Lipid and Nucleocapsid N-Protein Accumulation in COVID-19 Patient Lung and Infected Cells

Grootemaat, Anita E.; Niet, Sanne van der; Scholl, Edwin R.; Roos, Eva; Schurink, Bernadette; Bugiani, Marianna; Miller, Sara; Larsen, Per; Pankras, Jeannette; Reits, Eric; Wel, Nicole N. van der

doi:10.1128/spectrum.01271-21

Cited by 15 publications

(29 citation statements)

References 81 publications

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“…The binding of N to heparin, which limits coagulation at inflammation sites, suggests a possible role for secreted N in promoting coronavirus disease (COVID)–associated clotting abnormalities. N is present in intestine and lungs from recovered and fatal patients with COVID-19, respectively, while virus-like particles are rarely detected ( 26 , 27 ), consistent with this intriguing possibility and a role in the chronic low-level inflammation that causes “long COVID-19” symptoms.…”

Section: Discussionmentioning

confidence: 52%

Cell surface SARS-CoV-2 nucleocapsid protein modulates innate and adaptive immunity

et al. 2022

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SARS-CoV-2 nucleocapsid protein (N) induces strong antibody (Ab) and T cell responses. Although considered to be localized in the cytosol, we readily detect N on the surface of live cells. N released by SARS-CoV-2–infected cells or N-expressing transfected cells binds to neighboring cells by electrostatic high-affinity binding to heparan sulfate and heparin, but not other sulfated glycosaminoglycans. N binds with high affinity to 11 human chemokines, including CXCL12β, whose chemotaxis of leukocytes is inhibited by N from SARS-CoV-2, SARS-CoV-1, and MERS-CoV. Anti-N Abs bound to the surface of N-expressing cells activate Fc receptor–expressing cells. Our findings indicate that cell surface N manipulates innate immunity by sequestering chemokines and can be targeted by Fc-expressing innate immune cells. This, in combination with its conserved antigenicity among human CoVs, advances its candidacy for vaccines that induce cross-reactive B and T cell immunity to SARS-CoV-2 variants and other human CoVs, including novel zoonotic strains.

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Section: Discussionmentioning

confidence: 52%

Cell surface SARS-CoV-2 nucleocapsid protein modulates innate and adaptive immunity

et al. 2022

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Section: Complementary Methods For Virus Detectionmentioning

confidence: 99%

“…Other methods for IEM exist, including ultrathin cryosections, which expose viral antigens, but this method requires special tissue preparation and also produces a result that requires practiced interpretation since the ultrastructural appearance differs from the conventional EM appearance. Grootemaat et al have elegantly used this technique to demonstrate antigens of coronavirus grown in tissue culture(Grootemaat et al, 2022). Despite these limitations, IEM can still be a valuable tool to confirm the presence of a virus in cells.5 | ULTRASTRUCTURAL CHANGES CAUSED BY SARS-COV-2 INFECTIONAn increasing number of articles have included descriptions of ultrastructural changes in SARS-CoV-2 positive autopsy tissues(Ackermann et al, 2020;Akilesh, Nast, et al, 2021;Deinhardt-Emmer, Böttcher, et al, 2021; Deinhardt-Emmer, Wittschieber, et al, 2021;Duarte-Neto et al, 2021;Lüke et al, 2020;Rizzo et al, 2021;Santana et al, 2021;Saraiva et al, 2021).…”

mentioning

confidence: 99%

Detection and identification of coronaviruses in human tissues using electron microscopy

Bullock

Goldsmith

Miller

2022

Microscopy Res & Technique

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The identification of viral particles within a tissue specimen requires specific knowledge of viral ultrastructure and replication, as well as a thorough familiarity with normal subcellular organelles. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has underscored how challenging the task of identifying coronavirus by electron microscopy (EM) can be. Numerous articles have been published mischaracterizing common subcellular structures, including clathrin‐ or coatomer‐ coated vesicles, multivesicular bodies, and rough endoplasmic reticulum, as coronavirus particles in SARS‐CoV‐2 positive patient tissue specimens. To counter these misinterpretations, we describe the morphological features of coronaviruses that should be used to differentiate coronavirus particles from subcellular structures. Further, as many of the misidentifications of coronavirus particles have stemmed from attempts to attribute tissue damage to direct infection by SARS‐CoV‐2, we review articles describing ultrastructural changes observed in specimens from SARS‐CoV‐2‐infected individuals that do not necessarily provide EM evidence of direct viral infection. Ultrastructural changes have been observed in respiratory, cardiac, kidney, and intestinal tissues, highlighting the widespread effects that SARS‐CoV‐2 infection may have on the body, whether through direct viral infection or mediated by SARS‐CoV‐2 infection‐induced inflammatory and immune processes.

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“…The localization of NC to LDs indicates a link between SARS-CoV-2 and lipid metabolism and LD biogenesis. An association between SARS-CoV-2 infection and lipid metabolism and LDs has been demonstrated in cell culture and animal models as well as in virus-infected patients [ 22 , 35 , 65 ]. NC has been shown to induce expression of diacylglycerol acyltransferase (DGAT) and LD formation [ 22 , 116 ].…”

Section: Discussionmentioning

confidence: 99%

Evidence of SARS-CoV-2 infection in postmortem lung, kidney, and liver samples, revealing cellular targets involved in COVID-19 pathogenesis

et al. 2023

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There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1β-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34+ liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.

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Lipid and Nucleocapsid N-Protein Accumulation in COVID-19 Patient Lung and Infected Cells

Cited by 15 publications

References 81 publications

Cell surface SARS-CoV-2 nucleocapsid protein modulates innate and adaptive immunity

Cell surface SARS-CoV-2 nucleocapsid protein modulates innate and adaptive immunity

Detection and identification of coronaviruses in human tissues using electron microscopy

Evidence of SARS-CoV-2 infection in postmortem lung, kidney, and liver samples, revealing cellular targets involved in COVID-19 pathogenesis

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