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 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.

scholarly journals Infection of Primary Human Alveolar Macrophages Alters Staphylococcus aureus Toxin Production and Activity

2019 ◽  
Vol 87 (7) ◽  
Author(s):  
Katelynn R. Brann ◽  
Marissa S. Fullerton ◽  
Frances I. Onyilagha ◽  
Andrew A. Prince ◽  
Richard C. Kurten ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Alveolar Macrophages ◽  
Severe Pneumonia ◽  
Opportunistic Pathogen ◽  
Phagocytic Cells ◽  
Methicillin Resistant ◽  
Content Type ◽  
Human Lungs ◽  
Human Alveolar Macrophages

ABSTRACT Pulmonary pathogens encounter numerous insults, including phagocytic cells designed to degrade bacteria, while establishing infection in the human lung. Staphylococcus aureus is a versatile, opportunistic pathogen that can cause severe pneumonia, and methicillin-resistant isolates are of particular concern. Recent reports present conflicting data regarding the ability of S. aureus to survive and replicate within macrophages. However, due to use of multiple strains and macrophage sources, making comparisons between reports remains difficult. Here, we established a disease-relevant platform to study innate interactions between S. aureus and human lungs. Human precision-cut lung slices (hPCLS) were subjected to infection by S. aureus LAC (methicillin-resistant) or UAMS-1 (methicillin-sensitive) isolates. Additionally, primary human alveolar macrophages (hAMs) were infected with S. aureus, and antibacterial activity was assessed. Although both S. aureus isolates survived within hAM phagosomes, neither strain replicated efficiently in these cells. S. aureus was prevalent within the epithelial and interstitial regions of hPCLS, with limited numbers present in a subset of hAMs, suggesting that the pathogen may not target phagocytic cells for intracellular growth during natural pulmonary infection. S. aureus-infected hAMs mounted a robust inflammatory response that reflected natural human disease. S. aureus LAC was significantly more cytotoxic to hAMs than UAMS-1, potentially due to isolate-specific virulence factors. The bicomponent toxin Panton-Valentine leukocidin was not produced during intracellular infection, while alpha-hemolysin was produced but was not hemolytic, suggesting that hAMs alter toxin activity. Overall, this study defined a new disease-relevant infection platform to study S. aureus interaction with human lungs and to define virulence factors that incapacitate pulmonary cells.

Quantification of Silica Uptake by Alveolar Macrophages - An Emperical Scanning Electron Microprobe Method

1982 ◽  
Vol 40 ◽  
pp. 332-333
Author(s):  
V. V. Damiano ◽  
R. P. Daniele ◽  
H. T. Tucker ◽  
J. H. Dauber
Keyword(s):  
Quantitative Analysis ◽  
Alveolar Macrophages ◽  
Bulk Sample ◽  
Silica Particles ◽  
Empirical Method ◽  
Phagocytic Cells ◽  
Calibration Standards ◽  
X Ray ◽  
Accurate Quantitative Analysis ◽  
Scanning Electron

An important example of intracellular particles is encountered in silicosis where alveolar macrophages ingest inspired silica particles. The quantitation of the silica uptake by these cells may be a potentially useful method for monitoring silica exposure. Accurate quantitative analysis of ingested silica by phagocytic cells is difficult because the particles are frequently small, irregularly shaped and cannot be visualized within the cells. Semiquantitative methods which make use of particles of known size, shape and composition as calibration standards may be the most direct and simplest approach to undertake. The present paper describes an empirical method in which glass microspheres were used as a model to show how the ratio of the silicon Kα peak X-ray intensity from the microspheres to that of a bulk sample of the same composition correlated to the mass of the microsphere contained within the cell. Irregular shaped silica particles were also analyzed and a calibration curve was generated from these data.

The Oral Intake of Organic Germanium, Ge-132, Elevates α-Tocopherol Levels in the Plas-ma and Modulates Hepatic Gene Expression Profiles to Promote Immune Activation in Mice

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0183-0195 ◽  
Author(s):  
Takashi Nakamura ◽  
Tomoya Takeda ◽  
Yoshihiko Tokuji
Keyword(s):  
Gene Expression ◽  
Immune Activation ◽  
Expression Profiles ◽  
Water Soluble ◽  
Alpha Tocopherol ◽  
Hepatic Gene Expression ◽  
Tocopherol Concentration ◽  
Altered Expression ◽  
Atp Production ◽  
Transfer Protein

The common water-soluble organic germanium compound poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) exhibits activities related to immune responses and antioxidant induction. In this study, we evaluated the antioxidative effect of dietary Ge-132 in the plasma of mice. Male ICR mice (seven mice per group) received an AIN-76 diet with 0.05 % Ge-132; three groups received the Ge-132-containing diet for 0, 1 or 4 days. The plasma alpha-tocopherol (α-tocopherol) concentration increased from 6.85 to 9.60 μg/ml after 4 days of Ge-132 intake (p < 0.05). We evaluated the changes in hepatic gene expression related to antioxidative activity as well as in the entire expression profile after one day of Ge-132 intake, using DNA microarray technology. We identified 1,220 genes with altered expression levels greater than 1.5-fold (increased or decreased) as a result of Ge-132 intake, and α-tocopherol transfer protein (Ttpa) gene expression was increased 1.62-fold. Immune activation was identified as the category with the most changes (containing 60 Gene Ontology (GO) term biological processes (BPs), 41 genes) via functional clustering analysis of altered gene expression. Ge-132 affected genes in clusters related to ATP production (22 GO term BPs, 21 genes), lipid metabolism (4 GO term BPs, 38 genes) and apoptosis (5 GO term BPs). Many GO term BPs containing these categories were significantly affected by the Ge-132 intake. Oral Ge-132 intake may therefore have increased plasma α-tocopherol levels by up-regulating α-tocopherol transfer protein (Ttpa) gene expression.

Inflammational Animal Models for Schizophrenia

2015 ◽  
Vol 223 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Georg Juckel
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Immune Activation ◽  
Microglial Activation ◽  
Treatment Options ◽  
Early Adulthood ◽  
Brain Regions ◽  
Synaptic Connections ◽  
Preventive Interventions ◽  
Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

Immune activation in functional dyspepsia: A result of psychological co-morbidity?

2009 ◽  
Vol 47 (09) ◽  
Author(s):  
T Liebregts ◽  
B Adam ◽  
M Gururatsakul ◽  
NJ Talley ◽  
G Gerken ◽  
...  
Keyword(s):  
Functional Dyspepsia ◽  
Immune Activation ◽  
Co Morbidity
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