Abstract
Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1β. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1β release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.
Highlights
Viral infections and infection-associated complications represent a major global health problem
We aimed to decipher the effect of purified viral glycoproteins of various viruses (SARS-CoV-2, SARS-CoV-1, HCMV, and HCV) on the activation of the NLRP3 inflammasome
As an in vitro model, we used human THP-1 monocytes, which were differentiated to macrophages using PMA
Summary
Viral infections and infection-associated complications represent a major global health problem. In addition to the spectrum of severity, viral diseases differentiate highly in contagiosity, including a low infectivity to highly pathogenic viruses, which can cause global pandemics affecting millions of people. In addition to the ongoing HIV pandemic, several outbreaks have aroused public attention in the last years as the SARS epidemic in 2003 or several. The world is facing an ongoing coronavirus disease 19 (COVID-19) pandemic with over 220 million confirmed cases and over 4 million deaths worldwide [1]. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). As some patients fail to control viral infection, SARS-CoV-2 can cause severe viral pneumonia leading to respiratory failure [4]. Similar to COVID-19, patients presented fever, cough, myalgia, and dyspnea and developed in some cases atypical pneumonia [5]
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