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Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip

Human-to-human transmission of viruses, such as influenza viruses and coronaviruses, can promote virus evolution and the emergence of new strains with increased potential for creating pandemics. Clinical studies analyzing how a particular type of virus progressively evolves new traits, such as resis...

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Autores principales: Si, Longlong, Bai, Haiqing, Oh, Crystal Yuri, Jin, Lei, Prantil-Baun, Rachelle, Ingber, Donald E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557867/
https://www.ncbi.nlm.nih.gov/pubmed/34523991
http://dx.doi.org/10.1128/Spectrum.00257-21
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author Si, Longlong
Bai, Haiqing
Oh, Crystal Yuri
Jin, Lei
Prantil-Baun, Rachelle
Ingber, Donald E.
author_facet Si, Longlong
Bai, Haiqing
Oh, Crystal Yuri
Jin, Lei
Prantil-Baun, Rachelle
Ingber, Donald E.
author_sort Si, Longlong
collection PubMed
description Human-to-human transmission of viruses, such as influenza viruses and coronaviruses, can promote virus evolution and the emergence of new strains with increased potential for creating pandemics. Clinical studies analyzing how a particular type of virus progressively evolves new traits, such as resistance to antiviral therapies, as a result of passing between different human hosts are difficult to carry out because of the complexity, scale, and cost of the challenge. Here, we demonstrate that spontaneous evolution of influenza A virus through both mutation and gene reassortment can be reconstituted in vitro by sequentially passaging infected mucus droplets between multiple human lung airway-on-a-chip microfluidic culture devices (airway chips). Modeling human-to-human transmission of influenza virus infection on chips in the continued presence of the antiviral drugs amantadine or oseltamivir led to the spontaneous emergence of clinically prevalent resistance mutations, and strains that were resistant to both drugs were identified when they were administered in combination. In contrast, we found that nafamostat, an inhibitor targeting host serine proteases, did not induce viral resistance. This human preclinical model may be useful for studying viral evolution in vitro and identifying potential influenza virus variants before they appear in human populations, thereby enabling preemptive design of new and more effective vaccines and therapeutics. IMPORTANCE The rapid evolution of viruses, such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is challenging the use and development of antivirals and vaccines. Studies of within-host viral evolution can contribute to our understanding of the evolutionary and epidemiological factors that shape viral global evolution as well as development of better antivirals and vaccines. However, little is known about how viral evolution of resistance to antivirals occurs clinically due to the lack of preclinical models that can faithfully model influenza infection in humans. Our study shows that influenza viral evolution through mutation or gene reassortment can be recapitulated in a human lung airway-on-a-chip (airway chip) microfluidic culture device that can faithfully recapitulate the influenza infection in vitro. This approach is useful for studying within-host viral evolution, evaluating viral drug resistance, and identifying potential influenza virus variants before they appear in human populations, thereby enabling the preemptive design of new and more effective vaccines and therapeutics.
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spelling pubmed-85578672021-11-08 Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip Si, Longlong Bai, Haiqing Oh, Crystal Yuri Jin, Lei Prantil-Baun, Rachelle Ingber, Donald E. Microbiol Spectr Research Article Human-to-human transmission of viruses, such as influenza viruses and coronaviruses, can promote virus evolution and the emergence of new strains with increased potential for creating pandemics. Clinical studies analyzing how a particular type of virus progressively evolves new traits, such as resistance to antiviral therapies, as a result of passing between different human hosts are difficult to carry out because of the complexity, scale, and cost of the challenge. Here, we demonstrate that spontaneous evolution of influenza A virus through both mutation and gene reassortment can be reconstituted in vitro by sequentially passaging infected mucus droplets between multiple human lung airway-on-a-chip microfluidic culture devices (airway chips). Modeling human-to-human transmission of influenza virus infection on chips in the continued presence of the antiviral drugs amantadine or oseltamivir led to the spontaneous emergence of clinically prevalent resistance mutations, and strains that were resistant to both drugs were identified when they were administered in combination. In contrast, we found that nafamostat, an inhibitor targeting host serine proteases, did not induce viral resistance. This human preclinical model may be useful for studying viral evolution in vitro and identifying potential influenza virus variants before they appear in human populations, thereby enabling preemptive design of new and more effective vaccines and therapeutics. IMPORTANCE The rapid evolution of viruses, such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is challenging the use and development of antivirals and vaccines. Studies of within-host viral evolution can contribute to our understanding of the evolutionary and epidemiological factors that shape viral global evolution as well as development of better antivirals and vaccines. However, little is known about how viral evolution of resistance to antivirals occurs clinically due to the lack of preclinical models that can faithfully model influenza infection in humans. Our study shows that influenza viral evolution through mutation or gene reassortment can be recapitulated in a human lung airway-on-a-chip (airway chip) microfluidic culture device that can faithfully recapitulate the influenza infection in vitro. This approach is useful for studying within-host viral evolution, evaluating viral drug resistance, and identifying potential influenza virus variants before they appear in human populations, thereby enabling the preemptive design of new and more effective vaccines and therapeutics. American Society for Microbiology 2021-09-15 /pmc/articles/PMC8557867/ /pubmed/34523991 http://dx.doi.org/10.1128/Spectrum.00257-21 Text en Copyright © 2021 Si et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Si, Longlong
Bai, Haiqing
Oh, Crystal Yuri
Jin, Lei
Prantil-Baun, Rachelle
Ingber, Donald E.
Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title_full Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title_fullStr Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title_full_unstemmed Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title_short Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip
title_sort clinically relevant influenza virus evolution reconstituted in a human lung airway-on-a-chip
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557867/
https://www.ncbi.nlm.nih.gov/pubmed/34523991
http://dx.doi.org/10.1128/Spectrum.00257-21
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