Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip.
Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip.
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芯片上人类肺部气道重构临床相关流感病毒进化
DOI：
10.1128/spectrum.00257-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Ingber DE
中科院分区：
文献类型：
--
作者：
Si L;Bai H;Oh CY;Jin L;Prantil-Baun R;Ingber DE
病毒的人际传播，如流感病毒和冠状病毒，可以促进病毒进化和新毒株的出现，增加了造成大流行病的可能性。由于挑战的复杂性、规模和成本，分析特定类型的病毒如何在不同的人类宿主之间传播而逐渐演变出新的特征（例如对抗病毒治疗的抗性）的临床研究很难进行。在这里，我们证明了通过突变和基因重配的甲型流感病毒的自发进化可以通过在多个人肺气道芯片微流体培养装置（气道芯片）之间顺序传代感染的粘液滴在体外重建。在抗病毒药物金刚烷胺或奥司他韦持续存在的情况下，在芯片上模拟流感病毒感染的人际传播，导致临床流行的耐药突变的自发出现，并且当两种药物联合给药时，鉴定出对这两种药物具有耐药性的菌株。相比之下，我们发现萘莫司他，一种靶向宿主丝氨酸蛋白酶的抑制剂，不诱导病毒耐药性。这种人类临床前模型可能有助于研究病毒的体外进化，并在流感病毒出现在人群中之前识别潜在的流感病毒变体，从而能够抢先设计新的和更有效的疫苗和治疗方法。重要性流感病毒和严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）等病毒的快速进化对抗病毒药物和疫苗的使用和开发提出了挑战。宿主内病毒进化的研究有助于我们理解形成病毒全球进化的进化和流行病学因素，以及开发更好的抗病毒药物和疫苗。然而，由于缺乏能够忠实地模拟人类流感感染的临床前模型，关于病毒对抗病毒药物的抗性进化如何在临床上发生的知之甚少。我们的研究表明，流感病毒通过突变或基因重配的进化可以在人肺气道芯片（气道芯片）微流控培养装置中重现，该装置可以忠实地重现体外流感感染。这种方法可用于研究宿主内病毒进化，评估病毒耐药性，并在流感病毒出现在人群中之前识别潜在的流感病毒变体，从而能够抢先设计新的和更有效的疫苗和治疗方法。
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.