Deleterious Effects of SARS-CoV-2 Infection on Human Pancreatic Cells.

Syairah Hanan Shaharuddin,Roberta S Santos,Vaithilingaraja Arumugaswami,Wohaib Hasan,Gustavo Garcia,Victoria Wang,Harneet Jawanda,Andrew Gross,Yi Zhang,Yizhou Wang,Dhruv Sareen

doi:10.3389/fcimb.2021.678482

Abstract

COVID-19 pandemic has infected more than 154 million people worldwide and caused more than 3.2 million deaths. It is transmitted by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and 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. Importantly, 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. Since 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, we 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. Interestingly, iPSC-derived pancreatic cultures allow SARS-CoV-2 entry and establish infection, thus perturbing their normal molecular and cellular phenotypes. The infection increased a key cytokine, CXCL12, known to be involved in inflammatory responses in the pancreas. Transcriptome analysis of infected pancreatic cultures confirmed that SARS-CoV-2 hijacks the ribosomal machinery in these cells. Notably, the SARS-CoV-2 infectivity of the pancreas was 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. Thus, we demonstrate that SARS-CoV-2 can directly infect human iPSC-derived pancreatic cells with strong 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.

Highlights

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus2), initiated in China at the end of 2019 and rapidly escalated to global outbreak, infecting more than 154 million people and resulting in related fatalities in more than 3.2 million by beginning of May 2021 (JHU Dataset 2021)
Protocols for differentiation after the pancreatic progenitor stage were directed to bias the cell fate of the cultures containing either exocrine acinar cells or exocrine ductal cells. iPanEXO Acinar cultures express some markers that are characteristic of mature acinar cultures such as cytoplasmic staining of digestive enzymes Amylase (AMY) and Chymotrypsin C (CTRC), and greater staining of nuclear transcription factor MIST1, which is characteristic of acinar cells that are not fully mature
AngiotensinConverting Enzyme 2 (ACE2) and TMPRSS2 gene expression was measured in induced pluripotent stem cells (iPSCs)-derived pancreatic cultures

Summary

Introduction

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus2), initiated in China at the end of 2019 and rapidly escalated to global outbreak, infecting more than 154 million people and resulting in related fatalities in more than 3.2 million by beginning of May 2021 (JHU Dataset 2021). Many other cells besides lung alveolar epithelial cells express ACE2 receptors, including heart, pancreas, GI tract, kidney, testis and other organs (Liu et al, 2020), making them a target for the virus. This is supported by studies demonstrating that virus can affect other tissues, including the heart (Sharma et al, 2020), vascular endothelial cells (Varga et al, 2020), kidney (Pelayo et al, 2020), liver (Amin, 2020) and the pancreas (Mukherjee et al, 2020; Pinte and Baicus, 2020; Tuttolomondo et al, 2020; Müller et al, 2021). The virus was isolated from stool and from a pseudocyst of a COVID-19 patient with acute pancreatitis (de-Madaria and Capurso, 2021)

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