Coronavirus molecule
Recent analyzes show that Omicron variants of SARS-CoV-2 suppress class I major histocompatibility complex expression more strongly than previous versions of the virus. During the pandemic, the latest versions of SARS-CoV-2 have adapted well to our immune system to avoid clearance.
Once the virus enters the cell, it not only suppresses the cell’s ability to mount an active defense itself, but also suppresses the cell’s ability to signal to other cells that it is infected, effectively hides from cytotoxic T cells, which could otherwise kill it. . SARS-CoV-2 does this by downregulating the antigen-presenting markers most important for recognizing and killing infected cells: MHC class I and II.
Previous studies showed that the NSP5 protein downregulates MHC-II. Here, Moriyama et al. show that the Omicron variant of SARS-CoV-2 also efficiently downregulates MHC-I, rendering it invisible.
Moriyama et al. discovered that the wild-type strain of SARS-CoV-2 strongly suppresses MHC-I expression, meaning the virus bypassed the surface marker system so critical to immune system clearance. This suppression is not found in influenza virus infection, meaning it is a specific feature of SARS-CoV-2.
Further, empathize Experiments showed that variants of concern before Omicron shared similar levels of MHC-I suppression, despite more evolved immune evasion mutations in these variants.
One of the SARS-CoV-2 proteins known to play a role in MHC-I suppression is Orf8. This accessory protein is often mutated in variants of concern, leading Moriyama et al. to analyze the mutations individually to discern their impact on MHC-I suppression.
Isolation of the seven most common Orf8 mutations in vitro and applying them to HEK293T cells equipped with MHC-I expression-detecting plasmids, they found that all mutations inhibited MHC-I suppression. In the case of the Alpha variant that spread in late 2020 and early 2021, the Orf8 protein is completely truncated at position 27 by a mutation, completely abrogating the downregulation of MHC-I.
In other words, the original SARS-CoV-2 Orf8 protein was better at suppressing MHC-I than the Orf8 proteins of variants that followed, in stark contrast to most immune suppression functions that only improved with further mutation.
By extending this point to current Omicron variants, the Orf8 protein is much less mutated than in previous variants of concern. In the most common Omicron variants, the protein is completely intact in most cases.
As expected, in testing the Omicron variant for MHC-I suppression, Moriyama et al. found improved suppression compared to the low-performing variants of concern and even stronger suppression than the wild-type virus. The fully intact Orf8 protein complements the enhanced immune evasive capabilities of the rest of the virus.
The researchers found that a common mutation in Omicron likely contributes to enhanced MHC-I suppression, namely T9I in the E protein, shared among the subvariants they examined.
Omicron’s superior ability to suppress MHC-I is a major contributor to the ongoing havoc since November 2021. By bypassing cytotoxic T cells, the virus avoids immune clearance much more effectively, leaving host cells more susceptible for infection long after the host first came into contact with the pathogen.
So what can we do with this information? One of the key features of the Covid-19 pandemic is that the virus mutates to escape immune surveillance. The most well-known escape method is by altering the spike protein. However, it is now known that the virus has many other activities that downregulate the innate immune response.
The virus downregulates signaling molecules released by infected cells. As shown here, it also regulates the antigen-presenting molecules, MHC class one and two, that normally allow T cells and other immune components to eliminate SARS-CoV-2.
Another feature is the continued evolution towards increased infectivity, where lower doses of the virus can initiate infection; For example, Omicron is about ten times more contagious than the original Wuhan wild-type. While most research has focused on the virus’ exterior, the spike protein, it is now abundantly clear that immune escape mutations elsewhere in the virus are increasingly potent in reducing innate immunity and immune recognition.