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Article ; Online: Illuminating COVID-19 lung disease through autopsy studies

David K. Meyerholz / Paul B. McCray, Jr.

EBioMedicine, Vol 57, Iss , Pp 102865- (2020)

2020

Keywords	Medicine ; R ; Medicine (General) ; R5-920 ; covid19
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub, Matthew D / McCray, Jr., Paul B

Genes. 2020 May 13, v. 11, no. 5

2020

Abstract: Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for ... ...

Abstract	Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.
Keywords	biogenesis ; cystic fibrosis ; genes ; high-throughput screening methods ; mutants ; mutation ; quality control ; temperature ; therapeutics ; transcriptomics
Language	English
Dates of publication	2020-0513
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11050546
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: CFTR-rich ionocytes mediate chloride absorption across airway epithelia

Lei Lei / Soumba Traore / Guillermo S. Romano Ibarra / Philip H. Karp / Tayyab Rehman / David K. Meyerholz / Joseph Zabner / David A. Stoltz / Patrick L. Sinn / Michael J. Welsh / Paul B. McCray Jr. / Ian M. Thornell

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 20

Abstract: The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl– into the airway surface liquid through cystic fibrosis transmembrane conductance regulator ( ... ...

Abstract	The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl– into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl– channels in their basolateral membrane. Disrupting barttin/Cl– channel function impaired liquid absorption, and overexpressing barttin/Cl– channels increased absorption. Together, apical CFTR and basolateral barttin/Cl– channels provide an electrically conductive pathway for Cl– flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption.
Keywords	Cell biology ; Pulmonology ; Medicine ; R
Subject code	621
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sensitization of Non-permissive Laboratory Mice to SARS-CoV-2 with a Replication-Deficient Adenovirus Expressing Human ACE2

Lok-Yin Roy Wong / Kun Li / Jing Sun / Zhen Zhuang / Jincun Zhao / Paul B. McCray, Jr. / Stanley Perlman

STAR Protocols, Vol 1, Iss 3, Pp 100169- (2020)

2020

Abstract: Summary: Common laboratory mice such as BALB/c and C57BL/6 mice are not permissive to SARS-CoV2 infection. Sensitization of laboratory mice with Adenovirus expressing human ACE2 (Ad5-hACE2) provides a rapid model for testing viral intervention in vivo. ... ...

Abstract	Summary: Common laboratory mice such as BALB/c and C57BL/6 mice are not permissive to SARS-CoV2 infection. Sensitization of laboratory mice with Adenovirus expressing human ACE2 (Ad5-hACE2) provides a rapid model for testing viral intervention in vivo. Despite the lack of lethal outcome, Ad5-hACE2-sensitized mice show 20% weight loss on average upon viral challenge with infectious virus being detected at the site of sensitization. This protocol describes the sensitization and subsequent infection of common laboratory mice for use in testing anti-viral interventions.For complete details on the use and execution of this protocol, please refer to Sun et al. (2020).
Keywords	Immunology ; Model Organisms ; Science (General) ; Q1-390
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

Miguel E. Ortiz / Andrew Thurman / Alejandro A. Pezzulo / Mariah R. Leidinger / Julia A. Klesney-Tait / Philip H. Karp / Ping Tan / Christine Wohlford-Lenane / Paul B. McCray, Jr. / David K. Meyerholz

EBioMedicine, Vol 60, Iss , Pp 102976- (2020)

2020

Abstract: Background: Zoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding ... ...

Abstract	Background: Zoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the receptor for SARS-CoV-2. Numerous reports describe ACE2 mRNA abundance and tissue distribution; however, mRNA abundance is not always representative of protein levels. Currently, there is limited data evaluating ACE2 protein and its correlation with other SARS-CoV-2 susceptibility factors. Materials and methods: We systematically examined the human upper and lower respiratory tract using single-cell RNA sequencing and immunohistochemistry to determine receptor expression and evaluated its association with risk factors for severe COVID-19. Findings: Our results reveal that ACE2 protein is highest within regions of the sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe disease development, respectively. In the lung parenchyma, ACE2 protein was found on the apical surface of a small subset of alveolar type II cells and colocalized with TMPRSS2, a cofactor for SARS-CoV2 entry. ACE2 protein was not increased by pulmonary risk factors for severe COVID-19. Additionally, ACE2 protein was not reduced in children, a demographic with a lower incidence of severe COVID-19. Interpretation: These results offer new insights into ACE2 protein localization in the human respiratory tract and its relationship with susceptibility factors to COVID-19.
Keywords	Lung ; Expression ; Alveolar type II cells ; Ciliated cells ; Immunohistochemistry ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Innate immune functions of the airway epithelium.

Bartlett, Jennifer A / Fischer, Anthony J / McCray, Paul B Jr

Contributions to microbiology

2008 Volume 15, Page(s) 147–163

Abstract: The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these ... ...

Abstract	The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these challenges many strategies have evolved to protect the host. These include the barrier functions of the epithelium, cough, mucociliary clearance, resident professional phagocytes, and the secretion of a number of proteins and peptides with host defense functions. Thus, the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity. In addition, this tissue may serve the function of a secondary amplifier of innate immune responses following neurohumoral input, stimulation with cytokines from cells such as alveolar macrophages, or engagement of pattern recognition receptors. Here, we provide an overview of the airway epithelium's role in pulmonary innate immunity, especially in the context of bacterial and viral infections, emphasizing findings from human cells and selected animal models. We also provide examples of human disease states caused by impaired epithelial defenses in the lung.
MeSH term(s)	Animals ; Anti-Infective Agents/immunology ; Anti-Infective Agents/pharmacology ; Antimicrobial Cationic Peptides/immunology ; Antimicrobial Cationic Peptides/pharmacology ; Cystic Fibrosis/genetics ; Cystic Fibrosis/immunology ; Cystic Fibrosis/microbiology ; Epithelium/immunology ; Epithelium/microbiology ; Epithelium/virology ; Humans ; Immunity, Innate ; Kartagener Syndrome/genetics ; Kartagener Syndrome/immunology ; Kartagener Syndrome/microbiology ; Receptors, Immunologic/immunology ; Respiratory System/immunology ; Respiratory System/microbiology ; Respiratory System/virology
Chemical Substances	Anti-Infective Agents ; Antimicrobial Cationic Peptides ; Receptors, Immunologic
Language	English
Publishing date	2008-05-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1420-9519
ISSN	1420-9519
DOI	10.1159/000136349
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An Activated Immune and Inflammatory Response Targets the Pancreas of Newborn Pigs with Cystic Fibrosis

Abu-El-Haija, Maisam / Sinkora, Marek / Meyerholz, David K. / Welsh, Michael J. / McCray, Jr., Paul B. / Butler, John / Uc, Aliye

Pancreatology

2011 Volume 11, Issue 5, Page(s) 506–515

Abstract: ... to non-CF. B cells, effector (MHC-II) and cytotoxic (CD2CD8) γδ T cells, activated (MHC-II and/or CD25 ...

Institution	Departments of Pediatrics Pathology Microbiology, and Internal Medicine, and Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Immunology and Gnotogiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Novy Hradek, Czech Republic
Abstract	Background/Aims: In cystic fibrosis (CF), pancreatic disease begins in utero and progresses over time to complete destruction of the organ. Although inflammatory cells have been detected in the pancreas of humans and pigs with CF, their subtypes have not been characterized. Methods: Using four-color flow cytometry, we analyzed the surface antigens of leukocytes in pancreas, blood, and mesenteric lymph nodes (MLN) of newborn pigs with CF (CFTR and CFTRΔF508/ΔF508) and in those without CF (CFTR, CFTRΔF508CFTR). Pancreatic histopathology was examined with HE stain. Results: CF pig pancreas had patchy distribution of inflammatory cells with neutrophils/macrophages in dilated acini, and lymphocytes in the interstitium compared to non-CF. B cells, effector (MHC-II) and cytotoxic (CD2CD8) γδ T cells, activated (MHC-II and/or CD25) and effector (CD4CD8) αβ T helper cells, effector natural killer cells (MHC-IICD3CD8), and monocytes/macrophages and neutrophils were increased in the CF pig pancreas compared to pigs without CF. Blood and MLN leukocyte populations were not different between CF and non-CF pigs. Conclusions: We discovered an activated immune response that was specific to the pancreas of newborn CF pigs; inflammation was not systemic. The presence of both innate and adaptive immune cells suggests that the disease process is complex and extensive.
Keywords	Cystic fibrosis ; Pancreatitis ; Flow cytometry ; Inflammation ; Lymphocytes ; Neutrophils ; Macrophages ; NK cells
Language	English
Publishing date	2011-11-01
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Original Paper
ZDB-ID	2056680-3
ISSN	1424-3911 ; 1424-3903
ISSN (online)	1424-3911
ISSN	1424-3903
DOI	10.1159/000332582
Database	Karger publisher's database

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Article: Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein

Brindley, Melinda A / Hunt, Catherine L / Kondratowicz, Andrew S / Bowman, Jill / Sinn, Patrick L / McCray, Paul B., Jr / Quinn, Kathrina / Weller, Melodie L / Chiorini, John A / Maury, Wendy

Virology. 2011 July 5, v. 415, no. 2

2011

Abstract: In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ... ...

Abstract	In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and α-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl.
Keywords	RNA interference ; Zaire Ebola virus ; antiserum ; cell membranes ; gene expression ; genes ; glycoproteins ; messenger RNA ; precipitin tests ; receptor protein-tyrosine kinase ; virion ; virus receptors ; viruses ; covid19
Language	English
Dates of publication	2011-0705
Size	p. 83-94.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2011.04.002
Database	NAL-Catalogue (AGRICOLA)

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Article: Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions

Lorentzen, Daniel / Durairaj, Lakshmi / Pezzulo, Alejandro A / Nakano, Yoko / Launspach, Janice / Stoltz, David A / Zamba, Gideon / McCray, Paul B., Jr / Zabner, Joseph / Welsh, Michael J / Nauseef, William M / Bánfi, Botond

Free radical biology & medicine. 2011 May 1, v. 50, no. 9

2011

Abstract: A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN−) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN−). Airway epithelial cultures have been shown to secrete SCN− in a CFTR-dependent manner. Thus, ... ...

Abstract	A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN−) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN−). Airway epithelial cultures have been shown to secrete SCN− in a CFTR-dependent manner. Thus, reduced SCN− availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing the SCN− concentration in the nasal airway surface liquid (ASL) of CF patients and non-CF subjects and in the tracheobronchial ASL of CFTR-ΔF508 homozygous pigs and control littermates. In the nasal ASL, the SCN− concentration was ~30-fold higher than in serum independent of the CFTR mutation status of the human subject. In the tracheobronchial ASL of CF pigs, the SCN− concentration was somewhat reduced. Among human subjects, SCN− concentrations in the ASL varied from person to person independent of CFTR expression, and CF patients with high SCN− levels had better lung function than those with low SCN− levels. Thus, although CFTR can contribute to SCN− transport, it is not indispensable for the high SCN− concentration in ASL. The correlation between lung function and SCN− concentration in CF patients may reflect a beneficial role for SCN−.
Keywords	blood serum ; cystic fibrosis ; genes ; homozygosity ; humans ; lung function ; mutation ; nose ; pathogenesis ; patients ; swine
Language	English
Dates of publication	2011-0501
Size	p. 1144-1150.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2011.02.013
Database	NAL-Catalogue (AGRICOLA)

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Article: Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth

Rogan, Mark P / Reznikov, Leah R / Pezzulo, Alejandro A / Gansemer, Nicholas D / Samuel, Melissa / Prather, Randall S / Zabner, Joseph / Fredericks, Douglas C / McCray, Paul B. Jr / Welsh, Michael J / Stoltz, David A

Proceedings of the National Academy of Sciences of the United States of America. 2010 Nov. 23, v. 107, no. 47

2010

Abstract: People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been blamed on malnutrition and pulmonary inflammation. However, ... ...

Abstract	People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been blamed on malnutrition and pulmonary inflammation. However, patients with CF already have a reduced weight at birth, a manifestation not likely secondary to poor nutrition or inflammation. We found that, like humans, CF pigs were smaller than non-CF littermates and had lower IGF1 levels. To better understand the basis of IGF1 reduction, we studied newborn pigs and found low IGF1 levels within 12 h of birth. Moreover, humerus length and bone mineral content were decreased, consistent with less IGF1 activity in utero. These findings led us to test newborn humans with CF, and we found that they also had reduced IGF1 levels. Discovering lower IGF1 levels in newborn pigs and humans indicates that the decrease is not solely a consequence of malnutrition or pulmonary inflammation and that loss of cystic fibrosis transmembrane conductance regulator function has a more direct effect. Consistent with this hypothesis, we discovered reduced growth hormone release in organotypic pituitary slice cultures of newborn CF pigs. These findings may explain the long-standing observation that CF newborns are smaller than non-CF babies and why some patients with good clinical status fail to reach their growth potential. The results also suggest that measuring IGF1 levels might be of value as a biomarker to predict disease severity or the response to therapeutics. Finally, they raise the possibility that IGF1 supplementation beginning in infancy might be beneficial in CF.
Keywords	biomarkers ; birth weight ; cystic fibrosis ; disease severity ; humans ; humerus ; infancy ; inflammation ; insulin-like growth factor I ; malnutrition ; mineral content ; neonates ; nutrition ; patients ; somatotropin ; swine ; therapeutics
Language	English
Dates of publication	2010-1123
Size	p. 20571-20575.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1015281107
Database	NAL-Catalogue (AGRICOLA)

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