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1.
bioRxiv ; 2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-900750

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. However, previous studies only characterized short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7-10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed Zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of 2.5 × 10 5 virions per cm 2 of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2.

2.
Endocr Metab Immune Disord Drug Targets ; 20(6): 807-811, 2020.
Article in English | MEDLINE | ID: covidwho-689779
3.
Front Immunol ; 11: 1626, 2020.
Article in English | MEDLINE | ID: covidwho-646832

ABSTRACT

Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF, and IL-1ß increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine storm syndrome (CSS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.


Subject(s)
Acute Lung Injury/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Lung/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Systemic Inflammatory Response Syndrome/immunology , Acute Lung Injury/pathology , Acute Lung Injury/therapy , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Humans , Lung/pathology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2 , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/therapy , Systemic Inflammatory Response Syndrome/pathology , Systemic Inflammatory Response Syndrome/therapy
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