With each new mutation, SARS-CoV-2 increases infectivity:

  • The D614G strain appeared in February 2020. An amino acid change occurred in this strain’s spike protein (S): glycine replaced aspartic acid. Thanks to this mutation, the coronavirus could replicate faster in the respiratory tract’s nasal cavity and epithelial cells and become more infectious.
  • The Alpha strain was first registered in the UK in September 2020. There are 13 mutations in the spike protein that facilitate the transmission of the virus. One of the mutations caused some PCR tests to stop detecting coronavirus RNA.
  • The Beta strain was discovered in South Africa in August 2020. There are 10 mutations in the spike protein that increase infectivity and contribute to immune evasion.
  • The Delta strain appeared in Maharashtra, India, in October 2020. The S protein contains multiple amino acid substitutions that enhance binding to the ACE2 receptor, facilitate virus transmission, and help the virus bypass immune defenses.
  • The Omicron strain was discovered in Botswana and South Africa in November 2021. The spike protein has 37 amino acid substitutions. 15 of them are located in the S-protein fragment, which is involved in binding to the ACE2 receptor. Amino acid substitutions increase the infectivity of the Omicron strain and reduce the effectiveness of neutralizing antibodies that have appeared in response to vaccination or past COVID-19. In addition, Omicron neutralizes therapeutically administered monoclonal antibodies worse.

Chinese scientists compared Omicron with previous strains of SARS-CoV-2. Scientists have studied coronavirus replication in the bronchi and lung parenchyma tissue.

Omicron Multiplies More Intensively in The Bronchi

Omicron replicated 70 times more intensively in the bronchi than wild-type SARS-CoV-2 and the Delta strain. However, in the lungs, Omicron replicated worse than the previous strains.

Immunohistochemical staining showed that, like other strains, Omicron infects bronchial tissue: ciliated epithelium, goblet cells, and Clara cells, as well as spindle-shaped cells, which are similar in structure to type 1 pneumocyte covering the surface of the alveoli. However, if during infection with Omicron in the bronchial epithelium, a more significant number of infected cells were observed, then Omicron damaged the lung tissue less than the previous strains.

ACE2 And TMPRSS2 Expression in The Airways

Enzymes ACE2 and TMPRSS2 promote the entry of SARS-CoV-2 into cells. ACE2 is expressed on the cell surface and exists in both short and long forms, with the short form not binding to the spike protein of SARS-CoV-2.

The expression of both the long and short forms of ACE2 is significantly higher in bronchi than in the lungs. The expression of TMPRSS2 is also considerably higher in the bronchi.

Omicron Quickly Enters The Cell

For SARS-CoV-2 to enter the cell, cleavage of its spike protein is necessary. The S-protein can be cleaved by the TMPRSS2 enzyme located on the cell membrane, or cathepsins, intracellular enzymes. Cathepsins are needed to digest the molecules that it absorbs with the help of the membrane vesicle endosome.

The scientists found that, compared to the Delta strain, Omicron is less dependent on TMPRSS2 expression but more sensitive to the cathepsin inhibitor. It means that Omicron enters the cells after absorption by the endosome, while the Delta strain needs to be fused with the cell under the influence of TMPRSS2. Therefore, Omicron can infect a more extensive range of cells that express ACE2, regardless of the presence of TMPRSS2.

Cells that express ACE2 and cathepsins are more abundant in the upper respiratory tract than cells that express ACE2 and TMPRSS2. It explains the increased replication capacity of Omicron in the bronchi.

Conclusions

According to British epidemiologists, the risk of infection with Omicron is 3.2 times higher than with the Delta strain. Increased infectivity is caused by mutations that allow Omicron to penetrate the cell more quickly and remain invisible to antibodies developed after vaccination or infection. Another reason for infectivity is that the ability of Omicron to replicate in the bronchi is 70 times higher than that of Delta, which increases the amount of contagious virus that the patient releases when breathing and talking, therefore increasing the risk of airborne transmission of SARS-CoV-2.

Omicron intensively multiplies in the bronchi but affects the lungs less. Therefore, Omicron is more manageable: the number of hospitalizations with Omicron is lower than with Delta. But even if the risk of pneumonia is lower with Omicron, the high contagiousness poses a severe threat to health systems. Therefore, regardless of antibodies, it is still necessary to observe preventive measures.

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SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo

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