Coronavirus News: Cedars-Sinai Medical Center Study Confirms That The SARS-CoV-2 Virus Infects The Pancreas Directly

Coronavirus News: Researchers from Cedars-Sinai Medical Center-California and the University of California, Los Angeles have in a new study confirmed that the SARS-CoV-2 coronavirus is able to infect and damage the pancreas directly, challenging the initial hypothesis that organ damages including the pancreas were only due to effects of cytokine storms alone and not direct viral invasion.


 
It is known that the SARS-CoV-2 coronavirus affects the respiratory tract as well as extra-pulmonary systems, including the pancreas, that express the virus entry receptor, Angiotensin-Converting Enzyme 2 (ACE2) receptor.
 
It must be noted that the endocrine and exocrine pancreas, the latter composed of ductal and acinar cells, express high levels of ACE2, which correlates to impaired functionality characterized as acute pancreatitis observed in some cases presenting with COVID-19.
 
As acute pancreatitis is already one of the most frequent gastrointestinal causes of hospitalization in the U.S. and the majority of studies investigating the effects of SARS-CoV-2 on the pancreas are clinical and observational, the study team from Cedars-Sinai Medical Center utilized human iPSC technology to investigate the potential deleterious effects of SARS-CoV-2 infection on iPSC-derived pancreatic cultures containing endocrine and exocrine cells.
 
It was found that SARS-CoV-2 is capable of infecting iPSC-derived pancreatic cells, thus perturbing their normal molecular and cellular phenotypes. The infection increased a key inflammatory cytokine, CXCL12, known to be involved in pancreas dysfunction. Transcriptome analysis of infected pancreatic cultures confirmed that SARS-CoV-2 hijacks the ribosomal machinery in these cells.
 
Importantly the SARS-CoV-2 infectivity of the pancreas is confirmed in post-mortem tissues from COVID-19 patients, which showed co-localization of SARS-CoV-2 in pancreatic endocrine and exocrine cells and increased the expression of some pancreatic ductal stress response genes.
 
Hence the study team from Cedars-Sinai Medical Center demonstrated for the first time that SARS-CoV-2 can directly infect human iPSC-derived pancreatic cells with supporting evidence of presence of the virus in post-mortem pancreatic tissue of confirmed COVID-19 human cases. This novel model of iPSC-derived pancreatic cultures will open new avenues for the comprehension of the SARS-CoV-2 infection and potentially establish a platform for endocrine and exocrine pancreas-specific antiviral drug screening.
 
The study finding also has implications with regards to possibility of viral persistence in the pancreas for those who have so called ‘recovered’ from the COVID-19 disease.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2021.02.01.21250846v1
 
The COVID-19, caused by the SARS-CoV-2 virus, has infected over 105 million lives and caused over 2.35 million deaths globally. In the United States, more than 460,000 Americans have now died while in the United Kingdom more than 112,000 British citizens have perished in th e COVID-19 crisis. These are merely estimates as in many cases excess deaths due to COVID-19 have not been taken into consideration. It is estimated that more people are dying from Post COVID-19 complications triggered by the virus but it is not being reported as such, for example the number of deaths due to strokes, cardiovascular events, kidney failure, liver and pancreas damage etc have increased drastically over the last 10 months globally!
 
Though predominantly considered a respiratory disease, more than thirty percent of the COVID-19 patients also present other symptoms, often related to the gastrointestinal or nervous systems.
 
There are numerous other cells in the body besides lung alveolar epithelial cells express angiotensin-converting enzyme 2 (ACE2) receptors-the means through which the virus enters host cells. The heart, pancreas, GI tract, kidney, testis and other organs which express ACE2 receptors and studies demonstrated that the virus infects the heart, vascular endothelial cells, kidney, liver and the pancreas.
 
In certain cases, COVID-19 patients present acute pancreatitis- a condition where the pancreas-inflammation causes abdominal pain. Acute pancreatitis is also one of the most frequent gastrointestinal causes of hospitalization in the US. Currently, there is no knowledge on how SARS-CoV-2 infects the pancreas and what the impacts are.
 
In order to understand how SARS-CoV-2 infects the pancreas and investigate its effects, the study team used the human iPSC (induced pluripotent stem cells)-derived pancreatic cultures and analyzed the post-infection cellular and molecular changes.
 
Most significantly the interdisciplinary team from the Cedars-Sinai Medical Center, and the University of California-Los Angeles demonstrated for the first time that SARS-CoV-2 can directly infect the human iPSC-derived pancreatic cells, with supporting evidence of the presence of the virus in post-mortem pancreatic tissue of confirmed COVID-19 human cases.
 
The study team found that SARS-CoV-2 infection of infecting iPSC-derived pancreatic cells increased a key inflammatory cytokine, CXCL12. It is known to be involved in pancreas dysfunction. They observed that the SARS-CoV-2 hijacked the ribosomal machinery in the pancreatic cells and also increased the expression of some pancreatic ductal stress response genes. Prominently, the genes CXCL12, NFKB1, and STAT3 showed significant upregulation as compared to the control.
 
The team report that the transcriptional analysis of SARS-CoV-2 infected iPSC-derived pancreatic cultures demonstrated active viral replication and pancreas-specific COVID-19 associated disease signatures. The SRP-protein targeting processes were upregulated, indicating that host cell machinery was being repurposed for viral replication.
 
In this research, established cell lines do not represent the human pancreas pathophysiology. Because the primary human pancreatic cells are largely inaccessible, the researchers developed novel methods to generate pancreatic progenitors from human induced pluripotent stem cells (iPSCs), which can be differentiated into endocrine (islet β-cells) and exocrine (acinar and ductal) cells.
 
The study team generated the highly stable iPSCs from healthy volunteers at the iPSC Core at Cedars-Sinai Medical Center from the peripheral blood mononuclear cells (PMBCs) utilizing non-integrating oriP/EBNA1-based episomal plasmid vectors.
 
These human iPSCs were then differentiated into pancreatic adherent (2D) and organoid (3D) cultures.
 
According to the study team, these cultures contain cells that are representative of human endocrine pancreas expressing endocrine NKX6.1 and C-peptide, exocrine acinar Amylase and Chymotrypsin (CTRC) and exocrine ductal Cytokeratin19 (CK19) and SOX9 cells.
 
Importantly from RNA-sequencing studies, they established that the pancreas, specifically the exocrine compartment (acinar and ductal cells), has high expression of ACE2.
 
It was found that gender and age present no difference in the expression of the ACE2 receptors. The researchers demonstrated that the iPSC-derived pancreatic cells used in this study exhibit ACE2 and TMPRSS2 expression. Both the receptors are present in the pancreas, especially in the exocrine portion.
 
It should also be noted that in the context of the endocrine pancreas, it is well-established that patients with type I and type II diabetes have a higher risk for COVID-19 associated mortality. Diabetic COVID-19 patients, with associated comorbidities such as cardiovascular diseases and renal impairment, succumb to the severity of the infection. It is thus important to know the mechanism of the SARS-CoV-2 infection on human endocrine and exocrine pancreas.
 
The study team showed that the pancreatic cells including the endocrine and the exocrine cell types (acinar, and ductal) are susceptible to SARS-CoV-2 infection, resulting in morphological perturbations as well as impaired expression of key markers.
 
The team demonstrated for the first time that SARS-CoV-2 can directly infect human iPSC-derived pancreatic cells. They support this with evidence of the presence of the virus in post-mortem pancreatic tissue of confirmed COVID-19 human cases.
 
Also corresponding with the infection, the study shows important inflammatory signatures.
 
Corresponding author Dr Dhruv Sareen from the department of Biomedical Sciences, Cedars-Sinai Medical Center told Thailand Medical News, “The iPSC-based model described here provides a valuable novel platform for understanding the pancreas-specific cellular responses to SARS-CoV-2 as well as for antiviral drug development against SARS-CoV-2. This research presents a novel model of iPSC-derived pancreatic cultures as a new avenue for understanding the SARS-CoV-2 infection. It potentially establishes an excellent platform for endocrine and exocrine pancreas-specific antiviral drug screening.”
 
The study team is next planning to also explore the mode of infection and damage caused by the SARS-CoV-2 coronavirus on other organs such as the kidneys and also the heart.
 
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