@article{e711ebb3e2664a8d9774099cd3bf0bdc,
title = "Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections",
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 na{\"i}ve 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",
author = "Bramer, {Lisa M.} and Hontz, {Robert D.} and Eisfeld, {Amie J.} and Sims, {Amy C.} and Kim, {Young Mo} and Stratton, {Kelly G.} and Nicora, {Carrie D.} and Gritsenko, {Marina A.} and Schepmoes, {Athena A.} and Osamu Akasaka and Michiko Koga and Takeya Tsutsumi and Morio Nakamura and Ichiro Nakachi and Rie Baba and Hiroki Tateno and Shoji Suzuki and Hideaki Nakajima and Hideaki Kato and Kazunari Ishida and Makoto Ishii and Yoshifumi Uwamino and Keiko Mitamura and Paurus, {Vanessa L.} and Nakayasu, {Ernesto S.} and Attah, {Isaac K.} and Letizia, {Andrew G.} and Waters, {Katrina M.} and Metz, {Thomas O.} and Karen Corson and Yoshihiro Kawaoka and Gerbasi, {Vincent R.} and Hiroshi Yotsuyanagi and Kiyoko Iwatsuki-Horimoto",
note = "Funding Information: We thank Dr. Timothy J. Garrett at the University of Florida for sharing metabolite standard formulations. We thank Michael Perkins for assistance with generating figures. We thank Eisuke Adachi, Makoto Saito, and Hiroyuki Nagai at Institute of Medical Science of the University of Tokyo, Takayuki Ogura at Saiseikai Utsunomiya Hospital, Naoki Hasegawa, Tomoyasu Nishimura, and Katsunori Masaki at Keio University School of Medicine, Takahide Kikuchi, Daisuke Taniyama, and Kazuto Itoh at Saiseikai Central Hospital, and Shuichi Yoshida and Isano Hase at Saitama City Hospital for assistance with preparing clinical samples. VRG was supported by the Biomedical Resilience and Readiness in Adverse Operating Environment Initiative at PNNL . This work was supported by the National Security Mission Seed , under the Laboratory Directed Research and Development ( LDRD ) Program at Pacific Northwest National Laboratory ( PNNL ). PNNL is a multi-program national laboratory operated for the U.S. Department of Energy ( DOE ) by Battelle Memorial Institute under Contract No. DE-AC05-76RL01830 . Sample testing and data analysis was funded by the U.S. Department of Defense's Joint Program Executive Office ( JPEO ) COVID-19 FY20/21 CARES Act to U.S. Naval Medical Research Unit TWO (NAMRU-2) via Naval Medical Research Center (Appropriation: 9700130 , JON: SW713 ). These funds were transferred via two Military Interagency Purchase Requests (MIPRs) from NAMRU-2 to PNNL ( MIPRN6281420MPNX005 , MIPRN6281421MPNX003 ) under a Memorandum of Agreement between the U.S. Departments of Defense and Energy (MOA; USA000707-13-DPAP dtd May 01, 2013 ).The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. RDH, KC, and AGL are military Service member or employees of the United States Government. This work was prepared as part of their official duties. Title 17, U.S.C., §105 provides that {\textquoteleft}copyright protection under this title is not available for any work of the United States Government.{\textquoteright} Title 17, U.S.C., §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. The study protocol was approved by the University of Wisconsin Health Sciences Institutional Review Board (IRB protocol # 2015-0802-CR006 ) in compliance with all applicable federal regulations governing the protection of human subjects. Funding Information: We thank Dr. Timothy J. Garrett at the University of Florida for sharing metabolite standard formulations. We thank Michael Perkins for assistance with generating figures. We thank Eisuke Adachi, Makoto Saito, and Hiroyuki Nagai at Institute of Medical Science of the University of Tokyo, Takayuki Ogura at Saiseikai Utsunomiya Hospital, Naoki Hasegawa, Tomoyasu Nishimura, and Katsunori Masaki at Keio University School of Medicine, Takahide Kikuchi, Daisuke Taniyama, and Kazuto Itoh at Saiseikai Central Hospital, and Shuichi Yoshida and Isano Hase at Saitama City Hospital for assistance with preparing clinical samples. VRG was supported by the Biomedical Resilience and Readiness in Adverse Operating Environment Initiative at PNNL. This work was supported by the National Security Mission Seed, under the Laboratory Directed Research and Development (LDRD) Program at Pacific Northwest National Laboratory (PNNL). PNNL is a multi-program national laboratory operated for the U.S. Department of Energy (DOE) by Battelle Memorial Institute under Contract No. DE-AC05-76RL01830. Sample testing and data analysis was funded by the U.S. Department of Defense's Joint Program Executive Office (JPEO) COVID-19 FY20/21 CARES Act to U.S. Naval Medical Research Unit TWO (NAMRU-2) via Naval Medical Research Center (Appropriation: 9700130, JON: SW713). These funds were transferred via two Military Interagency Purchase Requests (MIPRs) from NAMRU-2 to PNNL (MIPRN6281420MPNX005, MIPRN6281421MPNX003) under a Memorandum of Agreement between the U.S. Departments of Defense and Energy (MOA; USA000707-13-DPAP dtd May 01, 2013).The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. RDH, KC, and AGL are military Service member or employees of the United States Government. This work was prepared as part of their official duties. Title 17, U.S.C. §105 provides that {\textquoteleft}copyright protection under this title is not available for any work of the United States Government.{\textquoteright} Title 17, U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. The study protocol was approved by the University of Wisconsin Health Sciences Institutional Review Board (IRB protocol # 2015-0802-CR006) in compliance with all applicable federal regulations governing the protection of human subjects. Publisher Copyright: {\textcopyright} 2023 Battelle Memorial Institute, The Author(s)",
year = "2023",
month = mar,
doi = "10.1016/j.heliyon.2023.e13795",
language = "English",
volume = "9",
journal = "Heliyon",
issn = "2405-8440",
publisher = "Elsevier BV",
number = "3",
}