key: cord-1011547-u3puhzfz
authors: Coate, Katie C.; Cha, Jeeyeon; Shrestha, Shristi; Wang, Wenliang; Fasolino, Maria; Morgan, Ashleigh; Dai, Chunhua; Saunders, Diane C.; Aramandla, Radhika; Jenkins, Regina; Kapp, Meghan E.; Stein, Roland; Kaestner, Klaus H.; Vahedi, Golnaz; Brissova, Marcela; Powers, Alvin C.
title: SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but Not in Islet Endocrine Cells
date: 2020-08-31
journal: bioRxiv
DOI: 10.1101/2020.08.31.275719
sha: 465727da0f9f9eb0d57867e82dbb0f7efbd090c0
doc_id: 1011547
cord_uid: u3puhzfz

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This model would require binding and entry of SARS-CoV-2 into host cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from any of these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of ACE2 and TMPRSS2 co-expression in islet endocrine cells makes it unlikely that SARS-CoV-2 directly affects pancreatic islet β cells.

In coronavirus disease of 2019 , elevated plasma glucose levels and diabetes have been identified as independent risk factors of morbidity and mortality with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) infection (Cariou et al., 2020; Riddle et al., 2020; Zhu et al., 2020) . Isolated cases of new-onset diabetes and diabetic emergencies such as ketoacidosis and hyperosmolar hyperglycemia have been reported with COVID-19 (Chee et al., 2020; Goldman et al., 2020; Kim et al., 2020; Li et al., 2020a; Rafique and Ahmed, 2020) , leading to the hypothesis that SARS-CoV-2 has a diabetogenic effect mediated by direct cytotoxicity to pancreatic islet b cells.

In vitro studies have shown that SARS-CoV-2 entry into human host cells requires binding to the cell surface receptor angiotensin converting enzyme 2 (ACE2) as well as proteolytic cleavage of the viral spike (S) protein by transmembrane serine protease 2 (TMPRSS2) (Hoffmann et al., 2020; Lan et al., 2020; Shang et al., 2020; Wiersinga et al., 2020) .

In 2010, Yang and colleagues (Yang et al., 2010) examined autopsy samples from patients infected by SARS-CoV-1, which uses similar machinery for binding and cellular entry, and reported expression of ACE2 in pancreatic islet cells from a single deceased donor. Though the identity of these islet cells was not assessed, the authors suggested that binding of ACE2 by SARS-CoV-1 damages islets and causes acute diabetes, which could be reversed after viral recovery (Yang et al., 2010) . There have been occasional reports of other viral infections eliciting a diabetogenic effect (reviewed in (Filippi and von Herrath, 2008) ). More recently, Yang and colleagues reported that b-like cells derived from human pluripotent stem cells (hPSCs) as well as b-cells of primary human islets express ACE2, raising the possibility of direct infection and cytotoxicity of b cells by SARS-CoV-2 (Yang et al., 2020) . Importantly, neither of these prior studies (Yang et al., 2010; Yang et al., 2020) characterized the expression of TMPRSS2, an obligate co-factor for SARS-CoV-2 cellular entry. Thus, a more detailed analysis of both ACE2

Coate-4 and TMPRSS2 expression and localization in human pancreatic tissue from normal donors and those with diabetes is urgently needed. The purpose of this study was to test the hypothesis that pancreatic islet b cells possess the cellular machinery that could render them direct targets of SARS-CoV-2. Importantly, we found that ACE2 and TMPRSS2 are not detectable in human islet endocrine cells from normal donors or those with diabetes, making a direct diabetogenic effect of SARS-CoV-2 unlikely.

ACE2 and TMPRSS2 mRNA expression is minimal in human a or b cells.

We first evaluated mRNA expression of ACE2 and TMPRSS2 in FACS-sorted human islet a and b cells from two existing bulk RNA-sequencing (RNA-seq) datasets (Arda et al., 2016; Blodgett et al., 2015) and compared their expression to that of key islet-enriched genes, most of which are normally expressed at relatively low levels in islet cells (e.g., transcription factors).

Median expression level of ACE2 and TMPRSS2 mRNA was much less than transcripts of such key islet-enriched genes in human a and b cells (~84% and 92% lower than a and b cellenriched transcripts, respectively, for DNA-binding transcription factors) ( Figure 1A ; n=7-8 adult donors per study). In addition, analysis of four single-cell (sc) RNA-seq datasets of human pancreatic islets (Baron et al., 2016; Camunas-Soler et al., 2020; Kaestner et al., 2019; Segerstolpe et al., 2016) revealed that ACE2 and TMPRSS2 transcripts were either undetectable or minimally expressed in all endocrine subsets (Figure 1B and S3J) . We note that this includes analysis of the robust Human Pancreas Analysis Program (HPAP) dataset that includes more than 25,000 cells (Kaestner et al., 2019) from 11 normal donors and is confirmed by the analysis of three previously reported, but smaller, datasets ( Figure 1B and S3J) .

Notably, less than 1% of b cells across all four scRNA-seq datasets expressed ACE2 or

As for non-endocrine cells, the HPAP dataset (Kaestner et al., 2019) revealed that a small subset (< 5%) of endothelial and stellate cells (which include pericytes) expressed moderate to high levels of ACE2, whereas only ~1-3% of either population expressed ACE2 in the datasets by Baron et al. (Baron et al., 2016) and Segerstolpe et al. (Segerstolpe et al., 2016) ( Figure 1B) . This difference most likely stems from the number of cells analyzed in that the HPAP dataset contains ~2.5-and 20-fold more cells than that of Baron et al. (Baron et al., 2016) or Segerstolpe et al. (Segerstolpe et al., 2016) , respectively. In addition, pooled analysis of the Coate-6 HPAP (Kaestner et al., 2019) , Baron et al. (Baron et al., 2016) , and Camunas-Soler et al. (Camunas-Soler et al., 2020) datasets showed that less than 1% of acinar or ductal cells expressed ACE2, whereas ~35% of both cell types expressed TMPRSS2. In the dataset by Segerstolpe et al. (Segerstolpe et al., 2016) , ACE2 was expressed in ~20% of acinar and ductal cells, whereas TMPRSS2 was expressed in greater than 75% of both populations ( Figure 1B) .

Given that ACE2 and TMPRSS2 co-expression is required for SARS-CoV-2 host cell entry (Hoffmann et al., 2020) , we evaluated this occurrence and found that on average, less than 1% of acinar, ductal, endothelial and stellate cells co-expressed both transcripts in the HPAP (Kaestner et al., 2019) , Baron et al. (Baron et al., 2016) and Camunas-Soler et al. (Camunas-Soler et al., 2020) datasets. In the Segerstolpe et al. dataset (Segerstolpe et al., 2016) , ~5% of acinar cells and 15% of ductal cells co-expressed ACE2 and TMPRSS2. Notably, no islet endocrine cells co-expressed ACE2 and TMPRSS2 in any of these four datasets.

Altogether, these findings greatly reduce the likelihood that SARS-CoV2 can bind and enter human b cells and have direct cytotoxicity.

ACE2 and TMPRSS2 protein are not detected in adult or juvenile human islet a or b cells.

Recently, Yang and colleagues (Yang et al., 2020) reported that ACE2 protein was present in a and b cells from primary human islets and in b-like cells derived from hPSCs. To investigate these possibilities, we assessed ACE2 expression by immunostaining on cryosections of intact isolated human islets using the same ACE2 antibody as used by Yang and colleagues (Yang et al., 2020) . In accordance with the transcriptomic data reported above, ACE2 was not detected in insulin-positive b cells or glucagon-positive a cells in our samples; instead, ACE2 signal was prominent in supporting cells such as those of the microvasculature ( Figure 1C , top panels).

Since hPSC-derived b-like cells differentiated in vitro are considered "juvenile-like" and not functionally mature b cells (Nair et al., 2019) , one possibility is that ACE2 is expressed in less Coate-7 differentiated cells, or in the cultured, immortalized b cells (EndoCbH1) studied by Fignani et al. (preprint: Fignani, 2020) . We investigated such a possibility by staining for ACE2 in pancreatic sections from juvenile human donors (age range 5 days to 5 years) using the same ACE2 antibody as used by Yang et al. (Yang et al., 2020) . However, ACE2 was not detected in these juvenile b or a cells ( Figure 1C , bottom panels), making this possibility less likely.

To further characterize ACE2 and TMPRSS2 protein expression in the native pancreas, we next analyzed human pancreatic tissue sections from normal donors (ND, n=14; age range 18-59 years) and those with type 2 diabetes (T2D, n=12; age range 42-66 years) or type 1 diabetes (T1D, n=11; age range 13-63 years). ACE2 protein did not co-localize with markers of a or b (Figures 2F', 2L ', and 2R'). We did not detect differences in the signal intensity or spatial distribution of ACE2 or TMPRSS2 between ND and T2D tissue (Figures 2 and S2 ) but labeling for both proteins appeared to be reduced in T1D pancreatic sections. Altogether, these data indicate that the host cell surface proteins required for SARS-CoV-2 entry and infection are not present on islet endocrine cells from normal or diabetic donors.

Recent in silico analyses by Vankadari et al. (Vankadari and Wilce, 2020) and Li et al. (Li et al., 2020b) suggested that human dipeptidyl peptidase 4 (DPP4) may interact with SARS-CoV-2 and facilitate its entry into host cells. Therefore, we examined the distribution of DPP4 in human pancreas and found that it localized to a cells, but not b cells, of ND, T2D and T1D islets ( Figure S3A-I) . This finding is consistent with our analysis of four scRNA-seq datasets showing DPP4-enriched a cells (Figures 1A and S3J) . Given that we did not detect TMPRSS2 within islets, these data suggest that DPP4 is an unlikely mediator of b cell entry by SARS-CoV-2 (Drucker, 2020) .

The discrepancy between our data and that of previous studies (Yang et al., 2010) (Yang et al., 2020 ) (preprint: Fignani, 2020 are likely explained by important differences in experimental approaches and contexts. Yang et al. (Yang et al., 2010) showed ACE2 staining in a single donor islet and did not identify its cellular identity with endocrine markers. Furthermore, the ACE2 antibody used in their study was not reported, which precluded replication of their finding. Fignani et al. (preprint: Fignani, 2020) identified ACE2 protein in presumed islet endocrine cells from seven non-diabetic donors; however, ACE2 was primarily seen in subcellular compartments rather than the expected cell surface location. Colocalization of ACE2 with insulin granules in this study raises the possibility of a staining artifact.

The non-endocrine cell staining pattern of ACE2 in islets prompted us to examine whether ACE2 was expressed in the microvasculature, as described in other organs (Hamming et al., 2004) . Indeed, staining of adult and juvenile human pancreatic tissue sections with CD31, an endothelial cell marker, revealed that ACE2 labeling was localized to the perivascular (Almaca et al., 2018) . These data support our scRNA-seq analysis of the HPAP dataset which identified a subset of pericytes, marked by PDGFRB and COL1A1, that express moderate levels of ACE2 ( Figure 1B ). In addition, our findings are supportive of recent reports of pericyte-specific vascular expression of ACE2 in brain and heart tissue He, 2020) . Importantly, the absence of TMPRSS2 co-expression makes it highly unlikely that islet pericytes are susceptible to direct SARS-CoV-2 infection.

Our work indicated that TMPRSS2 protein was localized to the apical surface of intercalated To further ascertain ductal expression of TMPRSS2 and determine whether ACE2 was expressed beyond exocrine tissue capillaries, we visualized expression of these two proteins in relationship to cytokeratin-19 protein (KRT19), a ductal cell marker. TMPRSS2, but not ACE2, was expressed by KRT19-positive cells on the apical surface of intercalated and larger ducts throughout the exocrine compartment ( Figure   4A-D') . Rarely, both ACE2 and TMPRSS2 were found on the apical surface of ductal epithelial cells but appeared to be spatially distinct ( Figure 4E-H') . These findings support our scRNA-seq Coate-10 analysis in which TMPRSS2 was more highly expressed in ductal cells than ACE2, but cells positive for both ACE2 and TMPRSS2 were scarce. Nevertheless, it is possible that SARS-CoV-2 may target such ductal cells and trigger inflammation in those infrequent ductal areas where both ACE2 and TMPRSS2 reside. Although TMPRSS2 mRNA was detected in acinar cells by scRNA-seq (Figure 1B) , TMPRSS2 protein was undetectable by immunofluorescence analysis (Figure 4) .

While recent case reports of patients with COVID-19 have included mild elevations of amylase and lipase or frank pancreatitis (Karimzadeh et al., 2020; Meireles et al., 2020; Rabice et al., 2020; , the vast majority of patients with COVID-19 have neither elevated pancreatic enzymes nor frank pancreatitis (Ashok et al., 2020; Bonney et al., 2020; Bruno et al., 2020) . Because rare cells in the exocrine compartment co-express ACE2 and TMPRSS2, it is possible that SARS-CoV-2 could infect those cells, induce pancreatitis, and consequently impact islet function. We examined pancreatic specimens from individuals infected with SARS-CoV-2. Histologic analysis of pancreatic tissue from seven COVID-19 patients, three of whom had diabetes, did not show signs of pancreatitis ( Figure 4I ). Further evaluation of exocrine inflammation in COVID-19 autopsy samples, particularly in those with new-onset diabetes, will be of interest.

Caveats related to the current study include: 1) while it is possible that ACE2 and TMPRSS2

are not the only means for SARS-CoV-2 entry into host cells, the preponderance of literature strongly suggests this is the case (Hoffmann et al., 2020; Lan et al., 2020; Sanders et al., 2020; Shang et al., 2020) ; 2) we indirectly assessed the permissiveness of human islet endocrine cells to SARS-CoV-2 by examining the expression of ACE2 and TMPRSS2 in human pancreas, but we did not directly measure binding or viral entry into b cells; and 3) we did not analyze ACE2 and TMPRSS2 expression in pancreatic samples from diabetic patients infected with SARS-CoV-2, so changes in the expression and/or localization of these receptors in the setting of COVID-19 infection cannot be excluded.

In summary, recent reviews, commentaries, and clinical guidelines (Apicella et al., 2020; Bornstein et al., 2020; Goldman et al., 2020; Heaney et al., 2020) have highlighted an attractive hypothesis of SARS-CoV-2 direct cytotoxicity to b cells. Here, we addressed the fundamental question of whether SARS CoV-2 cell entry machinery is present in b cells of human pancreatic tissue. By examining pancreatic ACE2 and TMPRSS2 expression in normal donors and in those with diabetes, we found that, 1) neither protein is detectable in a or b cells; 2) ACE2 is primarily expressed in the islet and exocrine tissue capillaries, and a subset of ductal cells whereas TMPRSS2 is primarily expressed in ductal cells; 3) ACE2 and TMPRSS2 protein expression and distribution appear similar in ND and T2D pancreata; and 4) ACE2 and TMPRSS2 are infrequently co-expressed in pancreatic ducts. Together, these mRNA and protein data do not support the hypothesis that SARS-CoV-2 can bind and infect islet a or b cells and lead to cytotoxicity, causing their demise and eliciting new-onset diabetes. Our results indicate that the impact of SARS-CoV-2 on glucose homeostasis is likely mediated by systemic inflammation or changes in organs such as liver, muscle or adipose tissue. Future studies evaluating the status of ACE2 and TMPRSS2 in these tissues will be of interest. 

Lead contact. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Alvin C. Powers (al.powers@vumc.org).

Data and Code Availability. All data generated or analyzed during this study are included in this published article or in the data repositories listed in the Key Resources Table. Original/source data for Figure 1A (bulk RNA-seq of FACS sorted human islet a and b cells) is available under NCBI GEO accession numbers GSE67543 (Blodgett et al., 2015) and GSE57973 (Arda et al., 2016) . Original/source data for Figure 1B and Figure S3J Coate-17 (IIDP), and local organ procurement organizations. Pancreata from normal donors were processed either for islet isolation (Balamurugan et al., 2003) and/or histological analysis as described previously (described below and in Table S1 ) (Brissova et al., 2018; Dai et al., 2017) .

Pancreata from COVID-19 decedents after autopsy were obtained from Vanderbilt University Medical Center (Nashville, TN) and processed for histological analysis as according to standard procedures for clinical diagnostics (VUMC Histology Peloris Processing Protocol). Samples from donors of both sexes were used in our analyses. Donor demographic information is summarized in Table S1 . The Vanderbilt University Institutional Review Board does not consider de-identified human pancreatic specimens to be human subject research.

Pancreata from juvenile, adult, T1D and T2D donors were obtained within 18 hours from crossclamp and maintained in cold preservation solution on ice until processing, as described previously (Balamurugan et al., 2003; Brissova et al., 2018) . Pancreata recovered from seven COVID-19 decedants were obtained from Vanderbilt University Medical Center (Nashville, TN) within 8-27 hours of death. Donor demographic information is summarized in Table S1 . Human kidney samples were provided by Dr. Agnes Fogo, Vanderbilt University. The Vanderbilt University Institutional Review Board has declared that studies on de-identified human pancreatic specimens do not quality as human subject research.

Mice were maintained on standard rodent chow under a 12-hour light/dark cycle. Kidney from adult NOD.Cg-Prkdc scid Il2rg tm1Wjl / Sz (NSG) mice ages 12 to 18 weeks (Jackson Laboratory) were isolated. Tissue specimens were processed for cryosections as described previously (Brissova et al., 2018) .

Immunohistochemical Analysis. Immunohistochemical analysis was performed on 5-µm cryosections (Figure 2A (Brissova et al., 2014; Brissova et al., 2018; Wright et al., 2020) . FFPE sections were first deparaffinized in xylene and ethanol followed by heat-induced epitope retrieval in a citratebased antigen unmasking solution, pH 6.0 (see Key Resources Table) . Immunofluorescence analysis of isolated islets was performed on 8-µm cryosections of islets embedded in collagen gels as described previously (Brissova et al., 2005; Brissova et al., 2018) . Primary antibodies to

all antigens and their working dilutions are listed in the Key Resources Table. The antigens were visualized using appropriate secondary antibodies listed in the Key Resources Table. Digital images were acquired with an Olympus FLUOVIEW FV3000 laser scanning confocal microscope (Olympus Corporation). 

Million (RPKM) normalized counts were extracted from publicly available RNA-seq datasets (Arda et al., 2016; Blodgett et al., 2015) . The sources of the datasets are summarized in the Key Resources Table. GraphPad Prism v8 was used to generate plots in Figures 1A. Single Cell RNA-seq Data Acquisition. Raw gene count matrices were extracted from existing single cell RNA-seq datasets (Baron et al., 2016; Segerstolpe et al., 2016 , Camunas-Soler et al., 2020 and from the Human Pancreas Analysis Program (HPAP) Database (https://hpap.pmacs.upenn.edu), a Human Islet Research Network consortium. The sources of the datasets are summarized in the Key Resources Table. Gene count matrices were further analyzed using the R package Seurat version 3.1 . Gene count measurements were normalized for each cell by library size and log-transformed using a size factor of 10,000 molecules per cell. The data was further scaled to unit variance and zero mean implemented in the "ScaleData" function. Cell types already annotated by the authors in the Coate-20 original study were used and thus, no clustering was performed. Seurat's "DotPlot" function was used to generate plots shown in Figure 1B to visualize ACE2 and TMPRSS2 scaled expression.

Statistical analysis. Bulk RNA-seq data are expressed as mean ± standard error of mean (Figures 1A) . Sample size (n) is provided as the number of independent donor samples. A pvalue less than 0.05 was considered significant. Statistical analysis (unpaired t-test) was performed using GraphPad Prism software.

None. Human islet and pancreatic donor information is available in Table S1 

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RRID:AB_2340826 Donkey anti-mouse-Cy3 (1:500) Jackson ImmunoResearch Cat# 715-165-150, RRID:AB_2340813 Donkey anti-mouse-Cy5

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Human pancreatic tissue National Disease Research Interchange (NDRI)

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Cat# 4368814 Deposited Data RNA-seq data for FACS purified human alpha and beta cells (Blodgett et al., 2015) NCBI Gene Expression Omnibus GEO: GSE67543 RNA-seq data for FACS purified human alpha and beta cells (Arda et al., 2016) NCBI Gene Expression Omnibus GEO: GSE57973 Single-cell RNA-seq data for human islets (Baron et al., 2016)