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

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 & Computational Biology, School of Science, Edith Cowan University, Joondalup, 6027, Australia.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.
Jieun 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

medRxiv : the preprint server for health sciences

Abstract

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, 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. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.

DOI

10.1101/2020.09.06.20189159

Publication Date

9-8-2020

Identifier

32935119 (pubmed); PMC7491534 (pmc); 10.1101/2020.09.06.20189159 (doi); 2020.09.06.20189159 (pii)

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