Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10) and small HDL particles (p=6.0x10) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.PID2020-116146RB-I00 from the Ministerio de Ciencia e Innovación with European Regional Development Funds (FEDER), BMD-3724 from the Comunidad de Madrid, 202020E169 from the CSIC, 2020PANDE00082 from the Generalitad de Cataluña and Fundación Hay Esperanza

Regulation of zinc homeostatic genes by environmental pH in the filamentous fungus Aspergillus fumigatus

Aspergillus fumigatus can grow over a broad range of pH values even though zinc availability is greatly conditioned by ambient pH. It has been previously shown that regulation of zinc homeostatic genes in this fungus relies on the transcription factor ZafA. In addition, their expression is further modulated by the transcription factor PacC depending on ambient pH, which allows this fungus to grow in diverse types of niches, including soils and the lungs of immunosuppressed hosts. In this work the regulation by PacC of genes zrfB and zrfC that are expressed, respectively, under acidic and alkaline zinc-limiting conditions have been analysed in detail. Thus, data that extend the current model for PacC function, including the role of the full-length PacC72 protein and the PacC processed forms (PacC53 and PacC27 ) on gene expression has been provided, and a new mechanism for the repression of acid-expressed genes in alkaline media based on interference with the start of transcription has been described. Moreover, it was proposed that the transcription of both acid-expressed and alkaline-expressed genes under zinc-limiting conditions might also rely on a third factor (putatively Pontin/Reptin), which may be required to integrate the action of PacC and ZafA into gene specific transcriptional responses.This work was supported by the Ministerio de Ciencia e Innovación (Spain) and Consejería de Educación de la Junta de Castilla y León (Spain) through grants PID2019-110994RB-I00 and SA020G18, respectively, awarded to JAC. HT was supported through a predoctoral contract from the Program III of the Universidad de Salamanca (Salamanca, Spain) funded by the Banco Santander (Spain). CIS was supported by a fellowship from the Universidad Industrial de Santander (Bucaramanga, Colombia) through resolution n° 2604 (December, 2014)