Galani Ioanna-Evdokia, Rovina Nikoletta, Lampropoulou Vicky, Triantafyllia Vasiliki, Manioudaki Maria, Pavlos Eleftherios, Koukaki Evangelia, Fragkou Paraskevi C, Panou Vasiliki, Rapti Vasiliki, Koltsida Ourania, Mentis Andreas, Koulouris Nikolaos, Tsiodras Sotirios, Koutsoukou Antonia, Andreakos Evangelos
Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
ICU, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Medical School, 'Sotiria' General Hospital of Chest Diseases, Athens, Greece.
Nat Immunol. 2021 Jan;22(1):32-40. doi: 10.1038/s41590-020-00840-x. Epub 2020 Dec 4.
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage. 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-λ 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-λ 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-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ 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.
免疫的一个核心范式是，干扰素（IFN）介导的抗病毒反应先于促炎反应，从而优化宿主保护并将附带损害降至最低。在此，我们报告，对于2019冠状病毒病（COVID-19）而言，这一范式并不适用。通过调查32例因肺炎住院的中重度COVID-19患者的IFN和炎性细胞因子的时间模式，并对其呼吸衰竭和死亡的发生情况进行纵向跟踪，我们发现IFN-λ和I型IFN的产生均减少且延迟，仅在一部分患者病情危重时才被诱导产生。相反，在所有患者中，肿瘤坏死因子（TNF）、白细胞介素（IL）-6和IL-8等促炎细胞因子在IFN之前产生，并持续较长时间。这种情况反映在血液转录组中，其中显著的IFN特征仅在病情危重且炎症增强的患者中出现。相比之下，在16例因肺炎住院且临床病理特征与COVID-19患者相似的流感患者以及24例症状较轻的非住院流感患者中，IFN-λ和I型IFN更早、更强地被诱导产生，且与疾病严重程度无关，而促炎细胞因子仅急性产生。值得注意的是，COVID-19患者中较高的IFN-λ浓度与支气管吸出物中较低的病毒载量、更快的病毒清除相关，而较高的IFN-λ与I型IFN比值与危重患者的较好预后相关。此外，与流感相比，COVID-19患者细胞因子模式的改变与更长的住院时间、更高的危重病发病率和死亡率相关。这些数据表明COVID-19中抗病毒反应失调，导致病毒持续存在、炎症反应过度和呼吸衰竭。
