On the whereabouts of SARS-CoV-2 in the human body: A systematic review

Trypsteen, Wim; Cleemput, Jolien Van; Snippenberg, Willem van; Gerlo, Sarah; Vandekerckhove, Linos

doi:10.1371/journal.ppat.1009037

Cited by 189 publications

(200 citation statements)

References 196 publications

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“…extracted from the PAXdb database [40]. Different tissues are shown in the order corresponding to the SARS-CoV-2 presence, starting, at the top, from the highest virus presence [6]. The shown relative scale of ACE2 expression is also taken from [6].…”

Section: Sars-cov-2 N Protein Co-expression With Pkamentioning

confidence: 99%

“…Different tissues are shown in the order corresponding to the SARS-CoV-2 presence, starting, at the top, from the highest virus presence [6]. The shown relative scale of ACE2 expression is also taken from [6]. The total abundance of the seven human 14-3-3 isoforms in a given tissue and the average abundance of an isoform in 12 selected tissues are also indicated.…”

Section: Sars-cov-2 N Protein Co-expression With Pkamentioning

confidence: 99%

“…Like SARS-CoV and HCoV-NL63, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as entry receptor [5]. The ACE2 expression roughly correlates with the evidenced SARS-CoV-2 presence in different tissue types, which explains the multi-organ character of the disease [6] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins

Tugaeva

Hawkins

Smith

et al. 2020

Preprint

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The coronavirus nucleocapsid protein (N) controls viral genome packaging and contains numerous phosphorylation sites located within unstructured regions. Binding of phosphorylated SARS-CoV N to the host 14-3-3 protein in the cytoplasm was reported to regulate nucleocytoplasmic N shuttling. All seven isoforms of the human 14-3-3 are abundantly present in tissues vulnerable to SARS-CoV-2, where N can constitute up to ~1% of expressed proteins during infection. Although the association between 14-3-3 and SARS-CoV-2 N proteins can represent one of the key host-pathogen interactions, its molecular mechanism and the specific critical phosphosites are unknown. Here, we show that phosphorylated SARS-CoV-2 N protein (pN) dimers, reconstituted via bacterial co-expression with protein kinase A, directly associate, in a phosphorylation-dependent manner, with the dimeric 14-3-3 protein, but not with its monomeric mutant. We demonstrate that pN is recognized by all seven human 14-3-3 isoforms with various efficiencies and deduce the apparent KD to selected isoforms, showing that these are in a low micromolar range. Serial truncations pinpointed a critical phosphorylation site to Ser197, which is conserved among related zoonotic coronaviruses and located within the functionally important, SR-rich region of N. The relatively tight 14-3-3/pN association can regulate nucleocytoplasmic shuttling and other functions of N via occlusion of the SR-rich region, while hijacking cellular pathways by 14-3-3 sequestration. As such, the assembly may represent a valuable target for therapeutic intervention.HighlightsSARS-CoV-2 nucleocapsid protein (N) binds to all seven human 14-3-3 isoforms. This association with 14-3-3 strictly depends on phosphorylation of N. The two proteins interact in 2:2 stoichiometry and with the Kd in a μM range. Affinity of interaction depends on the specific 14-3-3 isoform. Conserved Ser197-phosphopeptide of N is critical for the interaction.

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Section: Sars-cov-2 N Protein Co-expression With Pkamentioning

confidence: 99%

Section: Sars-cov-2 N Protein Co-expression With Pkamentioning

confidence: 99%

See 1 more Smart Citation

The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins

Tugaeva

Hawkins

Smith

et al. 2020

Preprint

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“…The ensuing infection is accompanied by inflammatory lung injury and death and has caused a worldwide epidemic since its start at the end of 2019 (Pedersen and Ho., 2020). Although the lungs are the major target of the virus, its spread to the heart, kidney, and brain has also been observed in human patients ( Trypsteen et al, 2020 ). This multi-organ target of the virus infection has been associated with the dysfunction of affected organs and poor survival ( Chen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Singh

Beer

Kraus

et al. 2021

Brain, Behavior, and Immunity

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Background The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the viral surface. Recent clinical data have demonstrated that patients with previous episodes of brain injuries are a high-risk group for SARS-CoV-2 infection. An explanation for this finding is currently lacking. Sterile tissue injuries including stroke induce the release of several inflammatory mediators that might modulate the expression levels of signaling proteins in distant organs. Whether systemic inflammation following brain injury can specifically modulate ACE2 expression in different vital tissues has not been investigated. Methods For the induction of brain stroke, mice were subjected to a surgical procedure for transient interruption of blood flow in the middle cerebral artery for 45 min and sacrificed after 1 and 3 days for analysis of brain, lung, heart, and kidney tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. The level of soluble ACE2 in plasma and bronchial alveolar lavage (BAL) was measured using an immunoassay. Immune cell populations in lymphoid organs were analyzed by flow cytometry. Post-stroke pneumonia in mice was examined by bacterial cultures from lung homogenates and whole blood. Results Strikingly, 1 day after surgery, we observed a substantial increase in the protein levels of ACE2 in the lungs of stroke mice compared to sham-operated mice. However, the protein levels of ACE2 were found unchanged in the heart, kidney, and brain of these animals. In addition, we found increased transcriptional levels of alveolar ACE2 after stroke. The increased expression of ACE2 was significantly associated with the severity of behavioral deficits after stroke. The higher protein levels of alveolar ACE2 persisted until 3 days of stroke. Interestingly, we found reduced levels of soluble ACE2 in plasma but not in BAL in stroke-operated mice compared to sham mice. Furthermore, stroke-induced parenchymal and systemic inflammation was evident with the increased expression of IL-6 and IL-1β. Reduced numbers of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. Conclusions We demonstrate specific augmented alveolar ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings suggest that patients with brain injuries may have increased binding affinity to SARS-CoV-2 in their lungs which might explain why stroke is a risk factor for higher susceptibility to develop COVID-19.

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“…This outbreak marks the third coronavirus causing large-scale threat and harm to the population in the 21 st century, after the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2002 and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. Like SARS and MERS, viral infection with SARS-CoV-2 can lead to Acute Respiratory Distress Syndrome, with potentially long-term reduction in lung function, heart arrhythmia, and death [ [2] , [3] , [4] ]. However, COVID-19 has shown a much greater propensity for infectivity relative to SARS and MERS, which has made the current global pandemic more difficult to contain.…”

Section: Introductionmentioning

confidence: 99%

FN3-based monobodies selective for the receptor binding domain of the SARS-CoV-2 spike protein

et al. 2021

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A phage library displaying 10 10 variants of the fibronectin type III (FN3) domain was affinity selected with the biotinylated form of the receptor binding domain (RBD, residues 319-541) of the SARS-CoV-2 virus spike protein. Nine binding FN3 variants (i.e. monobodies) were recovered, representing four different primary structures. Soluble forms of the monobodies bound to several different preparations of the RBD and the S1 spike subunit, with affinities ranging from 3 to 14 nM as measured by bio-layer interferometry. Three of the four monobodies bound selectively to the RBD of SARS-CoV-2, with the fourth monobody showing slight cross-reactivity to the RBD of SARS-CoV-1 virus. Examination of binding to the spike fragments and its trimeric form revealed that the monobodies recognise at least three overlapping epitopes on the RBD of SARS-CoV-2. While pairwise tests failed to identify a monobody pair that could bind simultaneously to the RBD, one monobody could simultaneously bind to the RBD and the ectodomain of the cellular receptor angiotensin converting enzyme 2 (ACE2). All four monobodies successfully bound the RBD after overexpression in Chinese hamster ovary (CHO) cells as fusions to the Fc domain of human IgG1.

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On the whereabouts of SARS-CoV-2 in the human body: A systematic review

Cited by 189 publications

References 196 publications

The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins

The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

FN3-based monobodies selective for the receptor binding domain of the SARS-CoV-2 spike protein

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