key: cord-0695483-ado7z092
authors: Radzikowska, U.; Ding, M.; Tan, G.; Zhakparov, D.; Peng, Y.; Wawrzyniak, P.; Wang, M.; Li, S.; Morita, H.; Altunbulakli, C.; Reiger, M.; Neumann, AU.; Lunjani, N.; Traidl-Hoffmann, C.; Nadeau, K.; O’Mahony, L.; Akdis, CA.; Sokolowska, M.
title: Distribution of ACE2, CD147, cyclophilins, CD26 and other SARS-CoV-2 associated molecules in human tissues and immune cells in health and disease
date: 2020-05-15
journal: bioRxiv
DOI: 10.1101/2020.05.14.090332
sha: 658d8397e3226c1c04c1579c7cb60784b580c027
doc_id: 695483
cord_uid: ado7z092

Background Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19. Methods We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status. Results ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of ACE2- and CD147-related genes in the lesional skin of patients with atopic dermatitis. Conclusions Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related with age, gender, obesity and smoking, as well as with the disease status might contribute to COVID-19 morbidity and severity patterns.

Introduction 82 ATc4 (encoded by NFATC4) and NF-AT5 (encoded by NFAT5) 41, 42 . NFAT complex is a major 146 transcriptional regulator in naive T cells and differentiated effector T cells, dependent on 147 calcium/PLCg/calmodulin/calcineurin signaling 41, 42 . It is also crucial in regulation of T cell anergy and 148 in differentiation and function of T regulatory (Treg) cells 42 . CD147 has been reported as a marker of 149 human Treg cells with highly suppressive activity 43 . NFAT signaling is also important in other cell 150 types such as DCs, mast cells and B cells 41 . Since cyclophilins are regulators of NFAT activation, the 151 extracellular binding of the virus through cyclophilin-CD147 complex, as well as intracellular 152

interactions of cyclophilins with the virus proteins might be important in CD26 (encoded by DPP4), has emerged recently as a potential receptor for SARS-CoV-2, due 154 to the fact that it is a main cellular entry for 45 . Recent structural studies predict that 155 SARS-CoV-2 spike protein directly interact with CD26 on the host cells 22 . CD26 is a cell surface 156 glycoprotein involved in T-cell receptor-mediated T-cell activation and proliferation. It is highly 157 expressed in CD4 and CD8 T cells, and in lower quantities also in NK cells and DCs. As an additional 158 function, it acts as a serine exopeptidase, cleaving peptides of various chemokines, growth factors 159 and peptide hormones. Interestingly, it is also involved in extracellular matrix cleavage. It has been 160 shown in human cells that several polymorphisms in CD26 gene reduce entry of MERS into the host 161 cells 46 . It remains to be functionally determined if this protein can be a functional receptor for SARS-162 The aim of our study was to analyze the gene expression of ACE2, CD147, cyclophilins, CD26 164 and other SARS-CoV-2-related molecules in the broad range of primary human innate and adaptive 165 immune cells and tissues, based on our own next generation sequencing data and public databases 166 from different human cell types and across the diseases which are known to predispose to 169 170

Study subjects, samples and study description 173

We analyzed gene expression of SARS-CoV-2 receptors and related molecules' (Table S1) Table S2 ) . 185

We further investigated different expression patterns of ACE-2-, CD147-and CD26-related 186 genes in the context of potential COVID-19 risk factors, namely age, gender, smoking status, diagnosis 187 of asthma, chronic obstructive pulmonary disease (COPD), hypertension, obesity, atopic dermatitis 188 (AD) (Table S3) . Briefly, we performed in-depth curated analysis of HBECs (Control = 5, Asthma = 6, 189 COPD =5 ), bronchial biopsies (Control = 16, Asthma = 22, COPD = 3, Non-obese = 20, Obese = 21, 190 Normotension = 32, Hypertension = 9, Smoker = 21, Female = 14, Mal e= 27), BAL 191 fluid (Control = 16, Asthma = 22, COPD = 2, Normotension = 31, 192 Hypertension = 9, Smoker = 20, Female = 14, Male = 26) , whole blood (Control = 193 17, Asthma = 21, COPD = 3, Non-obese = 20, Obese = 21, Normotension = 32, Hypertension = 9, Smoker = 21, Female = 14, Male = 27) . In addition, we analyzed gene expression in 195

PBMCs from infants and young children at age of 5-17 or 12-36 months (n=21 and 14, respectively), 196 older children and adolescents at age of 4-16 years (n=16) and adults at age of 16-67 years (n=19), 197 naïve CD4 + T cells from children at age 12 months (n=18) and adults at age 20-35 years (n=4) and skin 198 biopsies (control: n=6, atopic dermatitis: non lesional sites n=11, lesional sites n=11). All studies were 199 accompanied by the relevant ethical permissions, given by the appropriate Institutional Review 200

Board. Each control and diseased subject gave informed consent. Total RNA from evaluated cells and 201 tissues was extracted and transcriptome was analyzed with use of RNA-seq approaches. 202

Signatures of ACE2-, CD147-and CD26-related genes were curated from GSEA and MSigDB 204 Database (Broad Institute, Massachusetts Institute of Technology, and Regents of the University of 205 California) and from literature. Full sets of analyzed genes are described in the Table S1 . Genes of 206 interest were extracted from all data sets. RNA-seq data were processed with inhouse workflow 207 available at https://github.com/uzh/ezRun. Significance threshold for differentially expressed genes 208 was set to p < 0.05 and was calculated for the entire gene lists in each project. All calculations 209 between different conditions were done using the edgeR R package 47 . Spearman correlation 210 coefficient was calculated using Hmisc R package, with the threshold for significance set to α = 0.05. 211

Correlation plots were done using Python's Seaborn library. Coexpression heatmaps as well as 212 correlation heatmaps were done using the corrplot R package 213

Detailed description of each study is included in the Supplementary Methods and the Table  214 S3. First, we analyzed the baseline expression and co-expression of ACE2-, CD147-and CD26-223 related genes in several immune cell types from control, non-diseased adult individuals. In 224 agreement with other recent reports, we observed the expression of ACE2 mainly in epithelial 225 tissues, such as human bronchial epithelial cells and bronchial and skin biopsies ( Figure 1A and S1) 226 6,48 . ACE2 was more abundant in the lung, when compared with the skin barrier sides. In bronchial 227 biopsies ACE2 was co-expressed with TMPRSS2 ( Figure S2 ). Also, in the skin TMPRSS2 was very 228 prominent, while we did not find SLC6A19 in any of the analyzed cells and tissues ( Figure 1B and S1). including SARS-CoV, HIV-1, measles and others 11-13 . All investigated cell populations showed high 246 expression of cyclophilin A and B (PPIA and PPIB) ( Figure 1D and E, Figure S1 ). Interestingly, 247 cyclophilin A was highly expressed in all ILC. In addition, cyclophilin B was highly expressed in pDCS, 248 ILC and plasmablasts. S100A9 was highly expressed not only in bronchial epithelium, but also in the 249 whole blood, neutrophils, classical monocytes and, surprisingly, in naïve B cells ( Figure 1F and Figure 250 S1). 251

Next, we examined transmembrane and intracellular partners of CD147 (BSG), because its 252 cytoplasmic tail, bound to many transmembrane partners, is essential in the entry of other viruses 253 29 . We observed that monocarboxylate transporters, such as SLC16A7 (MCT2) and SLC2A1 (GLUT1) 254 are highly expressed not only at the barrier sites, but also in ILC (MCT2), pDCs, NK cells, T cells and B 255 cells (MCT2, GLUT1) ( Figure 1G and H). CD44 is highly expressed in majority of cells, with the 256 exceptionally high expression in BAL, classical monocytes, naïve CD4 + T cells, terminal effector CD4+ 257 T cells, naïve CD8 + T cells and effector memory CD8 + T cells ( Figure 1I ). ITGB1 (Integrin b-1) and other 258 integrins are highly expressed in airway epithelial cells, but also other cells expressed them ( Figure  259 1J and Figure S1 ). NF-ATc1-3 (NFATC1, NFATC2, NFATC3) were expressed predominantly in CD4 + and 260 CD8 + T and naïve B cells, whereas expression of NFAT4 and NFAT5 was higher in the lung and skin 261 ( Figure 1K and Figure S1 ). 262

Finally, we looked at the expression of CD26 (DPP4). Notably, it was expressed highly in all 263 ILC, and in naïve CD4 + and CD8 + T cells, as well as in pDCs and effector memory CD8 + T cells ( Figure  264 1L and Figure S1 ). 265 266

Clinical evidence from COVID-19 patients worldwide clearly demonstrate an association 269 between disease severity and morbidity with age 1 . In China, less than 1% of the SARS-CoV-2 positive 270 cases were in children younger than 10 years of age 50,51 . Therefore, we analyzed expression patterns 271 of ACE2-, CD147-, and CD26-related genes in peripheral blood mononuclear cells ( Next, we compared ACE2-, CD147-and CD26-related gene expression profile in the purified 283 naïve CD4 + T cells between young children and adults ( Figure 2B ). Low expression of ACE2-related 284 genes was observed in both children and adults. Several CD147-related genes showed higher 285 expression in adults, including CD44, certain MCTs, SLC3A2 (CD98), SLC2A1 (GLUT1), NFATC1 and 286 NFATC3. Also, CD26 (DPP4) was expressed at a higher level in adults. In contrast, other CD147-related 287 genes were expressed at lower levels in adults, such as cyclophilins A and B (PPIA and PPIB), S100A9, 288

LGALS3, integrins (ITGA6, ITGA3) and NFATC2. We analyzed expression of ACE2-, CD147-and CD26-related genes from different cells and 293 tissues in various comorbidities and risk factors, which have been shown, or are suspected to 294 predispose to SARS-CoV-2 infection and/or COVID-19 progression. Upper and lower airways are the 295 initial entry of SARS-CoV-2, thus we first analyzed gene expression in the HBECs and the bronchial 296 biopsies from patients with asthma or COPD as compared to the non-diseased controls. In our 297 cohorts, we did not see any significant difference in ACE2 expression in HBECs or bronchial biopsy 298 between control, asthma and COPD patients ( Figure 3A and B). However, in bronchial biopsies ACE2 299 expression was higher in smokers ( Figure 3B ). In HBECs, we observed higher expression of TMPRSS2 300 in asthma ( Figure 3A ), raising the possibility that in asthmatic airways the cleavage of spike protein 301 of SARS-CoV-2 might be more efficient. We also observed a trend of increased expression of CD147 302 (BSG) in HBECs ( Figure 3A ) and in bronchial biopsies ( Figure 3B ) from COPD patients. Additionally, 303 glucose transporter GLUT1 (SLC2A1), integrin a-3 (ITGA3) and galectin-3 (LGALS3) were higher 304 expressed in HBECs, whereas SLC7A5 (CD98), integrins a-3 (ITGA3) and a-6 (ITGA6) were higher 305 expressed in the bronchial biopsies of COPD patients. CD44 and APOD were higher expressed in 306 asthma ( Figure 3A , B and Figures S4, S5) . In bronchial biopsies, ACE2-, CD147-and CD26-related genes 307 showed similar cluster of co-expression in control and asthma ( Figure S2 and S6). Interestingly, ACE2 308 co-expressed with PPIB and NME1 in asthma, which was not found in controls ( Figure S6 ). Taken 309 together, airway epithelium in asthma and COPD showed a gene signature that potentially can 310 facilitate SARS-CoV-2 entry and enhance internalization after receptor binding. 311

Next, we analyzed BAL and whole blood gene expression in patients with asthma and controls 312 (Figure 3 C, D and Figure S7 , S8). Unfortunately, we have access to the limited number of BAL samples 313 from COPD patients. In BAL, which reflects local lung immune microenvironment, and in blood, 314 reflecting systemic immune responses, CD147 (BSG) was expressed equally high in asthma patients 315 and in controls ( Figure 3C , Figure S7 ). In blood, patients with asthma had also higher expression of 316 integrin ITGA6 and NFATC2, as compared to controls ( Figure 3D ). There was a greater abundance in 317 the cluster of co-expressed genes in asthma in BAL and especially in blood ( Figure S9 , S10). In asthma 318 patients, BSG (CD147) showed co-expression with SLC7A5 (CD98) in blood, DPP4 (CD26) also co-319 expressed with CD44 and ITGA6 ( Figure S10 ). 320

Next, we analyzed the ACE2-, CD147-and CD26-related gene expression in our controls, 321 asthma and COPD patients according to the additional clinical features, which have been reported as 322 a risk factor comorbidity for COVID-19, such as hypertension, smoking, gender and obesity 23,53 . We 323 did not see any major differences in the gene expression in the bronchial biopsies based on these 324 features, except higher ACE2 expression in smokers ( Figure 3B , Figure S5 ). However, we noted several 325 important differences in the BAL and in the whole blood ( Figure S7 , S8). In case of smoking, expression of S100A9 and CD44 was 329 elevated in both BAL ( Figure 3C , Figure S7 ) and blood ( Figure 3D , Figure S8 ). Obesity was an important 330 factor leading to the significant changes in the BAL and blood. We observed that MCT4 (SLC16A3), 331 integrin ITGA3, NFATC1 and PSEN1 were more expressed in the BAL of obese individuals ( Figure 3C , 332 Figure S7 ), whereas CD147 (BSG), PPIA, LGALS3 and NOD2 were more expressed in their blood ( Figure  333 3D). Finally, regarding gender in our cohort, MCT2 (SLC16A7), CD98 (SLC7A5), NFATC2 were higher 334 expressed in the BAL of male subjects ( Figure 3C , Figure S7 ). 335 336 Expression of CD147-related genes correlates with BMI and age in the BAL and blood 337

Since obesity and age were important variables, we additionally correlated these two 338 variables with the expression of ACE2-, CD147-and CD26-related genes in the bronchial biopsy, BAL 339 and blood of our adult non-diseased and diseased cohorts. We did not find any significant 340 correlations between BMI and age and the receptor-related gene expression in the bronchial 341 biopsies. However, we noted that the expression of SLC16A3 (MCT4), ITGA3, LGALS3 in BAL positively 342 correlated with BMI ( Figure 4A -C) and the expression of CD44 positively correlated with the age of 343 the subjects ( Figure 4D ). Interestingly, whole blood expression of CD147 (BSG), PPIA, S100A9, CD44 344 and LGALS3 correlated positively with the BMI, whereas SLC16A3 positively correlated with age 345 (Figure 4 E-J). In summary, these findings suggest that higher BMI and older age lead to higher 346 expression of CD147-related genes on immune cells, but not on the barrier cells, which potentially 347 can influence the development and the course of COVID-19. COVID-19 pandemic is developing at such a pace that extraordinary actions are being initiated to 363 learn quickly about its biology, transmission and potential means of prevention and treatment. In 364 this spirit, we first performed an extensive literature and database search and curated a list of proven 365 and potential receptors for SARS-CoV-2 and interaction partners, whose expression in different 366 tissues and cells might be involved in the course of immunological response in COVID-19 ( Figure 6 ) 367 55 . Next, we analyzed these genes in the broad spectrum of cell types and tissues in healthy controls 368 to evaluate the level of their expression and their co-expression profiles, as well as evaluated their 369 expression in healthy children, adolescents and adults. While interesting associations were observed 370 to be age-dependent, these findings must be further explored and repeated due to the possibility of 371 batch-specific systematic variations in the gene expression values between in-house and public 372 datasets. Despite our efforts in applying identical data analysis workflow for the datasets produced 373 by our group and those available in public repositories, different sequencing facilities and experiment 374 protocols can lead to altered gene expression values, especially for genes with extreme gene length 375 and G/C content. Finally, we analyzed gene expression in adults with known and potential COVID-19 376 comorbidities and risk factors such as COPD, asthma, hypertension, obesity, smoking, male gender 377 and AD. These conditions can be directly compared, as they were performed internally in the context 378 of same project. 379 ACE2 is a receptor for SARS-CoV-2 3 , whereas TMPRSS2 is a transmembrane host protease, 380 which cleaves the viral spike protein thus facilitating virus fusion to the cellular membranes process 381 (S) 3,56 . SLC6A19, physiologically a neutral amino acid transporter, potentially can block the access of 382 TMPRSS2 to ACE2 and subsequently reduce active infection 4,6 . Our results, in agreement with recent 383 reports 6,57,58 , indicate that airway epithelium has high ACE2 and TMPRSS2 co-expression, and no 384 expression of protective SLC6A19 and thus might be highly susceptible for SARS-CoV-2 infection. In 385 addition, it has been shown recently that ACE2 is highly expressed in naso-and oropharynx, which 386 are the sites of active SARS-CoV-2 replication and a main source of infectious particles 6,57,58 . 387

Interestingly, we observed high expression of ACE2 and TMPRSS2 in bronchial airway epithelium: in 388

HBECs ALI cultures in vitro, as well as in vivo in humans in bronchial biopsies, indicating that they can 389 be as important in initiation and progression of COVID-19, as recently shown for type II pneumocytes 390 58 . We have not observed the expression of SLC6A19 in any of the analyzed cells and tissues, yet it is 391 known to be expressed is intestine 59 . Interestingly, in contrast to Leung and colleagues 60 , we have 392 not seen higher expression of ACE2 in HBECs or bronchial biopsy of patients with COPD, but our 393 sample size was very limited, and potentially a bronchial biopsy site was different, which might be 394 the reason of this inconsistency. However, consistently with this report 61 , we observed higher 395 expression of ACE2 in the bronchial biopsy of current smokers, which might indicate that current 396 smoking status, might be a stronger factor of increased ACE2 expression in airway epithelium than 397 COPD per se. On the other hand, ACE2 and the angiotensin II type 2 receptor (AT2) were reported to 398 protect from severe acute lung injury in mice 62 , therefore an importance of ACE2 in SARS-CoV-2 399 infection and COVID-19 progression should be further explored. In addition, in HBECs of patients with 400 asthma, we observed higher expression of TMPRSS2, which increases the possibility of SARS-CoV-2 401 cleavage in asthmatic bronchi. Even though initially asthma was not reported to be a significant 402 comorbidity for COVID-19, more observations from Europe and the US seem to show otherwise 63 . It 403 might be related to the heterogeneity of asthma endotypes type 2 asthma (allergic) and non-type 2 404 (non-allergic). Allergen exposure, allergic sensitization and high IgE lead to lower ACE2 expression in 405 the nasal and bronchial epithelium of asthma patients 64 . Thus, it is possible that ACE2 expression in 406 the airways of allergic patients, even if slightly protective in terms of infection with SARS-CoV-2, 407 might also predispose to faster progression of COVID-19 to more severe forms, especially in case of 408 higher TMPRSS2 expression. 409

We found that immune cells do not express ACE2, TMPRSS2 or SLC6A19, which has also been 410 observed by others 2,5 . Importantly though, we found that CD147 and its extracellular agonists and 411 transmembrane partners are highly expressed in innate and adaptive immune cells in the lungs and 412 in the periphery, suggesting that they should be further investigated in SARS-CoV-2 spread and 413 COVID-19 pathology 9 . Here, we report high expression of CD147 in both, epithelial tissues and innate 414 and adaptive immune cells. Potentially, epithelial cells, macrophages, monocytes, ILCs, NK cells, T 415 cells and B cells can be infected in the lungs or can carry SARS-CoV-2 from infected epithelial cells via 416 CD147 and participate in the local and systemic spread of the virus, and in exaggerated immune 417 response 65 . 418

We found here that CD147 is slightly higher expressed in the HBECs and bronchial biopsy of 419 COPD patients, as well as it is higher expressed in the blood of obese individuals. Obesity is one of 420 the main comorbidities reported in patients with severe COVID-19 63 , and since CD147 expression in 421 the whole blood correlates positively with BMI in our cohort, it certainly needs further attention in 422 relation to COVID-19. Importantly, CD147 expression is upregulated by high glucose concentrations 423 66 , which might reflect its correlation with obesity, and potentially also with diabetes, another very The differential profile of ACE2-, CD147-and CD26-related gene expression in healthy subjects 465 of different ages need to be interpreted with caution due to the distinct origins of these populations, 466 as well as potential experimental bias (even if we performed normalization strategies, similar 467 bioinformatic pipelines and cautious assessment of raw data quality, prior to analysis). Nevertheless, 468 our observations are largely in agreement with other recent findings correlating gene expression in 469 the whole blood and PBMCs with age 79 . Having this in mind, it is intriguing to observe that expression 470 of NOD2, some MCTs, integrins and NFATs seemed to increase with age, whereas the expression of 471 genes coding g-secretase complex is decreasing with age in PBMCs. CD44 and MCT4 also correlated 472 with age in BAL and blood, respectively. Moreover, some of the differences between children and 473 adults, such as higher expression of CD26, CD44, GLUT1 (SLC2A1) and specific NFATs in adults were 474 also observed in naïve purified CD4 + T cells. This requires further investigation, but differences in 475 expression pattern may be related to the striking differences in the morbidity of SARS-CoV-2 476 between children and adults 80 

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SARS-CoV-2 infects T lymphocytes through its spike protein-508 mediated membrane fusion

Function of HAb18G/CD147 in invasion of host cells by severe acute 510 respiratory syndrome coronavirus

CD147 facilitates HIV-1 infection by interacting 512 with virus-associated cyclophilin A

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Basigin (CD147), a multifunctional transmembrane glycoprotein with various 520 binding partners

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CD147 inhibits the nuclear factor of activated T-cells by 577 impairing Vav1 and Rac1 downstream signaling

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(n=4), naïve B cells (n=4), plasmablasts (n=4) and skin biopsies (n=6) from healthy adults. Data 687 obtained from in vitro approaches are highlighted in red. Names of the proteins encoded by analysed 688 genes are

bronchoalveolar fluid cells; Class. monocytes, classical monocytes; pDCs, plasmocytoid 690 dendritic cells; ILC1, group 1 innate lymphoid cells; ILC2, group 2 innate lymphoid cells, ILC3, group 3 691 innate lymphoid cells; NK, natural killer cells

A) Expression of ACE2-, CD147-, NFAT-and CD-26-related genes in the primary 697 human PBMCs in healthy children aged 5-17 months (n=21), 12-36 month (n=14), 4-16 years (n=16) 698 and healthy adults aged 16-67 years (n=19). B) Expression of ACE2

All heatmaps display normalized gene expression across the groups 701 (rows normalization). Color-coding represents gene families related with ACE2 (orange), CD147 702 (green), NF-ATs (purple) and CD26 (yellow). MO, months old, YO, years old

COPD, hypertension, smoking, obesity and gender is associated with differential 707 expression of ACE2-, CD147-, and CD26-related genes in immune cells and tissues. A) Differential 708 expression of ACE2, TMPRSS2, BSG, SLC2A1, CD44 and ITGA3 genes in in vitro Air Liquid Interface

asthma (n=6) and COPD (n=5) patients. B) Differential expression of ACE2, BSG, SLC7A5, ITGA3, ITGA6 711 genes in bronchial biopsies from non-diseased controls (n=16), patients with asthma (n=22) and

or in comparison of smokers (n=21) with non-smoking individuals (n=19). C) Differential 713 expression of BSG

or in comparison of hypertensive (n=9) with normotensive (n=31) individuals; smokers 716 (n=20) with non-smokers (n=19); obese (n=21) with non-obese (n=19); and males (n=26) with females 717 (n=14). D) Differential expression of BSG

or in comparison of hypertensive (n=9) with normotensive (n=32) individuals; smokers 720 (n=21), with non-smokers (n=19); obese (n=21) with non-obese individuals (n=20); and males (n=27) 721 with females (n=14). Names of the proteins encoded by analyzed genes are

bronchial biopsy; BAL, bronchoalveolar fluid cells; COPD, chronic obstructive pulmonary

Expression of certain CD147-related genes correlates with BMI and age in the BAL and blood

Correlation of E) BSG 730 expression and BMI, F) PPIA expression and BMI, G) S100A9 expression and BMI, H) CD44 expression 731 and BMI, I) LGALS3 expression and BMI, J) SLC16A3 and age in the whole blood. Spearman correlation 732 coefficient (r) was calculated, with the threshold of significance set to p = 0.05. Names of the proteins 733 encoded by analyzed genes are

Unique expression profile of ACE2-and CD147-related genes in lesional skin in patients with atopic 738 dermatitis. A) Expression of ACE2

SDC1 and DPP4 genes in the skin 740 of healthy controls (n=6) and in the lesional (n=11), and non-lesional (n=11) skin of atopic dermatitis 741 patients. Names of the proteins encoded by analyzed genes are stated in the margins

Summary of the tissue and cellular expression, and models of A) ACE2, B) CD147, C) CD26 and their 746 interaction partners. Please refer to the text for further details

Gal-3, Galectin 3; MCTs, Monocarboxylate transporters