Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to disease severity. Furthermore, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) — collectively known as RLRs (RIG-I-like receptors) — act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection and examine their role in determining the severity of both acute and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Finally, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will describe PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2.

The IFNAR2 gene encodes an essential component of the type I interferon receptor, which is essential for antiviral defense. It has been proven that the severity of COVID-19 may be influenced by the genetic variants in IFNAR2; however, the results are inconclusive in the African cohorts. Thus, in this study, we investigate the association between three IFNAR2 SNPs and the critical form of COVID-19 in the Tunisian population. A total of 413 COVID-19 patients classified as hospitalized with critical illness (ICU) (n = 46) and non-hospitalized (n = 367) are included. Genotyping of three IFNAR2 polymorphisms (rs1051393, rs2236757, rs9984273) was performed using Taq Man RT-PCR assays. rs2236757 (OR = 0.31, 95% CI: 0.16–0.60), p = 4 × 10⁻⁴) and rs9984273 (OR = 0.41, 95% CI: 0.22–0.76, p = 0.0055) were associated with COVID-19 severity with a potential protective effect. However, rs1051393 did not show a significant association with disease severity. Additionally, exploratory haplotype analysis suggested a possible protective association for the TAC haplotype (OR = 0.11, 95% CI: 0.02–0.86, p = 0.036), based on a very small number of carriers and not significant after correction for multiple testing. The GAC haplotype, absent from ICU patients, yielded a continuity-corrected OR of 0.03 (95% CI [0.002–0.53]); this estimate rests on a zero cell and is hypothesis-generating only. These preliminary findings, obtained from a single-center cohort with a limited number of critically ill patients, warrant replication in larger, independent, and multicentric populations.