Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections

Lisa M Bramer; Robert D Hontz; Amie J Eisfeld; Amy C Sims; Young-Mo Kim; Kelly G Stratton; Carrie D Nicora; Marina A Gritsenko; Athena A Schepmoes; Osamu Akasaka; Michiko Koga; Takeya Tsutsumi; Morio Nakamura; Ichiro Nakachi; Rie Baba; Hiroki Tateno; Shoji Suzuki; Hideaki Nakajima; Hideaki Kato; Kazunari Ishida; Makoto Ishii; Yoshifumi Uwamino; Keiko Mitamura; Vanessa L Paurus; Ernesto S Nakayasu; Isaac K Attah; Andrew G Letizia; Katrina M Waters; Thomas O Metz; Karen Corson; Yoshihiro Kawaoka; Vincent R Gerbasi; Hiroshi Yotsuyanagi; Kiyoko Iwatsuki-Horimoto

doi:10.1016/j.heliyon.2023.e13795

Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections

Heliyon. 2023 Mar;9(3):e13795. doi: 10.1016/j.heliyon.2023.e13795. Epub 2023 Mar 7.

Authors

Lisa M Bramer¹, Robert D Hontz², Amie J Eisfeld³, Amy C Sims¹, Young-Mo Kim¹, Kelly G Stratton¹, Carrie D Nicora¹, Marina A Gritsenko¹, Athena A Schepmoes¹, Osamu Akasaka⁴, Michiko Koga⁵, Takeya Tsutsumi⁵, Morio Nakamura⁶, Ichiro Nakachi⁷, Rie Baba⁷, Hiroki Tateno⁸, Shoji Suzuki⁸, Hideaki Nakajima⁹, Hideaki Kato⁹, Kazunari Ishida¹⁰, Makoto Ishii¹¹, Yoshifumi Uwamino¹², Keiko Mitamura¹³, Vanessa L Paurus¹, Ernesto S Nakayasu¹, Isaac K Attah¹, Andrew G Letizia², Katrina M Waters¹, Thomas O Metz¹, Karen Corson², Yoshihiro Kawaoka^{3

14

15}, Vincent R Gerbasi¹, Hiroshi Yotsuyanagi¹⁶, Kiyoko Iwatsuki-Horimoto¹⁷

Affiliations

¹ Pacific Northwest National Laboratory, Richland, WA, USA.
² U.S. Naval Medical Research Unit No. TWO (NAMRU-2), Singapore, Singapore.
³ Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.
⁴ Emergency Medical Center, Fujisawa City Hospital 2-6-1 Fujisawa, Fujisawa, Japan.
⁵ Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁶ Department of Pulmonary Medicine, Tokyo Saiseikai Central, Tokyo, Japan.
⁷ Pulmonary Division, Department of Internal Medicine, Utsunomiya Hospital, Utsunomiya, Japan.
⁸ Department of Pulmonary Medicine, Saitama City Hospital, Saitama, Japan.
⁹ Department of Hematology and Clinical Immunology, University School of Medicine, Yokohama, Japan.
¹⁰ Kobe Kaisei Hospital, Kobe, Japan.
¹¹ Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
¹² Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
¹³ Division of Infection Control, Eiju General Hospital, Tokyo, Japan.
¹⁴ Department of Microbiology and Immunology, Japan.
¹⁵ International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
¹⁶ Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo.
¹⁷ Division of Virology, Institute of Medical Science, University of Tokyo, Japan.

Abstract

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics and correlative analysis of an immunologically naïve SARS-CoV-2 clinical cohort from blood plasma of uninfected controls, mild, and severe infections. Consistent with previous observations, severe patient populations showed an elevation of pulmonary surfactant levels. Intriguingly, mild patients showed a statistically significant elevation in the carnosine dipeptidase modifying enzyme (CNDP1). Mild and severe patient populations showed a strong elevation in the metabolite L-cystine (oxidized form of the amino acid cysteine) and enzymes with roles in glutathione metabolism. Neutrophil extracellular traps (NETs) were observed in both mild and severe populations, and NET formation was higher in severe vs. mild samples. Our correlative analysis suggests a potential protective role for CNDP1 in suppressing PSPB release from the pulmonary space whereas NET formation correlates with increased PSPB levels and disease severity. In our discussion we put forward a possible model where NET formation drives pulmonary occlusions and CNDP1 promotes antioxidation, pleiotropic immune responses, and vasodilation by accelerating histamine synthesis.

Keywords: CNDP1; COVID-19; Carnosinase; Carnosine; Cystine; Glutathione; NETs; Neutrophils; ROS; SARS-CoV-2.