SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19

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Abstract

Objective

As SARS‐CoV‐2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous system proteins in living humans was used to investigate neuropathogenic mechanisms of long‐COVID‐19.

Methods

SARS‐CoV‐2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron‐derived extracellular vesicles (NDEVs) and astrocyte‐derived EVs (ADEVs) were quantified in resolved acute COVID‐19 without post‐acute sequelae of SARS‐CoV‐2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.

Results

NDEV and ADEV mean levels of SARS‐CoV‐2 S1 and nucleocapsid (N) proteins were higher in all PASC sub‐groups than controls, but only N levels were higher in PASC with than without NP. Exosome marker CD81‐normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, and neuroprotective MPs Humanin and mitochondrial open‐reading frame of the 12S rRNA‐c (MOTS‐c) all were decreased significantly in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MPs voltage‐dependent anion‐selective channel protein 1 (VDAC1) and N‐methyl‐D‐aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, whereas those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX) and leucine zipper EF‐hand containing transmembrane 1 protein (LETM1) were decreased only in PASC with NP. ADEV levels of MCU and NCLX only were increased in PASC without and with NP.

Interpretation

Abnormal NDEV and ADEV levels of SARS‐CoV‐2 N and S1 protein and MPs correlate with NP and may be biomarkers for long‐COVID prognostics and therapeutic trials.

Abstract

ANN NEUROL 2022

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Most cited references 41

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A brief measure for assessing generalized anxiety disorder: the GAD-7.

Robert L Spitzer, Kurt Kroenke, Janet B W Williams … (2006)

Generalized anxiety disorder (GAD) is one of the most common mental disorders; however, there is no brief clinical measure for assessing GAD. The objective of this study was to develop a brief self-report scale to identify probable cases of GAD and evaluate its reliability and validity. A criterion-standard study was performed in 15 primary care clinics in the United States from November 2004 through June 2005. Of a total of 2740 adult patients completing a study questionnaire, 965 patients had a telephone interview with a mental health professional within 1 week. For criterion and construct validity, GAD self-report scale diagnoses were compared with independent diagnoses made by mental health professionals; functional status measures; disability days; and health care use. A 7-item anxiety scale (GAD-7) had good reliability, as well as criterion, construct, factorial, and procedural validity. A cut point was identified that optimized sensitivity (89%) and specificity (82%). Increasing scores on the scale were strongly associated with multiple domains of functional impairment (all 6 Medical Outcomes Study Short-Form General Health Survey scales and disability days). Although GAD and depression symptoms frequently co-occurred, factor analysis confirmed them as distinct dimensions. Moreover, GAD and depression symptoms had differing but independent effects on functional impairment and disability. There was good agreement between self-report and interviewer-administered versions of the scale. The GAD-7 is a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research.

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Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Roujian Lu, Xiang Zhao, Juan Li … (2021)

Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.

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Is Open Access

A new coronavirus associated with human respiratory disease in China

Fan Wu, Su Zhao, Bin Yu … (2020)

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.

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Author and article information

Contributors

Edward J. Goetzl:

ORCID: https://orcid.org/0000-0002-0706-5371

edward.goetzl@ucsf.edu

Journal

Journal ID (nlm-ta): Ann Neurol

Journal ID (iso-abbrev): Ann Neurol

Journal ID (doi): 10.1002/(ISSN)1531-8249

Journal ID (publisher-id): ANA

Title: Annals of Neurology

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0364-5134

ISSN (Electronic): 1531-8249

Publication date (Electronic): 30 March 2022

Publication date PMC-release: 30 March 2022

Electronic Location Identifier: 10.1002/ana.26350

Affiliations

[ ¹ ] Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine University of California San Francisco San Francisco California USA

[ ² ] Intramural Research Program, National Institute on Aging Biomedical Research Center Baltimore Maryland USA

[ ³ ] Division of Experimental Medicine, Department of Medicine University of California San Francisco San Francisco California USA

[ ⁴ ] Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California USA

[ ⁵ ] Department of Medicine University of California San Francisco San Francisco California USA

[ ⁶ ] Research Department Campus for Jewish Living San Francisco California USA

Author notes

[*] [* ] Address correspondence to Goetzl, Geriatric Research Center, 1719 Broderick Street, San Francisco, CA 94115. E‐mail: edward.goetzl@ 123456ucsf.edu

Author information

Sarah A. Goldberg https://orcid.org/0000-0002-8642-1468

Edward J. Goetzl https://orcid.org/0000-0002-0706-5371

Article

Publisher ID: ANA26350

DOI: 10.1002/ana.26350

PMC ID: 9082480

PubMed ID: 35285072

SO-VID: 86cbd3cf-7e38-4b13-8cd7-221a1da468bc

License:

This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

History

Date revision received : 21 February 2022

Date received : 14 January 2022

Date accepted : 10 March 2022

Page count

Figures: 3, Tables: 3, Pages: 10, Words: 6222

Funding

Funded by: Intramural Program of the National Institute on Aging

Funded by: National Institutes of Health , doi 10.13039/100000002;

Award ID: NIAID3RO1AI141003‐03S1

Award ID: NIAIDK23AI157875

Funded by: UCSF Resource Allocation Program

Award ID: None

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details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.5 mode:remove_FC converted:09.05.2022

ScienceOpen disciplines: Neurology

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SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19

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Abstract

Objective

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Abstract

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 41

A brief measure for assessing generalized anxiety disorder: the GAD-7.

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

A new coronavirus associated with human respiratory disease in China

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Cited by 37

Most referenced authors 1,386