Abstract
Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.
Highlights
Patients with severe COVID-19 disease experience a “cytokine storm,” which is characterized by an increase in the amount of proinflammatory cytokines and an aggressive inflammatory response [12], and sex specificity in the immune response has been previously reported that could underlie these differences in clinical outcomes [1]
A previous study revealed that plasma metabolites in tryptophan and K metabolism correlated with IL-6 abundance in a sex-aggregated cohort of COVID-19 patients, but sex specificity was not examined [13]
A negative association was observed with the amounts of eotaxin, sCD40L, and PDGFs and the numbers of T cells, indicating that males with a high kynurenic acid (KA):K may have a poorer response to inflammation associated with COVID-19, including decreased eosinophil recruitment and T cell activation [14, 15]
Summary
Sex-related differences in coronavirus disease 2019 (COVID-19) severity and morbidity exist, with the male sex being a risk factor; compared to females, male COVID-19 patients have an increased risk of admission [odds ratio (OR), 1.68; 95% confidence interval (CI), 1.45 to 1.90] and in-hospital mortality (OR, 1.87; 95% CI, 1.33 to 2.63). Hospitalized patients with moderate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have increased amounts of inflammatory cytokines and chemokines, and sex differences exist in these immune responses [1]. Across all ages, female patients at baseline (when first admitted into hospital) have more robust T cell activation than males. Because immune responses are regulated, in part, by metabolites, it is possible that sex-related differences in metabolism could affect the host immune response to SARS-CoV-2 infection. Specific metabolites are required for macrophage, neutrophil, and T cell functions, enhancing glycolytic and fatty acid synthesis
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