Although Omicron has caused another global epidemic, its origin is still unclear. Understanding its origin will provide crucial clues to control it effectively and avoid other dangerous variants in the future.3 Some virologists suggested that Omicron may have diverged from other strains after long-term evolution by mutation or recombination in a population. with little vigilance.3 Based on GISAID data, before the first time point discovered (November 9, 2021) reported by WHO, samples of Omicron had already been collected, but were not sequenced and sent until much later.4 Otherwise, the characteristics of their decreased pathogenicity and S5 gene target failure could have effectively improved estimates of their pathogenicity and transmissibility, even before its official confirmation. Timely sequencing and presentation of positive samples is important to discover divergent variants and guide the prevention and control of the global SARS-CoV-2 epidemic. It is also possible that Omicron has evolved in patients with chronic infection and immunodeficiency.3,6 For example, persistent SARS-CoV-2 infection in an AIDS patient is related to the appearance of N501Y and D796Y mutations, which are also present. to the Omicron spike (S) protein.3,6 Therefore, global surveillance and sequencing of newly evolved variants in patients with COVID-19, especially in immunocompromised individuals, is important for the timely discovery and control of new and dangerous variants. .
The possibility of the guest jump in the evolution of Omicron has also been raised. In fact, many animals are susceptible to SARS-CoV-2 infection. For example, SARS-CoV-2 can effectively infect white-tailed deer with a well-defined deer-to-deer transmission pathway.7 Transmission of human mink SARS-CoV-2 has been reported on human farms. minks.8 Similarly, suspected cat-to-human transmission of SARS-CoV-2 was also reported in Thailand, where the owner’s SARS-CoV-2 infected the cat, and then transmitted to the veterinarian. .9 In addition, many Omicron mutations, such as Q493R, Q498R, and N501Y mutations have been reported in S protein in adapted strains of mice, leading to improved viral adaptation and receptor involvement. in the mouse host, especially in aged mice, 10,11 which could have served as a SARS incubator. -CoV-2.12 variants Interestingly, both Omicron BA.1 and BA.2 S trimers could bind with high affinity to the mouse ACE2, while the ancestral S trimer SARS-CoV-2 joined well in the cat’s ACE2, rather than the mouse. ACE2, which suggests a possible human-cat-mouse-human evolutionary pathway for the Omicron BA.1 and BA.2.12,13 underlines These ph Enumens suggest that Omicron’s predecessor may have undergone rapid evolution in the new host environment and then return to humans.14 Therefore, the possibility of transmission between Omicron species through host jump events deserves more detailed investigation and the possible animal reservoirs of SARS- CoV-2 and its variants s ‘must be strictly controlled.
The diffusion of Omicron underlines
From a global pandemic perspective, the Omicron variant has shown super transmissibility, quickly replacing the Delta variant, which had been the dominant epidemic variant in many countries until the end of 2021.15 On May 23, 2022, s’ had sent more than 3 million Omicron sequences and then further divided into more than one hundred sublines, such as BA.1 (original Omicron), BA.1.1, BA.2, BA.2.12.1, BA.2.3, BA .2.9, BA.3, BA.4 and BA.54 (Fig. 1a). These underlinings also exhibit different immune transmission and evasion capabilities. It should be noted that since February 2022, BA.2, which seems more transmissible, has become the most prevalent strain in many countries, such as South Africa, the United Kingdom (United Kingdom) and India, quickly replacing BA.1 and BA.1.116,17. (Fig. 1b). BA.2.12.1 also shows improved transmissibility and has become the dominant variant in the United States (Fig. 1b). However, BA.3 has shown limited transmissibility with few cases, 18 suggesting that randomly evolving Omicron partial underlinings only possess a noncompetitive propagation capacity. Therefore, the systematic comparison of sequence differences between rare and dominant underlines may reveal some critical mutations related to currently circulating strains. BA.4 and BA.5 also emerged recently, which have already caused many cases of infection in South Africa and are spreading to many other countries4 (Fig. 1b). The future spread of BA.4, BA.5 and other underlines should be closely monitored.
FIG. 1
Appearance and dissemination of Omicron underlines. a Pop-up timeline for Omicron underlines. The first date for each underline is cov-lineages.org (continuously updated) .2 b Prevalence of Omicron and other variant underlines in India, the United Kingdom, the United States, and South Africa based on all sequences available in GISAID over the past 6 months. c Schematic representation of the genomic domains of SARS-CoV-2 with mutations in Omicron sublines. PLpro (NSP3), papain-like protease; 3CLpro (NSP5), 3C-like protease; RdRp (NSP12), RNA-dependent RNA polymerase
Virological characteristics of Omicron underlines
Compared to the ancestral SARS-CoV-2, Omicron underlinings contain numerous amino acid sequences other than their S proteins, nucleocapsid proteins (N), and other structural or nonstructural proteins (Fig. 1c). In particular, protein S, the most important functional protein for viral entry and infection, contains 31-37 mutations, many of which are shared between these sublinings: G142D in the N-terminal domain (NTD) and G339D, S371L / F, S373P, S375F. , K417N, N440K, S477N, T478K, E484A, Q498R, N501Y and Y505H in the receptor binding domain (RBD), as well as in D614G, H655Y, N679K and P681H in subunit S1 and subunit S1 and subunit D794, N794H and N794H.
Some NTD mutations, including T19I, L24S, 25–27, G142D, and 143–145, have resulted in significant evasion of neutralizing antibodies (nAbs) targeting NTD.18 In addition, these shared mutations in RBD, combined with unique mutations, com BA .4-specific L452R and F486V mutations, or BA.2.12.1-specific L452Q mutations, play an important role in immune evasion, leading to numerous innovative vaccine infections and reinfections. capacity or even have an increased binding affinity with ACE2.20,21 Compared to subunit S1, subunit S2, which contains heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, has more conserved sequences . It also plays a key role in mediating viral fusion and entry into the target cell through the HR1-HR2 interaction to form six helices (6-HB). The BA.1-specific L981F mutation is outside the fusion core HR1.22 Similarly, Q954H and N969K to HR1, which are shared mutations in all Omicron sublinings, are in the non-critical positions involved in the HR1-HR2.22 interactions Therefore. , these HR1 mutations have little effect on fusion and 6-HB-mediated viral infection.
In addition, H655Y, N679K, and P681H mutations are found on the S1 / S2 border, which may affect the S1 / S2 cleavage process. Escalera et al. reported that the single H655Y mutation could significantly promote S-protein cleavage and activation, thus improving viral fusogenicity.23 It is also speculated that the N679K and P681H mutations, with their similarity to the Delta-specific P681R mutation , are beneficial for viral fusogenicity.24 However, the entire Omicron-BA.1 S protein showed significantly decreased fusogenicity compared to wild-type (WT) SARS-CoV-2.25 Some studies suggest that fusogenicity weakened Omicron-BA.1 is mainly related to the reduction of dependence on TMPRSS2. in its input process.25 However, the in-depth mechanism of reduced fusogenicity mediated by BA.1 mutations remains to be elucidated.
The fusogenicity of SARS-CoV-2 variants is positively correlated with their pathogenicity.24,26 For example, the Delta variant with higher fusogenicity showed higher pathogenicity in patients. In contrast, the BA.1 lineage with low fusogenicity exhibits milder pathogenicity in human lung tissue.27 Similarly, BA.2 also showed mild pathogenicity in mice and hamsters.28 However, one report has demonstrated that BA.2 S-mediated protein The formation of syncytia is more efficient than that of BA.1 S protein, 29 suggesting that BA.2 may have gained improved pathogenicity during its evolution. A recent report also showed that the S-protein-mediated fusogenicity of BA.2.12.1, BA.4 and BA.5 is significantly improved compared to that of the original BA.1 lineage.30 However, compared to previously dominant variants, these Omicron underlinings showed reduced clinical pathogenicity, possibly through the effects of routine vaccination, which is expected to effectively attenuate the severity of the disease, although it could not prevent viral infection. 31
In addition, some mutations are localized to spike-free proteins, e.g., P13L, del31-33, R203K, G204R to protein N; T9I to protein E; Q19E and A63T in protein M; P132H to NSP5 (3C, 3 CLpro-like protease) and some ORF mutations. The potential effect of these peakless mutations on transmissibility and viral pathogenicity is worthy of study.32 For example, although BA.3 protein S could mediate vaccine immune evasion and entry. cell comparable to that of BA.1 or BA. Few 2.33 cases of BA.3 infection have been reported, possibly due to the no-peak mutations that result in the limited spread of BA.3. In particular, although BA.4 and BA.5 share the same mutant profile in their S proteins, they showed different propagation trends, depending on the number of recently presented sequences from South Africa (Fig. 1b). Therefore, an additional study of the roles of their non-ear mutations is guaranteed. For example, compared to BA.5, BA.4 contains several unique mutations, such as 141-143 to NSP1, L11F to ORF7b, and P151S to N protein. Thus, its potential effect on viral transmission needs …