scholarly journals Comparative Replication and Immune Activation Profiles of SARS-CoV-2 and SARS-CoV in Human Lungs: An Ex Vivo Study With Implications for the Pathogenesis of COVID-19

2020 ◽  
Vol 71 (6) ◽  
pp. 1400-1409 ◽  
Author(s):  
Hin Chu ◽  
Jasper Fuk-Woo Chan ◽  
Yixin Wang ◽  
Terrence Tsz-Tai Yuen ◽  
Yue Chai ◽  
...  
Keyword(s):  
Immune Activation ◽  
Human Lung ◽  
Ex Vivo ◽  
Clinical Manifestations ◽  
Asymptomatic Infection ◽  
Replication Capacity ◽  
Cell Tropism ◽  
Human Lungs ◽  
Activation Profile ◽  
Underlying Mechanisms

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that has resulted in more than 2 000 000 laboratory-confirmed cases including over 145 000 deaths. Although SARS-CoV-2 and SARS-CoV share a number of common clinical manifestations, SARS-CoV-2 appears to be highly efficient in person-to-person transmission and frequently causes asymptomatic or presymptomatic infections. However, the underlying mechanisms that confer these viral characteristics of high transmissibility and asymptomatic infection remain incompletely understood. Methods We comprehensively investigated the replication, cell tropism, and immune activation profile of SARS-CoV-2 infection in human lung tissues with SARS-CoV included as a comparison. Results SARS-CoV-2 infected and replicated in human lung tissues more efficiently than SARS-CoV. Within the 48-hour interval, SARS-CoV-2 generated 3.20-fold more infectious virus particles than did SARS-CoV from the infected lung tissues (P < .024). SARS-CoV-2 and SARS-CoV were similar in cell tropism, with both targeting types I and II pneumocytes and alveolar macrophages. Importantly, despite the more efficient virus replication, SARS-CoV-2 did not significantly induce types I, II, or III interferons in the infected human lung tissues. In addition, while SARS-CoV infection upregulated the expression of 11 out of 13 (84.62%) representative proinflammatory cytokines/chemokines, SARS-CoV-2 infection only upregulated 5 of these 13 (38.46%) key inflammatory mediators despite replicating more efficiently. Conclusions Our study provides the first quantitative data on the comparative replication capacity and immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Our results provide important insights into the pathogenesis, high transmissibility, and asymptomatic infection of SARS-CoV-2.

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

2020 ◽  
Author(s):  
Hin Chu ◽  
Bingjie Hu ◽  
Xiner Huang ◽  
Yue Chai ◽  
Yixin Wang ◽  
...  
Keyword(s):  
Human Lung ◽  
Ex Vivo ◽  
Sialic Acids ◽  
Lung Epithelial Cells ◽  
Human Lung Tissue ◽  
Human Lungs ◽  
Lung Epithelial ◽  
Viral Determinants ◽  
Attachment Factor ◽  
Human Lung Epithelial Cells

Abstract SARS-CoV-2 has affected over 9 million patients with more than 460,000 deaths in about 6 months. Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells, which are not previously reported, may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we reported key host and viral determinants that were essential for efficient SARS-CoV-2 infection in the human lung. First, we identified heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Second, we demonstrated that while cell surface sialic acids significantly restricted SARS-CoV infection, SARS-CoV-2 could largely overcome sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissue explants. Third, we demonstrated that the inserted furin-like cleavage site in SARS-CoV-2 spike was required for efficient virus replication in human lung but not intestine tissues. Overall, these findings contributed to our understanding on efficient SARS-CoV-2 infection of human lungs.

Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia

1996 ◽  
Vol 80 (5) ◽  
pp. 1681-1686 ◽  
Author(s):  
T. Sakuma ◽  
S. Suzuki ◽  
K. Usuda ◽  
M. Handa ◽  
G. Okaniwa ◽  
...  
Keyword(s):  
Fluid Transport ◽  
Human Lung ◽  
Ex Vivo ◽  
Transport Mechanisms ◽  
Alveolar Fluid Clearance ◽  
Alveolar Epithelial ◽  
Severe Hypothermia ◽  
Human Lungs ◽  
Channel Transport

Although hypothermia abolishes alveolar fluid clearance in the in situ goat lung and in the ex vivo human lung, it is unknown whether alveolar fluid clearance resumes in lungs that are rewarmed after severe hypothermia. An isosmolar albumin solution was instilled into resected human lungs that were rewarmed to 37 degrees C after hypothermia (7 +/- 3 degrees C), and then alveolar fluid clearance was measured by the concentration of albumin in the alveolar fluid sample after 4 h. In control experiments in lungs that had not been cooled and rewarmed, alveolar fluid clearance was 11 +/- 2% over 4 h. In separate experiments, hypothermia completely abolished alveolar fluid clearance. However, alveolar fluid clearance resumed to a normal level of 12 +/- 1% over 4 h in the lungs that were rewarmed after hypothermia. Amiloride decreased alveolar fluid clearance by 47% in the rewarmed lungs. Terbutaline increased alveolar fluid clearance by nearly 300% in 2-h experiments in the rewarmed lungs (P < 0.05). The results of this study indicate that alveolar sodium-channel transport mechanisms are preserved in resected human lungs that are exposed to rewarming after hypothermia.

scholarly journals Acellular human lung scaffolds to model lung disease and tissue regeneration

2018 ◽  
Vol 27 (148) ◽  
pp. 180021 ◽  
Author(s):  
Sarah E. Gilpin ◽  
Darcy E. Wagner
Keyword(s):  
Human Lung ◽  
Ex Vivo ◽  
Lung Epithelial Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Lung Repair ◽  
Human Lungs ◽  
Lung Epithelial ◽  
The Matrix ◽  
Extracellular Environment

Recent advances in whole lung bioengineering have opened new doors for studying lung repair and regeneration ex vivo using acellular human derived lung tissue scaffolds. Methods to decellularise whole human lungs, lobes or resected segments from normal and diseased human lungs have been developed using both perfusion and immersion based techniques. Immersion based techniques allow laboratories without access to intact lobes the ability to generate acellular human lung scaffolds. Acellular human lung scaffolds can be further processed into small segments, thin slices or extracellular matrix extracts, to study cell behaviour such as viability, proliferation, migration and differentiation. Recent studies have offered important proof of concept of generating sufficient primary endothelial and lung epithelial cells to recellularise whole lobes that can be maintained for several days ex vivo in a bioreactor to study regeneration. In parallel, acellular human lung scaffolds have been increasingly used for studying cell–extracellular environment interactions. These studies have helped provide new insights into the role of the matrix and the extracellular environment in chronic human lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Acellular human lung scaffolds are a versatile new tool for studying human lung repair and regeneration ex vivo.

scholarly journals Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hin Chu ◽  
Bingjie Hu ◽  
Xiner Huang ◽  
Yue Chai ◽  
Dongyan Zhou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Ex Vivo ◽  
Sialic Acids ◽  
Lung Epithelial Cells ◽  
Human Lungs ◽  
Lung Epithelial ◽  
Viral Determinants ◽  
Attachment Factor ◽  
Human Lung Epithelial Cells

AbstractUnderstanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.

Human Lungs Show Limited Permissiveness for SARS-CoV-2 Due to Scarce ACE2 Levels But Strong Virus-Induced Immune Activation in Alveolar Macrophages

2020 ◽  
Author(s):  
Katja Hönzke ◽  
Benedikt Obermayer ◽  
Christin Mache ◽  
Diana Fatykhova ◽  
Mirjana Kessler ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Immune Activation ◽  
Human Lungs

scholarly journals Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities

2020 ◽  
Vol 22 (1) ◽  
pp. 165
Author(s):  
Lucía Pérez-Roque ◽  
Elena Núñez-Gómez ◽  
Alicia Rodríguez-Barbero ◽  
Carmelo Bernabéu ◽  
José M. López-Novoa ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Ex Vivo ◽  
Clinical Manifestations ◽  
High Plasma ◽  
Trophoblast Invasion ◽  
Future Research ◽  
Soluble Factors ◽  
Human Trophoblast ◽  
Soluble Endoglin ◽  
Pregnant Mice

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed.

scholarly journals Modulation of Intestinal Phosphate Transport in Young Goats Fed a Low Phosphorus Diet

2021 ◽  
Vol 22 (2) ◽  
pp. 866
Author(s):  
Joie L. Behrens ◽  
Nadine Schnepel ◽  
Kathrin Hansen ◽  
Karin Hustedt ◽  
Marion Burmester ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Phosphate Transport ◽  
Ussing Chambers ◽  
Intestinal Epithelia ◽  
Pi Transport ◽  
Low Phosphorus ◽  
Small Intestinal ◽  
Underlying Mechanisms ◽  
Growing Goats ◽  
1,25 Dihydroxy Vitamin D3

The intestinal absorption of phosphate (Pi) takes place transcellularly through the active NaPi-cotransporters type IIb (NaPiIIb) and III (PiT1 and PiT2) and paracellularly by diffusion through tight junction (TJ) proteins. The localisation along the intestines and the regulation of Pi absorption differ between species and are not fully understood. It is known that 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3) and phosphorus (P) depletion modulate intestinal Pi absorption in vertebrates in different ways. In addition to the apical uptake into the enterocytes, there are uncertainties regarding the basolateral excretion of Pi. Functional ex vivo experiments in Ussing chambers and molecular studies of small intestinal epithelia were carried out on P-deficient goats in order to elucidate the transepithelial Pi route in the intestine as well as the underlying mechanisms of its regulation and the proteins, which may be involved. The dietary P reduction had no effect on the duodenal and ileal Pi transport rate in growing goats. The ileal PiT1 and PiT2 mRNA expressions increased significantly, while the ileal PiT1 protein expression, the mid jejunal claudin-2 mRNA expression and the serum 1,25-(OH)2D3 levels were significantly reduced. These results advance the state of knowledge concerning the complex mechanisms of the Pi homeostasis in vertebrates.

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