SARS-CoV-2 cell tropism and multiorgan infection

Liu, Jia; Li, Yufeng; Liu, Qian; Yao, Qun; Wang, Xi; Zhang, Huanyu; Chen, Rong; Ren, Liang; Min, Juan; Deng, Fei; Yan, Bing; Liu, Liang; Wang, Manli; Wang, Manli; Zhou, Yiwu

doi:10.1038/s41421-021-00249-2

Cited by 180 publications

(200 citation statements)

References 15 publications

(17 reference statements)

Supporting

Mentioning

171

Contrasting

Unclassified

Order By: Relevance

“…The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is having a widespread impact on global health with substantial loss of life. SARS-CoV-2 infection in patients with COVID-19 can result in pulmonary distress, inflammation, and tropism to multiple organs [ 1 ]. Some infected individuals are asymptomatic whilst others mount an exaggerated immune response, or ‘cytokine storm’[ 2 , 3 ], which correlates with multiple organ failure and poor outcome [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

et al. 2021

View full text Add to dashboard Cite

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

show abstract

Section: Introductionmentioning

confidence: 99%

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Still, many have evaluated the permissiveness of various cell lines, which is hard to interpret. Autopsy analyses have shown the presence of SARS-CoV-2 antigens, by immunodetection, in the trachea, small intestine, the kidneys, pancreas, and vascular tissues of the brain and heart 19,20 . Our work identi ed as possible targets for infection, in addition to some cells of the respiratory tract, cells from the small intestine and pancreas.…”

Section: Discussionmentioning

confidence: 99%

An Approach to Cellular Tropism of SARS-Cov-2 Through Protein-Protein Interaction and Enrichment Analysis

Ortega-Bernal

Zárate

Cárdenas

et al. 2021

Preprint

View full text Add to dashboard Cite

COVID-19, caused by SARS-CoV-2, is a primarily pulmonary disease that can affect several organs, directly or indirectly. To date, there are many questions about the different pathological mechanisms. Here, we generate an approach to identify the cellular-level tropism of SARS-CoV-2 using human proteomics, virus-host interactions, and enrichment analysis. Through a network-based approach, the molecular context was visualized and analyzed. This procedure was also performed for SARS-CoV-1. We obtained proteomes and interactomes from 145 different cells corresponding to 57 different tissues. Not all cells had proteins such as ACE2 or TMPRSS2 (among others), so they were discarded. Of the remaining cells, a gradient of susceptibility to infection was observed. In addition, proteins associated with the coagulation cascade that can be directly or indirectly sequestered by viral proteins were identified. We have identified 55 potential cells that can be "cracked" with different susceptibilities. One of the main results being pneumocytes, as well as heart, kidney, liver, or small intestine. We also report how the coagulation cascade can be affected by SASR-CoV-2 infection. These results help us to explain the molecular context and provide elements for possible treatments in the current situation.

show abstract

“…Therefore, these viruses can directly fuse at the cell surface if the Spike protein is cleaved by a cell surface serine protease like TMPRSS2 [12,20], or utilize an endolysosomal route for fusion, where the Spike protein is primed by cysteine protease cathepsins [12,[21][22][23]. Viral entry and infection in different host cells is dependent on the expression of these key host factors [24]. Cell tropism studies revealed that SARS-CoV-2 infection is not only restricted to airway epithelium but the cells along the Gastrointestinal tract are also infected [25].…”

Section: Introductionmentioning

confidence: 99%

Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors

et al. 2021

View full text Add to dashboard Cite

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.

show abstract

SARS-CoV-2 cell tropism and multiorgan infection

Cited by 180 publications

References 15 publications

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

An Approach to Cellular Tropism of SARS-Cov-2 Through Protein-Protein Interaction and Enrichment Analysis

Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors

Contact Info

Product

Resources

About