Month: January 2022

A group from Department of Infectious Disease, Imperial College London, UK, etc. has reported about SARS-CoV-2 Omicron’s higher infectivity in human nasal epithelial cells (hNECs) and its possible reasons.
https://www.biorxiv.org/content/10.1101/2021.12.31.474653v1

SARS-CoV-2 Omicron showed a large early replication advantage in human nasal epithelial cells (hNECs), yielding viral titres ～100-fold higher than Delta by 24 hours post-infection. At 48 and 72 hours post-infection, viral titres were lower compared to Delta and at 72 hours the RNA collected from Omicron infected wells was fewer. In Vero-AT cells, replication of the two variants was equal. In Calu-3 cells, the viral yields of Omicron were lower than for Delta across all time points.

Previous SARS-CoV-2 variants, such as Delta, only enter cells efficiently by binding ACE2 and activating fusion via cell-surface protease TMPRSS2. Omicron, conversely, is able to enter cells in both a TMPRSS2-dependent and –independent manner, having evolved the ability to avoid endosomal restriction. This allows Omicron to infect any ACE2-expressing cell in the airway instead of relying solely on double ACE+ TMPRSS2+ cells.

It was also found omicron Spike bound better to mouse ACE2 than any previous variant, as several others have reported. This suggests a possibility that omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans.

A group from University of Chinese Academy of Sciences, Beijing 100049, China has proposed a hypothesis that the progenitor of Omicron evolved in mice.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8702434/

Generally speaking, the molecular spectrum of mutations that accumulate in a viral genome reflects a host-specific cellular environment.

The molecular spectrum of the pre-outbreak Omicron mutations was significantly different from the “standard” molecular spectrum for SARS-CoV-2 variants known to have evolved strictly in humans (hSCV2 spectrum), and interestingly, the molecular spectrum of the post-outbreak Omicron mutations was not significantly different from the hSCV2 spectrum. From a statistical point of view, these molecular spectrum analyses revealed that pre-outbreak Omicron mutations were unlikely to have been acquired in humans.

The molecular spectrum of post-outbreak Omicron mutations (which are known to have accumulated in humans) was located within the human 95% confidence ellipse. In contrast, the molecular spectrum of pre-outbreak Omicron mutations was within the mouse ellipse, suggesting that the pre-outbreak mutations accumulated in a rodent (in particular a mouse) host.

It was also confirmed that the pre-outbreak Omicron mutations in the RBD showed the greatest enhanced binding affinity for mouse ACE2 among 32 mammals with molecular docking analysis.

A group from Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Science (IMS), Yokohama, Japan, has reported that some types of HCoV-specific CD8⁺ T cells may be cross-reacting against SARS-CoV-2.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640030/

Recently, the relationship between Human Leukocyte Antigens (HLA alleles) and COVID-19 is attracting attentions.

Authors assessed the interaction between HLA-A*24:02, as one of the major HLAs, and CD8⁺ T cells cross-reactive for SARS-CoV-2. In-vitro expansion assays can be used to detect pre-existing CD8⁺ T cells against cancer or cross-reactive CD8⁺ T cells to SARS-CoV-2.
cited from https://www.jstage.jst.go.jp/article/mhc/23/2/23_115/_pdf/-char/ja

PBMCs were cultured in the presence of selected each peptide, and the frequencies of epitope-specific IFN-γ-producing CD8⁺ T cells were assessed on day 21. Although selected six peptides from SARS-CoV-2 Spike protein were expected to bind to HLA-A*24:02 with high affinity, five of these did not induce a T-cell response, and only Pep#3 (Amino acid sequence ＝ QYIKWPWYI, SARS-CoV-2 Spike position ＝ 1208-1216)-specific CD8⁺ T cell counts were elevated in cells derived from all unexposed healthy donors (UHDs). Intriguingly, Pep#3 exhibited high sequence homology with other coronaviruses, including four types of seasonal coronaviruses (HCoV). Although all the six peptides of S protein were predicted to exhibit high affinity to HLA-A*24:02, five peptides were not homologous to other seasonal coronaviruses.
These results suggest that HCoV-specific CD8⁺ T cells may be cross-reacting against SARS-CoV-2, and that pre-existing memory CD8⁺ T cells may be responsible for the immune response.

To understand why CD8⁺ T cells exhibit multiple responses to various coronaviruses and the underlying mechanisms, we studied the cross-reactivity of CD8⁺ T cells at the single TCR level. After restimulation with Pep#3, CD8⁺ T cells from Pep#3-specific CD8⁺ T cell lines were isolated by gating CD107a⁺CD8⁺ cells and performed single-cell analysis of TCR repertoires. To analyze the clonalities of Pep#3-reactive CD8⁺ T cells, a total of 227 T cells were screened, and 44 TCR clonotypes were identified from five UHDs and one patient with hematological malignancies (HM). Furthermore, we focused on the dominant TCR types from among the clonotypes and identified four types of TCRα and TCRβ pairs from four donors (three UHDs and one HM). To assess the specificity and functions of cloned TCRs, we transduced the TCRα and TCRβ genes into the SKW3-CD8AB (human T-ALL) cell line and demonstrated their peptide-specific response. Intriguingly, the four types of TCR repertoires varied from each other in their epitope recognition. TCR-T (TCR-T-1) cells from UHD2 responded well to all the epitopes derived from coronaviruses, whereas the TCR-T (TCR-T-2) cells from UHD8 responded only to SARS-CoV-1 and SARS-CoV-2.