Innate immune processes involved in SARS-CoV-2 recognition and resultant inflammation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19), which has caused the ongoing pandemic and has claimed over 5.7 million lives worldwide.

Study: Innate immunity: the first line of defense against SARS-CoV-2. Image Credit: Kateryna Kon/Shutterstock

The role of innate immunity against pathogen invasion has been established. Cell surface, endosomal and cytosolic pattern recognition receptors (PRRs) react to pathogen-associated molecular patterns (PAMPs) and initiate inflammatory responses and programmed cell death – that prevent infection and enhance viral clearance. However, an excessive inflammatory reaction in some individuals leads to severe disease.

The newer variants of SARS-CoV-2 employ immune evasion in the host to facilitate replication and transmission. A better understanding of innate immune mechanisms may aid in combatting viral immune evasion and devising preventive and treatment strategies for CoV infections.

The study

A new article published in Nature Immunology reviewed the innate immune detection and signaling pathways that the host uses against SARS-CoV-2, highlighting the role of viral entry, critical PRRs and signaling pathways, cytokine production, and cell death as well as viral immune evasion strategies.


Innate immune cells encompass macrophages, monocytes, dendritic cells, neutrophils, and innate lymphoid cells (ILCs), for instance – natural killer (NK) cells, which harbor PRRs that recognize pathogenic patterns or damage-associated molecular patterns (DAMPs). On recognition of PAMPs or DAMPs, PRRs induce inflammatory signaling pathways and immune responses. These responses trigger the generation of inflammatory cytokines and chemokines and induce apoptosis or cell death of the infected cells. PRRs found to be functional in activating signaling pathways in response to SARS-CoV-2 are toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and inflammasomes.

TLRs show heterogeneous expression across the innate immune cell population. Animal studies have shown that treatment of K18-hACE2 transgenic mice with a TLR2 inhibitor could reduce the levels of inflammatory cytokines and aid in improving survival following SARS-CoV-2 infection. Additionally, in silico studies demonstrated that the SARS-CoV-2 S protein may bind to TLR1, TLR4, and TLR6, while TLR4 had the highest affinity. However, precise information regarding which among TLR1, TLR4 or TLR6 can directly sense the S protein is yet to be ascertained.

Of note, TLR7 seems to have a protective role during SARS-CoV-2 infection as younger individuals with X chromosomal TLR7 genetic disorders tended to be vulnerable to severe COVID-19 disease. Yet, further research is warranted towards these assumptions.

RLRs, which include – MDA5, RIG-I, and LGP2, can also sense single-stranded RNA derived from intermediates of SARS-CoV-2. Furthermore, it has been observed that individuals with SARS-CoV-2 infection who harbor circulating autoantibodies that target type I interferon (IFN) show reduced responses and are likely to suffer from serious illness or death. Both overactivation and underactivation of IFN signaling can be harmful. Studies have found that silencing or deleting genes encoding MDA5, LGP2, or MAVS in human primary lung airway epithelial or Calu-3 cells reduced type I IFN expression during SARS-CoV-2 infection. However, confirmatory studies are warranted to understand this mechanism fully.

Additionally, NLRs can induce the generation of type I IFNs and pro-inflammatory cytokines. NLRP3 –catalyzed by PAMPs and DAMPs, activates caspase-1, produces and releases bioactive interleukin (IL)-1β and IL-18 and cleavage of gasdermin (GSDM) D. These proteins initiate cell death. NLRP3 and apoptosis-associated speck-like protein have been detected in monocytes and lung tissues of patients with SARS-CoV-2 infection. It was speculated that SARS-CoV-2 infection causes an imbalance in intracellular potassium efflux, enabling the activation of NLRP3 inflammasome and IL-1β and IL-18 release.

The accessory proteins of SARS-CoV-2 can antagonize cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thus, impeding antiviral immune responses. Animal studies have revealed that restoration of cGAS-STING signaling by administering the exogenous STING agonist, diABZI, can inhibit SARS-CoV-2 replication.

In individuals with SARS-CoV-2 infection, PRR signaling induces the concurrent release of both IFNs and other pro-inflammatory cytokines. Also, a positive feedback loop has been described – cytokine secretion causes the production of cytokines mediated by inflammatory cell death (PANoptosis), resulting in more cytokine release, which precipitates a cytokine storm – a life-threatening condition affecting multiple organs.

Structural damage to endothelial cell membranes leads to vascular leakage, precipitating acute respiratory distress in COVID-19. Furthermore, a cluster of hyperinflammatory shock syndromes – termed multisystem inflammatory syndrome in children (MIS-C), which is caused by vascular damage, has been described in children with COVID-19—with features identical to Kawasaki disease. It has been reported that endothelial cell-associated anticoagulant pathways could be dysfunctional due to the pro-inflammatory cytokines. These lead to the thromboembolic complications of severe COVID-19 and illustrate another pathogenic mechanism for cytokines causing damage to organ systems.

Therefore, although cytokines are essential for the innate immune response and maintaining cellular homeostasis, they must be modulated to prevent the systemic cytokine storm and pathogenic inflammation that transpires due to SARS-CoV-2 infection.

Therapeutic modalities targeting SARS-Cov-2 can be categorized as – antiviral or immunomodulatory therapies. Among the antivirals being used currently, remdesivir has been approved by the Food and Drug Administration (FDA), while molnupiravir, paxlovid (nirmatrelvir plus ritonavir), sotrovimab, and monoclonal antibody cocktails have received Emergency Use Authorisation (EUA).

The present review aimed to gain a clearer understanding of the disease pathogenesis to spot therapeutic windows. Immunomodulatory drugs that fine-tune inflammatory responses, for example, baricitinib and tocilizumab, have been granted EUA to combat severe COVID-19, while many others are under investigation. A more detailed understanding of the host innate immune response to SARS-CoV-2 may aid in optimizing antiviral responses and avoid complications impacting multiple organs systems.

Another advantage of targeting innate immunity as a treatment strategy is that the probability of viral evolution is minimized, and hence, the risks of variant emergence and resistance remain low. Meanwhile, the authors emphasized that in the setting of an increasing number of pediatric cases, the immune responses in this population must be studied. A deeper understanding of innate immunity to SARS-CoV-2 can help mitigate severe disease, provide newer treatments, and identify countermeasures to prevent further variants of concern and future pandemics.

Journal reference:
  • Diamond, M. and Kanneganti, T. (2022) "Innate immunity: the first line of defense against SARS-CoV-2", Nature Immunology, 23(2), pp. 165-176. doi: 10.1038/s41590-021-01091-0.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibody, Anticoagulant, Apoptosis, Autoantibodies, Cell, Cell Death, Chemokines, Children, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytokine, Cytokines, Drugs, Endothelial cell, Evolution, Food, Gene, Genes, Genetic, Immune Response, immunity, Immunology, Immunomodulatory, Inflammasome, Inflammation, Interferon, Interleukin, Intracellular, Kawasaki Disease, Monoclonal Antibody, Neutrophils, Nucleotide, Pandemic, Pathogen, Potassium, Programmed Cell Death, Protein, Remdesivir, Research, Respiratory, Retinoic Acid, Ritonavir, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Sotrovimab, Syndrome, Transgenic, Vascular

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Nidhi Saha

I am a medical content writer and editor. My interests lie in public health awareness and medical communication. I have worked as a clinical dentist and as a consultant research writer in an Indian medical publishing house. It is my constant endeavor is to update knowledge on newer treatment modalities relating to various medical fields. I have also aided in proofreading and publication of manuscripts in accredited medical journals. I like to sketch, read and listen to music in my leisure time.

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