Kynurenic acid underlies sex-specific immune responses to COVID-19

Dr. Caroline H Johnson
Dr. Caroline H Johnson

Environmental Health Sciences, Yale School of Public Health
60 College Street New Haven, CT 06520-8034

Hospitals involved

Yale New Haven Hospital

Type of analysis

In this project, we sought to identify metabolites that correlate with immune responses in COVID-19 patients. As the male sex is a risk factor for COVID-19 severity and morbidity, we also examined the sex-specificity of these responses. Using serum obtained from COVID-19 patients (n=22 females and n=17 males) and uninfected healthcare worker (HCW) controls (n=10 females and n=10 males), we first positively identified 75 metabolites in quality control samples pooled from all individuals in the study. We then carried out Spearman correlation analyses between the metabolites and previously measured immune markers from the same individuals. We observed that kynurenic acid (KA), and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. We also carried out logistic regression revealing that 17 metabolites were associated with COVID-19 status after adjustment for age, BMI, sex, and multiple comparison. Of these 17 metabolites, we observed that glutamate was lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses, of note, KA is known to inhibit glutamate release. We then analyzed Genotype-Tissue Expression (GTEx) data which revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. Sex-specific agonism of AhR has yet to be reported in humans, but appears to be a prominent feature in COVID-19 disease, potentially underlying the cytokine storm and dampening of T cell activation. Therefore our study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.






Protocol used