.2-85) and 17.5 (95% CI, 2-153), respectively. Furthermore, serum CRP in the LGI range was associated with PCS [adjusted OR=12.9 (95% CI, 1.3-121)], and in post-COVID persistent fatigue, the neutrophil count was significantly elevated (4.68±0.6 vs 3.37±0.1; p = 0.041), after controlling for confounders.CONCLUSIONSConsistent associations among PCS, anosmia, ageusia, and fatigue, with slight -but significant-elevated levels of inflammatory markers, have been observed. The neutrophil count was the most frequently involved marker. Sex-stratified analyses showed relevant differences between women and men concerning PCS and serum inflammatory markers.

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“…Endothelial dysfunction, small vessel microangiopathy, fibrin clotting within small capillaries may also contribute to decreased effective oxygen carrying capacity and contribute to shortness of breath and exercise intolerance 64 . A hyperinflammatory syndrome with persistent immune activation and dysregulation of the immune response has also been suggested as a possible mechanism for some of the symptoms 65 , 66 . The histopathological detection of autoreactive T cells in autopsy samples from individuals infected with COVID-19 supports this latter mechansim 67 , 68 .…”

Section: Pathophysiologymentioning

confidence: 99%