ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment following β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

“…SARS-CoV-2 is a positive sense, single-stranded RNA virus and belongs to β-coronavirus family. High dose infection or late infection with SARS-CoV-2 induce IFN-α/γ responses and the expression of ZBP1 [ 95 , 124 ]. In SARS-CoV-2 infected mice or BMDMs, the additional IFN-β inducing ZBP1 provokes PANoptosis via CASP1/3/7/8, GSDMD, GSDME, MLKL [ 75 , 95 , 125 ], and deletion of ZBP1 (ZBP1 −/− ) or Zα2 deficiency of ZBP1 (ZBP1 ΔZα2 ) substantially alleviated the inflammatory cell death and lethality of mice upon treatment with IFN and SARS-CoV-2 infection [ 95 ].…”

“…High dose infection or late infection with SARS-CoV-2 induce IFN-α/γ responses and the expression of ZBP1 [ 95 , 124 ]. In SARS-CoV-2 infected mice or BMDMs, the additional IFN-β inducing ZBP1 provokes PANoptosis via CASP1/3/7/8, GSDMD, GSDME, MLKL [ 75 , 95 , 125 ], and deletion of ZBP1 (ZBP1 −/− ) or Zα2 deficiency of ZBP1 (ZBP1 ΔZα2 ) substantially alleviated the inflammatory cell death and lethality of mice upon treatment with IFN and SARS-CoV-2 infection [ 95 ]. The ZBP1-mediated PANoptosis explains why non-early IFN treatment is not clinically helpful in treating SARS-CoV-2 infection [ 126 , 127 ].…”

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“…PANoptosis is a pro-inflammatory programmed cell death (PCD) pathway and has initially discovered in response to viral infections. Following infection with a virus such as influenza A virus (IAV), a master regulator of PANoptosis, Z-DNA-binding protein 1 (ZBP1) ( 41 , 42 ), interacts with RIPK3 via RIP homotypic interaction motif (RHIM) domains and forms a multimeric protein complex, PANoptosome. This single multimeric complex can concurrently activate NLRP3-dependent pyroptosis, Caspase-8-dependent apoptosis, and MLKL-dependent necroptosis ( 43 ).…”

The nervous system during COVID‐19: Caught in the crossfire

“…For instance, depending on the context, the overabundance of type I IFNs or cGAS‐STING activation can prevent or promote mortality in SARS‐CoV‐2 (A‐D) ‐infected wildtype mice and hamsters, complicating efforts for identifying antiviral therapies for COVID‐19. 131 , 155 , 156 , 157 Unaware of its future value, Dr. Stanley Perlman and colleagues in 2016 provided us with the best demonstration of type I IFN induction being a double‐edged sword during sarbecoronavirus disease. 158 In wildtype mice infected with hypervirulent SARS‐CoV MA15, the administration of type I IFNs 6 hours postinfection prevents mortality, while the administration of type I IFNs 24 hours postinfection leads to widespread mortality.…”

“…Due to the complexity of COVID‐19, there is a fine line between type I IFN‐induced protection and type I IFN‐driven pathology. For instance, depending on the context, the overabundance of type I IFNs or cGAS‐STING activation can prevent or promote mortality in SARS‐CoV‐2 (A‐D) ‐infected wildtype mice and hamsters, complicating efforts for identifying antiviral therapies for COVID‐19 131,155–157 . Unaware of its future value, Dr. Stanley Perlman and colleagues in 2016 provided us with the best demonstration of type I IFN induction being a double‐edged sword during sarbecoronavirus disease 158 .…”