bims-inflin Biomed News
on Inflammasome and infection
Issue of 2024–04–28
two papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection.
  2. SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells.
  1. PLoS Pathog. 2024 Apr 25. 20(4): e1012167
    The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection.
    Marcus P Wong, Evan Y W Juan, Felix Pahmeier, Sai S Chelluri, Phoebe Wang, Bryan Castillo-Rojas, Sophie F Blanc, Scott B Biering, Russell E Vance, Eva Harris.
      Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012167
  2. Cell Death Discov. 2024 Apr 25. 10(1): 191
    SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells.
    Magdalena Ambrożek-Latecka, Piotr Kozlowski, Grażyna Hoser, Magdalena Bandyszewska, Karolina Hanusek, Dominika Nowis, Jakub Gołąb, Małgorzata Grzanka, Agnieszka Piekiełko-Witkowska, Luise Schulz, Franziska Hornung, Stefanie Deinhardt-Emmer, Ewa Kozlowska, Tomasz Skirecki.
      Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger pyroptosis-like cell death and IL-1α release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1α and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1α as a potential novel component driving the pulmonary immunothromobosis in COVID-19.
    DOI:  https://doi.org/10.1038/s41420-024-01966-9
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