2. Academic Validation
  3. SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway

SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway

  • iScience. 2021 Apr 23;24(4):102295. doi: 10.1016/j.isci.2021.102295.
Grant R Campbell 1,  Rachel K To 1,  Jonathan Hanna 1,  Stephen A Spector 1 2
Affiliations

Affiliations

  • 1 Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • 2 Rady Children's Hospital, San Diego, CA 92123, USA.
PMID: 33718825 DOI: 10.1016/j.isci.2021.102295
Abstract

Macrophages promote an early host response to Infection by releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β), TNF, and IL-6. The bioactivity of IL-1β is classically dependent on NLRP3 inflammasome activation, which culminates in Caspase-1 activation and Pyroptosis. Recent studies suggest a role for NLRP3 inflammasome activation in lung inflammation and fibrosis in both COVID-19 and SARS, and there is evidence of NLRP3 involvement in HIV-1 disease. Here, we show that GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 trigger a TLR8-dependent pro-inflammatory cytokine response from human macrophages in the absence of Pyroptosis, with GU-rich RNA from the SARS-CoV-2 spike protein triggering the greatest inflammatory response. Using genetic and pharmacological inhibition, we show that the induction of mature IL-1β is through a non-classical pathway dependent on Caspase-1, Caspase-8, the NLRP3 inflammasome, potassium efflux, and Autophagy while being independent of TRIF (TICAM1), vitamin D3, and Pyroptosis.

Keywords

Immunology; Virology.

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