Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19

Zhang, Huilan; Zhou, Peng; Wei, Yuanhuan; Yue, Huihui; Wang, Yi; Hu, Ming; Zhang, Shu; Cao, Tanze; Yang, Chengqing; Li, Ming; Guo, Guangyun; Chen, Xianxiang; Chen, Ying; Lei, Mei; Liu, Huiguo; Zhao, Jianping; Peng, Peng; Wang, Cong Yi; Du, Ronghui

doi:10.7326/m20-0533

Cited by 472 publications

(530 citation statements)

References 2 publications

Supporting

Mentioning

476

Contrasting

Unclassified

Order By: Relevance

“…In addition, cell tropism of SARS-CoV12 and SARS-CoV-2 did not firmly associate with ACE2 expression. ACE2 is expressed on both type I and type II pneumocytes, whereas SARS-CoV and SARS-CoV-2 only make use of type II pneumocytes because the infection requires co-expression of ACE2 and TMPRSS2 as we described before [20,55,56]. Therefore, increasing ACE2 (especially circulating ACE2) or Ang-(1-7) is a potential approach to reduce SARS-CoV-2-induced severe damage and to protect organs.…”

Section: Increasing Ace2 or Ang-(1-7)mentioning

confidence: 98%

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Xiao

Sakagami

Miwa

2020

Viruses

176

177

View full text Add to dashboard Cite

Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.Viruses 2020, 12, 491 2 of 10 Profile of ACE2Human angiotensin-converting enzyme-related carboxypeptidase ACE2 is encoded by the ACE2 gene which maps to chromosome Xp22 [6]. ACE2 is a type I transmembrane protein, comprised of an extracellular heavily N-glycosylated N-terminal domain containing the carboxypeptidase site and a short intracellular C-terminal cytoplasmic tail [7]. The N-terminal peptidase domain is also the SARS-CoV binding site [8]. There are two forms of ACE2 protein: cellular (membrane-bound) form and circulating (soluble) form. Cellular ACE2 protein is the full-length protein which is expressed abundantly in pneumocytes and enterocytes of the small intestine [9]. ACE2 is also expressed in vascular endothelial cells of the heart, the kidneys, and other organs, such as the brain. However, ACE2 is absent in the spleen, thymus, lymph nodes, bone marrow, and cells of the immune system (including B and T lymphocytes, and macrophages) [10,11].Circulating ACE2 (with the N-terminal peptidase domain) is cleaved from the full-length ACE2 on the cell membrane by the metalloprotease ADAM17 and then released into the extracellular environment [7]. The type II transmembrane serine protease, TMPRSS2 was found to compete with ADAM17 for ACE2 shedding but cleaves ACE2 differently. Both ADAM17 and TMPRSS2 remove a short C-terminal fragment from ACE2. Arginine and lysine residues within amino acids 652 to 659 are critical for ADAM17 shedding, whereas arginine and lysine residues within amino acids 697 to 716 are essential for TMPRSS2 shedding. Only cleavage by TMPRSS2 results in augmented SARS-CoV cell entry [12][13][14][15]. There are two ways for SARS-CoV to enter the target cell: endocytosis, and fusion of the viral membrane with a membrane of the target cell, which is 100 times more efficient than endocytosis for viral replication [16]. With the help of TMPRSS2, ADAM17-regulated ectodomain shedding of ACE2 could induce SARS-CoV cell entry through endocytosis [7,12]; however, ADAM17 activity is not required for SARS-CoV cell entry through fusion [12]. As the N-terminal domain is the coronavirus binding site, circulating ACE2 also binds to the virus. Iwata-Yoshikawa et al. infected both ...

show abstract

Section: Increasing Ace2 or Ang-(1-7)mentioning

confidence: 98%

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Xiao

Sakagami

Miwa

2020

Viruses

176

177

View full text Add to dashboard Cite

show abstract

“…These techniques become paramount in particular for studies of a potential pathogen that does not cause overt, or causes only mild, disease, such as SARS-CoV-2 in the currently available animal models. Viral antigen-based immunostaining has been used to detect SARS-CoV-2 antigen in both post-mortem human and animal tissues (1, 16, 22, 25). However, the antibodies used in these studies were produced in-house and therefore are not commonly available.…”

Section: Introductionmentioning

confidence: 99%

Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens

Liu

Babka

Kearney

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than one million cases and tens of thousands of deaths. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.

show abstract

“…In addition, cleavage at a novel furin insertion site is predicted to facilitated membrane fusion and confer increased virulence, as has been previously reported with other viruses (Chen et al, 1998). Based on initial reports, infection of ACE2-expressing pneumocytes lining the pulmonary alveoli likely impairs release of surfactants that maintain surface tension, hindering the ability to prevent accumulation of fluid that may lead to acute respiratory distress syndrome (Xu et al, 2020;Zhang et al, 2020). The immune response of convalescent COVID-19 patients consists of antibody-secreting cells releasing IgG and IgM antibodies, increased follicular helper T cells, and activated CD4 and CD8 T cells (Thevarajan et al, 2020), suggesting that a broad humoral and T cell driven immune response mediates the clearance of infection.…”

Section: Introductionmentioning

confidence: 75%

A SARS-CoV-2 Vaccination Strategy Focused on Population-Scale Immunity

Yarmarkovich

Warrington

Farrel

et al. 2020

Preprint

View full text Add to dashboard Cite

Here we propose a vaccination strategy for SARS-CoV-2 based on identification of both highly conserved regions of the virus and newly acquired adaptations that are presented by MHC class I and II across the vast majority of the population, are highly dissimilar from the human proteome, and are predicted B cell epitopes. We present 65 peptide sequences that we expect to result in a safe and effective vaccine which can be rapidly tested in DNA, mRNA, or synthetic peptide constructs. These include epitopes that are contained within evolutionarily divergent regions of the spike protein reported to increase infectivity through increased binding to the ACE2 receptor, and within a novel furin cleavage site thought to increase membrane fusion. This vaccination strategy specifically targets unique vulnerabilities of SARS-CoV-2 and should engage a robust adaptive immune response in the vast majority of the human population.was not certified by peer review)

show abstract

Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19

Cited by 472 publications

References 2 publications

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens

A SARS-CoV-2 Vaccination Strategy Focused on Population-Scale Immunity

Contact Info

Product

Resources

About