SARS-CoV-2 Variants Show a Gradual Declining Pathogenicity and Pro-Inflammatory Cytokine Stimulation, an Increasing Antigenic and Anti-Inflammatory Cytokine Induction, and Rising Structural Protein Instability: A Minimal Number Genome-Based Approach

Abstract

Hyper-transmissibility with decreased disease severity is a typical characteristic of the SARS-CoV-2 Omicron variant. To understand this phenomenon, we used various bioinformatics approaches to analyze randomly selected genome sequences (one each) of the Gamma, Delta, and Omicron variants submitted to NCBI from December 15 to 31, 2021. We report that the pathogenicity of SARS-CoV-2 variants decreases in the order of Wuhan > Gamma > Delta > Omicron; however, the antigenic property follows the order of Omicron > Gamma > Wuhan > Delta. The Omicron spike RBD shows lower pathogenicity but higher antigenicity than other variants. The reported decreased disease severity by the Omicron variant may be due to its decreased pro-inflammatory and IL-6 stimulation and increased IFN-γ and IL-4 induction efficacy. The mutations in the N protein are probably associated with this decreased IL-6 induction and human DDX21-mediated increased IL-4 production for Omicron. Due to the mutations, the stability of S, M, N, and E proteins decreases in the order of Omicron > Gamma > Delta > Wuhan. Although a stronger spike RBD- h ACE2 binding of Omicron increases its transmissibility, the lowest stability of its spike protein makes spike RBD- h ACE2 interaction weak for systemic infection and for causing severe disease. Finally, the highest instability of the Omicron E protein may also be associated with decreased viral maturation and low viral load, leading to less severe disease and faster recovery. Our findings will contribute to the understanding of the dynamics of SARS-CoV-2 variants and the management of emerging variants. This minimal genome-based method may be used for other similar viruses avoiding robust analysis. Supplementary Information The online version contains supplementary material available at 10.1007/s10753-022-01734-w.

In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants

“…Performing analogous in silico modelling on other VoCs, including Alpha, Gamma, and Delta variant, showed a decrease in the number of dimerization modes after the Alpha variant, with 6, 7, 5, 4, and 3 modes of TLR4/MD2 dimerization for the wild-type, Alpha, Gamma, Delta, and Omicron VoCs, respectively (Figures for Alpha, Gamma, and Delta variants in Supplementary data, Tables S1-S3 and Figures S1-S3). These data correlate with data from recent studies, which indicate a narrowing cytokine pattern during evolution of the SARS-CoV-2 [82,83].…”

“…The study compared the cytokine profiles of patients with different variants of SARS-CoV-2 and showed that hypercytokinemia and cytokine storm become less threatening with the emergence of new mutations in the viral genome, being already visible with the Delta variant and most pronounced for the Omicron variant [82]. A similar tendency of decreasing pathogenicity has been shown by Barh et al showing decreasing pathogenicity (correlating with decreasing cytokine release) with virus evolution, with Wuhan strain > Gamma > Delta > Omicron [83].…”

“…A milder pathological picture was also shown for Omicron infected Syrian golden hamsters compared to Beside the significantly lower pathogenicity of Omicron, recent studies have indicated a generally narrowing cytokine pattern during evolution of the SARS-CoV-2 from the original Wuhan strain via the various VoCs, e.g., Alpha-Gamma-Delta-Omicron. Comparing the cytokine profiles of patients infected with different VoCs with those infected with the wild-type Wuhan variant, the studies showed that hypercytokinemia and cytokine storm become less threatening with the emergence of new mutations in the viral genome, this tendency being largely visible already with the Delta variant and with the most pronounced change for the Omicron variant [82,83].…”

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes Structure

“…These authors also reported that the so-called cytokine storm and the general "hypercytokinemia" exhibited a marked attenuation after emergence of the new Omicron variant. Interestingly, these findings were confirmed in a subsequent study published by Barh et al [41], who reported that pro-inflammatory cytokines production (especially interleukin 6) is decreased in patients infected with the Omicron compared to those infected by Delta variant. In keeping with these findings, Park et al studied nearly 30000 veterans with Alpha, Delta and Omicron infections [42] and observed that the risk of having enhanced levels of C Reactive protein was higher in those infected by Delta (Odds Ratio [OR], 2.30; 95%CI, 2.18-2.4) or Alpha (OR, 2.29; 95%CI, 2.14-2.45) compared to Omicron.…”

Impact of Climate on the Expansion of Dengue Fever in an Endemic Urban Area

“…Well established knowledge since pioneering work of May & Andersen [32], and widely demonstrated along the COVID-19 pandemic, transmissibility is not related, or even is inversely related, to virulence. Contrasting 2003 SARS epidemic to the most recent SARS-CoV-2 pandemic, it is clear that a virulent variant/genotype will decrease its incidence in the host population, while those genotypes which are less virulent may evolve towards forms which are more transmissible, thus, becoming highly incident, even though more difficult to detect due to low hospitalization [33][34][35][36][37] Even though virulence of dengue is expected to be preserved along time due to the insect vector phase, especially considering vertical transmission [38], a newly arriving serotype must cause more severe disease but not further dissemination. On the contrary, the fast hospitalization removes a host to the transmission cycle.…”