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Mater Sci Eng C Mater Biol Appl ; 116: 111260, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1452344


Polymeric nanoparticulate systems allow the encapsulation of bio-active substances, giving them protection against external agents and increasing the drug's bioavailability. The use of biocompatible and biodegradable polymers usually guarantees the harmless character of the formulation, and a controlled drug release is also assured. A relatively easy procedure to obtain polymeric formulations of bioactive agents is ionotropic gelation, which allows the synthesis of chitosan (CS) - sodium tri-polyphosphate nanoparticles (NPs) loading encapsulated proteins. In this work, Bovine serum albumin (BSA) model protein and a recombinant porcine alpha interferon variant were used to obtain nanoparticulate formulations. The internalization of the encapsulated material by cells was studied using a BSA-fluorescein system; the fluorescent conjugate was observable inside the cells after 20 h of incubation. The therapeutic CS-alpha interferon formulation showed a maximum of protein released in vitro at around 90 h. This system was found to be safe in a cytotoxicity assay, while biological activity experiments in vitro showed antiviral protection of cells in the presence of encapsulated porcine alpha interferon. In vivo experiments in pigs revealed a significant and sustained antiviral response through overexpression of the antiviral markers OAS2 and PKR. This proves the preservation of porcine alpha interferon biological activity, and also that a lasting response was obtained. This procedure is an effective and safe method to formulate drugs in nanoparticulate systems, representing a significant contribution to the search for more effective drug delivery strategies.

Chitosan , Nanoparticles , Pharmaceutical Preparations , Animals , Antiviral Agents/pharmacology , Biological Availability , Cattle , Drug Carriers , Drug Delivery Systems , Interferon-alpha , Particle Size , Polymers , Swine
J Med Virol ; 92(11): 2830-2838, 2020 11.
Article in English | MEDLINE | ID: covidwho-848038


Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leads to a series of clinical symptoms of respiratory and pulmonary inflammatory reactions via unknown pathologic mechanisms related to the viral infection process in tracheal or bronchial epithelial cells. Investigation of this viral infection in the human bronchial epithelial cell line (16HBE) suggests that SARS-CoV-2 can enter these cells through interaction between its membrane-localized S protein with the angiotensin-converting enzyme 2 molecule on the host cell membrane. Further observation indicates distinct viral replication with a dynamic and moderate increase, whereby viral replication does not lead to a specific cytopathic effect but maintains a continuous release of progeny virions from infected cells. Although messenger RNA expression of various innate immune signaling molecules is altered in the cells, transcription of interferons-α (IFN-α), IFN-ß, and IFN-γ is unchanged. Furthermore, expression of some interleukins (IL) related to inflammatory reactions, such as IL-6, IL-2, and IL-8, is maintained at low levels, whereas that of ILs involved in immune regulation is upregulated. Interestingly, IL-22, an IL that functions mainly in tissue repair, shows very high expression. Collectively, these data suggest a distinct infection process for this virus in respiratory epithelial cells, which may be linked to its clinicopathological mechanism.

Bronchi/cytology , Epithelial Cells/virology , SARS-CoV-2/physiology , Virus Replication , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Cell Line , Cytopathogenic Effect, Viral/immunology , Epithelial Cells/immunology , Humans , Immunity, Innate , Interleukins/immunology , Spike Glycoprotein, Coronavirus/metabolism
Antiviral Res ; 179: 104811, 2020 07.
Article in English | MEDLINE | ID: covidwho-133419


There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and ß (IFNα/ß). Treatment with IFN-α or IFN-ß at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-ß treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.

Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Interferon Type I/pharmacology , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Immunity, Innate , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Recombinant Proteins/pharmacology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects