Post by Nadica (She/Her) on Sept 4, 2024 22:33:30 GMT
Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19 - Published June 5, 2024
Abstract
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.
Author summary
Although the SARS-CoV-2 pandemic has significantly affected the worldwide population and contributed to the death of millions worldwide, the processes that lead to patient death are still obscure. In this study, we assessed lung autopsies of 47 fatal cases of COVID-19 and found a significant activation of the NLRP3 inflammasome in the lungs of patients. To investigate whether this correlation between NLRP3 activation and disease exacerbation implies a cause-and-effect relationship, we performed infections in transgenic mice expressing the human ACE2 receptor. These mice were successfully infected with SARS-CoV-2, and we demonstrated that Nlrp3-deficient mice were protected from disease development and lethality compared to littermate animals sufficient for NLRP3, indicating a cause-consequence effect. Moreover, we found that patients who succumbed to COVID-19 can be divided into two main groups: Cluster 1, composed of patients who died with higher viral loads and reduced inflammation in the lungs, as opposed to patients from Cluster 2. We found that pulmonary thrombosis and disseminated intravascular coagulation were higher in patients from Cluster 1, contrasting with the significant development of fibrosis and hyperinflammation in Cluster 2 patients. Our study demonstrates the existence of two distinct profiles in lethal cases of COVID-19, a feature that is important to our understanding of lethality in this disease. Understanding these processes will be important to direct future therapeutic strategies for severe cases of COVID-19, either to target viral replication and thrombosis or to target the excessive inflammatory process.
Abstract
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.
Author summary
Although the SARS-CoV-2 pandemic has significantly affected the worldwide population and contributed to the death of millions worldwide, the processes that lead to patient death are still obscure. In this study, we assessed lung autopsies of 47 fatal cases of COVID-19 and found a significant activation of the NLRP3 inflammasome in the lungs of patients. To investigate whether this correlation between NLRP3 activation and disease exacerbation implies a cause-and-effect relationship, we performed infections in transgenic mice expressing the human ACE2 receptor. These mice were successfully infected with SARS-CoV-2, and we demonstrated that Nlrp3-deficient mice were protected from disease development and lethality compared to littermate animals sufficient for NLRP3, indicating a cause-consequence effect. Moreover, we found that patients who succumbed to COVID-19 can be divided into two main groups: Cluster 1, composed of patients who died with higher viral loads and reduced inflammation in the lungs, as opposed to patients from Cluster 2. We found that pulmonary thrombosis and disseminated intravascular coagulation were higher in patients from Cluster 1, contrasting with the significant development of fibrosis and hyperinflammation in Cluster 2 patients. Our study demonstrates the existence of two distinct profiles in lethal cases of COVID-19, a feature that is important to our understanding of lethality in this disease. Understanding these processes will be important to direct future therapeutic strategies for severe cases of COVID-19, either to target viral replication and thrombosis or to target the excessive inflammatory process.