The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.

COVID-19 Pulmonary Pathology: The Experience of European Pulmonary Pathologists throughout the First Two Waves of the Pandemic.

Autoptic studies of patients who died from COVID-19 constitute an important step forward in improving our knowledge in the pathophysiology of SARS-CoV-2 infection. Systematic analyses of lung tissue, the organ primarily targeted by the disease, were mostly performed during the first wave of the pandemic. Analyses of pathological lesions at different times offer a good opportunity to better understand the disease and how its evolution has been influenced mostly by new SARS-CoV-2 variants or the different therapeutic approaches. In this short report we summarize responses collected from a questionnaire survey that investigated important pathological data during the first two pandemic waves (spring-summer 2020; autumn-winter 2020-2021). The survey was submitted to expert lung pathologists from nine European countries involved in autoptic procedures in both pandemic waves. The frequency of each lung lesion was quite heterogeneous among the participants. However, a higher frequency of pulmonary superinfections, both bacterial and especially fungal, was observed in the second wave compared to the first. Obtaining a deeper knowledge of the pathological lesions at the basis of this complex and severe disease, which change over time, is crucial for correct patient management and treatment. Autoptic examination is a useful tool to achieve this goal.

Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland.

We report postmortem cardio-pulmonary findings including detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in formalin-fixed paraffin embedded tissue in 12 patients with COVID-19. The 5 women and 7 men (median age: 73 years; range 35-96) died 6-38 days after onset of symptoms (median: 14.5 days). Eight patients received mechanical ventilation. Ten patients showed diffuse alveolar damage (DAD), 7 as exudative and 3 as proliferative/organizing DAD. One case presented as acute fibrinous and organizing pneumonia. Seven patients (58%) had acute bronchopneumonia, 1/7 without associated DAD and 1/7 with aspergillosis and necrotic bronchitis. Microthrombi were present in 5 patients, only in exudative DAD. Reverse transcriptase quantitative PCR detected high virus amounts in 6 patients (50%) with exudative DAD and symptom-duration ≤14 days, supported by immunohistochemistry and in-situ RNA hybridization (RNAscope). The 6 patients with low viral copy levels were symptomatic for ≥15 days, comprising all cases with organizing DAD, the patient without DAD and one exudative DAD. We show the high prevalence of DAD as a reaction pattern in COVID-19, the high number of overlying acute bronchopneumonia, and high-level pulmonary virus detection limited to patients who died ≤2 weeks after onset of symptoms, correlating with exudative phase of DAD.

Frequency and Significance of Pathologic Pulmonary Findings in Postmortem Examinations-A Single Center Experience before COVID-19.

Coronavirus disease 2019 (COVID-19) has shown the importance of postmortem investigation of deceased patients. For a correct interpretation of the pulmonary findings in this new era, it is, however, crucial to be familiar with pathologic pulmonary conditions observed in postmortem investigations in general. Adequate postmortem histopathological evaluation of the lungs may be affected by suboptimal gross work up, autolysis or poor fixation. Using a standardized preparation approach which consisted in instillation of 4% buffered formaldehyde through the large bronchi for proper fixation and preparing large frontal tissue sections of 1-2 cm thickness after at least 24 h fixation, we comprehensively analyzed postmortem pulmonary findings from consecutive adult autopsies of a two-year period before the occurrence of COVID-19 (2016-2017). In total, significant pathological findings were observed in 97/189 patients (51%), with 28 patients showing more than one pathologic condition. Acute pneumonia was diagnosed 33/128 times (26%), embolism 24 times (19%), primary pulmonary neoplasms 18 times (14%), organizing pneumonia and other fibrosing conditions 14 times (11%), pulmonary metastases 13 times (10%), diffuse alveolar damage 12 times (9%), severe emphysema 9 times (7%) and other pathologies, e.g., amyloidosis 5/128 times (4%). Pulmonary/cardiopulmonary disease was the cause of death in 60 patients (32%). Clinical and pathological diagnoses regarding lung findings correlated completely in 75 patients (40%). Autopsy led to confirmation of a clinically suspected pulmonary diagnosis in 57 patients (39%) and clarification of an unclear clinical lung finding in 16 patients (8%). Major discrepant findings regarding the lungs (N = 31; 16%) comprised cases with clinical suspicions that could not be confirmed or new findings not diagnosed intra vitam. A significant proportion of acute pneumonias (N = 8; 24% of all cases with this diagnosis; p = 0.011) was not diagnosed clinically. We confirmed the frequent occurrence of pulmonary pathologies in autopsies, including inflammatory and neoplastic lesions as the most frequent pathological findings. Acute pneumonia was an important cause for discrepancy between clinical and postmortem diagnostics.