Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison
Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison
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DOI：
10.1038/s41590-020-00840-x
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发表时间：
2020-12-04
影响因子：
30.5
通讯作者：
Andreakos, Evangelos
中科院分区：
文献类型：
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作者：
Galani, Ioanna-Evdokia;Rovina, Nikoletta;Andreakos, Evangelos
Andreakos和他的同事提供了一项纵向研究，比较了新冠肺炎患者和感染流感的患者。他们报告了一种干扰素反应的失调，即新冠肺炎患者干扰素-α和I型干扰素的产生减少和延迟，表现出与其他炎症细胞因子不协调的反应。免疫的一个中心范式是，干扰素介导的抗病毒反应先于促炎反应，优化宿主保护并将附带损害降至最低(1，2)。在此，我们报告，对于冠状病毒病2019(新冠肺炎)，这一范式不适用。通过对32例因肺炎入院并纵向随访发生呼吸衰竭和死亡的新冠肺炎患者的时间干扰素和炎症细胞因子模式的研究，发现干扰素-α和I型干扰素的产生均减少和延迟，仅在一小部分患者危重时诱导。相反，肿瘤坏死因子、白介素6和白介素8等促炎细胞因子在所有患者的IFN前产生，并持续较长时间。这种情况反映在血液转录本上，其中突出的干扰素信号仅在也表现出炎症加剧的危重患者中可见。相比之下，在16例临床病理特征与新冠肺炎相似的流感(流感)住院患者和24例症状较轻的非住院流感患者中，干扰素-α和I型干扰素的诱导时间更早、水平更高且与疾病严重程度无关，而促炎细胞因子仅迅速产生。值得注意的是，新冠肺炎患者体内较高的干扰素-lambda浓度与较低的支气管液病毒载量和较快的病毒清除速度以及较高的干扰素-lambda与I型干扰素比率与危重患者预后的改善相关。此外，与流感相比，新冠肺炎患者细胞因子模式的改变与更长的住院时间和更高的危重疾病发生率和死亡率相关。这些数据表明，新冠肺炎的抗病毒反应不协调，导致持续的病毒存在、过度炎症和呼吸衰竭。
Andreakos and colleagues provide a longitudinal study comparing patients with COVID-19 to patients infected with influenza. They report a dysregulated interferon response whereby IFN-lambda and type I IFN production were diminished and delayed in patients with COVID-19, exhibiting a response that is 'untuned' with other inflammatory cytokines.A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage(1,2). Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-lambda and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-lambda and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-lambda concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-lambda to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.