The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general cellular transcription or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37°C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.

中文翻译：

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升高的温度抑制了SARS-CoV-2在呼吸道上皮中的复制，独立于IFN介导的先天免疫防御的诱导

SAV-CoV-2是COVID-19的病原体，在大流行中传播，这是一个重大且持续的国际卫生危机。SARS-CoV-2感染的关键症状是发烧，其高温温度在38至41°C之间。发烧是对微生物感染和炎症的进化上保守的宿主反应，可影响病毒致病性的结果以及宿主固有和适应性免疫反应的调节。然而，仍然有待确定高温对SARS-CoV-2向性和复制有什么影响。利用3D气液界面（ALI）模型，该模型紧密模拟呼吸道中SARS-CoV-2感染的自然组织生理和细胞向性，我们确定组织温度在SARS-CoV-调节中起重要作用2感染。我们显示，温度升高会诱导影响多种途径（包括表观遗传调控和lncRNA表达）的调节的广泛转录组变化，而不会破坏一般细胞的转录或干扰素（IFN）介导的抗病毒免疫防御的诱导。在> 37°C的温度下温育的呼吸组织仍然允许SARS-CoV-2感染，但严重限制了病毒转录的启动，从而导致上皮内病毒RNA积累水平显着降低，传染性病毒的顶端脱落。据我们所知，我们提供了与COVID-19相关的发热温度抑制SARS-CoV-2复制的第一个证据。