Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Departamento de Patologia e Medicina Legal, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
PLoS Pathog. 2024 Jun 5;20(6):e1012222. doi: 10.1371/journal.ppat.1012222. eCollection 2024 Jun.
COVID-19 has affected more than half a billion people worldwide, with more than 6.3 million deaths, but the pathophysiological mechanisms involved in lethal cases and the host determinants that determine the different clinical outcomes are still unclear. In this study, we assessed lung autopsies of 47 COVID-19 patients and examined the inflammatory profiles, viral loads, and inflammasome activation. Additionally, we correlated these factors with the patient's clinical and histopathological conditions. Robust inflammasome activation was detected in the lungs of lethal cases of SARS-CoV-2. Experiments conducted on transgenic mice expressing hACE2 and infected with SARS-CoV-2 showed that Nlrp3-/- mice were protected from disease development and lethality compared to Nlrp3+/+ littermate mice, supporting the involvement of this inflammasome in disease exacerbation. An analysis of gene expression allowed for the classification of COVID-19 patients into two different clusters. Cluster 1 died with higher viral loads and exhibited a reduced inflammatory profile than Cluster 2. Illness time, mechanical ventilation time, pulmonary fibrosis, respiratory functions, histopathological status, thrombosis, viral loads, and inflammasome activation significantly differed between the two clusters. Our data demonstrated two distinct profiles in lethal cases of COVID-19, thus indicating that the balance of viral replication and inflammasome-mediated pulmonary inflammation led to different clinical outcomes. We provide important information to understand clinical variations in severe COVID-19, a process that is critical for decisions between immune-mediated or antiviral-mediated therapies for the treatment of critical cases of COVID-19.
COVID-19 已影响全球超过 5 亿人，导致超过 630 万人死亡，但导致致命病例的病理生理机制以及决定不同临床结果的宿主决定因素仍不清楚。在这项研究中，我们评估了 47 例 COVID-19 患者的肺尸检，并检查了炎症谱、病毒载量和炎性体激活。此外，我们将这些因素与患者的临床和组织病理学状况相关联。在 SARS-CoV-2 致死病例的肺部中检测到强烈的炎性体激活。在表达 hACE2 并感染 SARS-CoV-2 的转基因小鼠上进行的实验表明，与 Nlrp3+/+ 同窝小鼠相比，Nlrp3-/- 小鼠能够免受疾病发展和致死的影响，这支持了该炎性体在疾病恶化中的作用。基因表达分析允许将 COVID-19 患者分为两个不同的簇。簇 1 死亡时病毒载量更高，且炎症谱较簇 2降低。疾病持续时间、机械通气时间、肺纤维化、呼吸功能、组织病理学状态、血栓形成、病毒载量和炎性体激活在两个簇之间有显著差异。我们的数据显示 COVID-19 致死病例中有两种不同的表型，这表明病毒复制和炎性体介导的肺部炎症之间的平衡导致了不同的临床结果。我们提供了重要信息，以了解严重 COVID-19 的临床变化，这对于决定在 COVID-19 重症病例中采用免疫介导或抗病毒治疗至关重要。
