Differential activation of programmed cell death in patients with severe SARS-CoV-2 infection.
Ashleigh N RieglerPaul BensonKenneth LongSixto M LealPublished in: Cell death discovery (2023)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe lower airway disease and death in a subset of patients. Knowledge on the relative contribution of programmed cell death (PCD) to lung pathology is limited to few human autopsy studies with small sample size/scope, in vitro cell culture, and experimental model systems. In this study, we sought to identify, localize, and quantify activation of apoptosis, ferroptosis, pyroptosis, and necroptosis in FFPE lung tissues from patients that died from severe SARS-CoV-2 infection (n = 28) relative to uninfected controls (n = 13). Immunofluorescence (IF) staining, whole-slide imaging, and Image J software was used to localize and quantify expression of SARS-CoV-2 nucleoprotein and the following PCD protein markers: cleaved Caspase-3, pMLKL, cleaved Gasdermin D, and CD71, respectively. IF showed differential activation of each PCD pathway in infected lungs and dichotomous staining for SARS-CoV-2 nucleoprotein enabling distinction between high (n = 9) vs low viral burden (n = 19). No differences were observed in apoptosis and ferroptosis in SARS-CoV-2 infected lungs relative to uninfected controls. However, both pyroptosis and necroptosis were significantly increased in SARS-CoV-2-infected lungs. Increased pyroptosis was observed in SARS-CoV-2 infected lungs, irrespective of viral burden, suggesting an inflammation-driven mechanism. In contrast, necroptosis exhibited a very strong positive correlation with viral burden (R 2 = 0.9925), suggesting a direct SARS-CoV-2 mediated effect. These data indicate a possible novel mechanism for viral-mediated necroptosis and a potential role for both lytic programmed cell death pathways, necroptosis and pyroptosis, in mediating infection outcome.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- end stage renal disease
- cell death
- oxidative stress
- chronic kidney disease
- ejection fraction
- newly diagnosed
- nlrp inflammasome
- peritoneal dialysis
- early onset
- gene expression
- magnetic resonance
- healthcare
- endoplasmic reticulum stress
- endothelial cells
- prognostic factors
- hiv infected
- poor prognosis
- high resolution
- coronavirus disease
- computed tomography
- small molecule
- magnetic resonance imaging
- photodynamic therapy
- electronic health record
- long non coding rna
- mass spectrometry
- antiretroviral therapy