Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor

Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor. [Image: see text

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Predição da composição corporal e exigências líqüidas de macrominerais para ganho de peso de chinchila (Chinchilla lanigera) Body composition prediction and net macroelements requirements (Chinchilla lanigera)

Foram determinados os conteúdos corporais e as exigências líquidas para ganho de peso de corpo vazio e ganho de peso vivo em matéria mineral (MM), fósforo (P), potássio (K) e magnésio (Mg) para a espécie (Chinchilla lanigera). Foram abatidos 18 animais (seis machos e seis fêmeas em média com 750 dias de idade e seis animais juvenis de 40 dias de vida). Foi feito um teste de comparação de médias para as composições das diferentes categorias animal. Foram ajustadas equações logarítmicas da quantidade corporal de MM, P, K e Mg, em função do logaritmo do peso corporal vazio. As exigências líquidas em MM, P, K e Mg foram obtidas por derivação das equações de predição da composição corporal. As proporções corporais de matéria seca e de matéria mineral alteraram-se com o avanço da idade das chinchilas. Os animais juvenis apresentaram (P<0,05) menor percentual de matéria seca e maior percentual de matéria mineral quando comparados com os adultos. O conteúdo corporal e as exigências líquidas de MM, P, K e Mg para ganho de peso de corpo vazio e ganho de peso vivo, aumentaram quando o peso vivo dos animais variou entre 100 e 400 g, mantendo-se constante a partir deste peso.<br>Body composition and net requirements for empty body weight gain for mineral matter (MM), Phosphorous (P), potassium (K) and magnesium for chinchilla were determined. Eighteen animals (6 males, 6 females, 750 days old and six young animals 40 days old) were slaughtered. Minerals body content of different animals categories were compared and logarithmic equations were adjusted between minerals content and empty body weight. Body composition and net requirements for empty body weight gain for mineral matter (MM), Phosphorous (P), potassium (K) and magnesium for chinchilla were determined. Eighteen animals (6 males, 6 females, 750 days old and six young animals 40 days old) were slaughtered. Minerals body content of different animals categories were compared and logarithmic equations were adjusted between minerals content and empty body weight. Net requirements for MM, P, K and Mg were estimated through derivation of these equations. The body concentrations of dry and mineral matter changed with age. Younger animals had lower concentration of dry matter and higher concentration of minerals than the adults did. The body content and net requirements for empty body weight gain of MM, P, K and Mg increased as body weight varied from 100 to 400 g, remaining constant afterwards