Kynurenic acid may underlie sex-specific immune responses to COVID-19

Authors

Yuping Cai, Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.Follow
Daniel J. Kim, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.Follow
Takehiro Takahashi, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
David I. Broadhurst, Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Joondalup 6027, Australia.Follow
Hong Yan, Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.Follow
Shuangge Ma, Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA.
Nicholas J. Rattray, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.Follow
Arnau Casanovas-Massana, Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA.
Benjamin Israelow, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Jon Klein, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Carolina Lucas, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.Follow
Tianyang Mao, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Adam J. Moore, Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA.Follow
M Catherine Muenker, Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA.
Ji Eun Oh, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Julio Silva, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Patrick Wong, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

Document Type

Article

Publication Title

Science signaling

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.

DOI

10.1126/scisignal.abf8483

Publication Date

7-6-2021

Recommended Citation

Cai, Yuping; Kim, Daniel J.; Takahashi, Takehiro; Broadhurst, David I.; Yan, Hong; Ma, Shuangge; Rattray, Nicholas J.; Casanovas-Massana, Arnau; Israelow, Benjamin; Klein, Jon; Lucas, Carolina; Mao, Tianyang; Moore, Adam J.; Muenker, M Catherine; Oh, Ji Eun; Silva, Julio; and Wong, Patrick, "Kynurenic acid may underlie sex-specific immune responses to COVID-19" (2021). Surgery. 215.
https://scholar.bridgeporthospital.org/surgery/215

Identifier

34230210 (pubmed); PMC8432948 (pmc); 10.1126/scisignal.abf8483 (doi); 14/690/eabf8483 (pii)