Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Abstract

The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated innate immune responses can induce aberrant inflammation that is detrimental to the host. Therefore, careful innate immune regulation is critical during infections. The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in global morbidity and mortality as well as socio-economic stresses. Innate immune sensing of SARS-CoV-2 by multiple host cell pattern recognition receptors leads to the production of various pro-inflammatory cytokines and the induction of inflammatory cell death. These processes can contribute to cytokine storm, tissue damage, and acute respiratory distress syndrome. Here, we discuss the sensing of SARS-CoV-2 to induce innate immune activation and the contribution of this innate immune signaling in the development and severity of COVID-19. In addition, we provide a conceptual framework for innate immunity driving cytokine storm and organ damage in patients with severe COVID-19. A better understanding of the molecular mechanisms regulated by innate immunity is needed for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.

Keywords: IFN; Necroptosis; PANoptosis; PANoptosome; Pyroptosis; TNF.

Fig. 1

Pattern recognition receptor signaling and potential innate immune-mediated pathogenesis during SARS-CoV-2 infection. A Toll-like receptor (TLR) signaling: Different TLRs recognize diverse SARS-CoV-2 components. TLR2 and TLR4 recognize E protein and S protein, respectively; TLR3, TLR7, and TLR8 sense viral RNA. TLR7 and TLR8 also recognize antiphospholipid antibodies (aPL). Sensing of SARS-CoV-2 components leads to activation of innate immune signaling and production of pro-inflammatory cytokines, which can eliminate virus but also drive COVID-19 severity. B Retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) and stimulator of IFN genes (STING) signaling: Melanoma differentiation-associated protein 5 (MDA5) senses viral RNA. STING can be activated by STING agonists or mitochondrial DNA (mtDNA) released by damaged cells. Signaling through MDA5 and STING engages interferon (IFN) regulatory factor 3 (IRF3) activation for the production of IFNs. Early on, IFNs are important to clear viruses. Delayed production of IFNs is pathogenic. C Inflammasome signaling: The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is assembled following sensing of spike (S) and nucleocapsid (N) proteins, viral RNA, and open reading frame 3a (ORF3a). This assembly leads to the production of interleukin (IL)-1β, which has been reported to drive COVID-19 pathology. D Caspase-4 (CASP4)/caspase-11 (CASP11) signaling: CASP4 and the murine homolog CASP11 sense oxidized phospholipids released from damaged cells and produce pro-inflammatory cytokines, which can drive COVID-19 pathology. E C-type lectin receptor (CLR) signaling: S protein from SARS-CoV-2 is sensed by CLRs such as dendritic cell specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), liver/lymph node-specific intercellular adhesion molecule-3-grabbing non-integrin (L-SIGN), and liver sinusoidal endothelial cell lectin (LSECtin) to induce innate immune signaling and the production of pro-inflammatory cytokines, which can be pathogenic in COVID-19

Fig. 2

Interferon (IFN) therapy following SARS-CoV-2 infection induces cytokine storm, organ damage, and lethality. SARS-CoV-2 has evolved to evade innate immune sensing mechanisms. Several components from SARS-CoV-2 inhibit type I IFN production by interfering with molecules involved in IFN production such as melanoma differentiation-associated protein 5 (MDA5), mitochondrial antiviral signaling (MAVS), tumor necrosis factor receptor-associated factor (TRAF)-associated NF-κΒ (TANK)-binding kinase 1 (TBK1), and IFN regulatory factor 3 (IRF3). To overcome this, IFN therapy has been suggested to treat patients with COVID-19. However, IFNs induce multiple IFN stimulated genes (ISGs), which can have both anti-viral as well as pro-death functions. Z-DNA binding protein 1 (ZBP1) is one such molecule which senses viral RNA to assemble the ZBP1-PANoptosome, thereby executing PANoptosis to drive cytokine storm, organ damage, and even lethality. This can impact the efficacy of IFN therapy in COVID-19. Strategies to inhibit ZBP1 could improve the efficacy of IFN therapy in patients with COVID-19

Fig. 3

Cytokine storm: Molecular mechanism and potential therapeutics in COVID-19. Lung infection by SARS-CoV-2 leads to production of several pro-inflammatory cytokines by innate immune cells. The combination of tumor necrosis factor (TNF) and interferon (IFN)-γ activates PANoptosis leading to a cytokine storm loop, which further potentiates cytokine release and perpetuates PANoptosis. This positive feedback loop can result in systemic inflammation, multiorgan failure, and lethality. Synergism of TNF and IFN-γ activates signal transducer and activator of transcription 1 (STAT1) signaling and induces expression of IFN regulatory factor 1 (IRF1), which regulates inducible nitric oxide synthase (iNOS) for nitric oxide (NO) production. This pathway leads to the induction of PANoptosis, which is regulated through a multiprotein complex called the PANoptosome. Based on the molecular mechanisms engaged by TNF and IFN-γ for the activation of PANoptosis, several drugs can potentially be repurposed for COVID-19 treatment