Texas A&M, Hokkaido researchers detect how SARS-CoV-2 virus blocks body's immune response
Understanding the mechanism of how the SARS-CoV-2 virus, the virus responsible for COVID-19, evades the body's natural immune system is key to devising targeted therapies to stop the virus.
Understanding the mechanism of how the SARS-CoV-2 virus, the virus responsible for COVID-19, evades the body's natural immune system is key to devising targeted therapies to stop the virus.
Recently, scientists from Texas A&M University College of Medicine, and Hokkaido University in Japan discovered how SARS-CoV-2 infection affects the MHC Class I pathway, which is crucial for immune function. Their work appears in the journal Nature Communications, Nov. 15, 2021.
A Hokkaido University news release on the discovery reports that the scientists used a bioinformatics approach comparing the gene expression in the immune systems of SARS-CoV-2-infected patients and uninfected individuals. This enabled them to compare how the complicated cell signaling pathways spark the immune system into action.
The researchers were able to validate their discoveries by looking at gene expression in cell lines that they infected with the virus in vitro. They found that ORF6, a protein from the SARS-CoV-2 virus, turns off the expression of NLRC5 and also blocks its functioning.
Research with other viruses has shown that MHC Class I immune responses are important in defending the body against viral infection. MHC stands for major histocompatibility complex. Class I molecules on the surface of cells are responsible for recognizing virus-infected cells and signaling the immune system to attack the virus.
The MHC Class I pathway helps defend the body against viral invasion by mobilizing the body's T lymphocytes (killer T cells) to destroy virus-infected cells. If this doesn't happen, the virus thrives. People infected with SARS-CoV-2 have "a tendency toward reduced quantity and quality of functional T lymphocytes, which is closely associated with disease severity and high mortality," the article states.
Many viral species, the researchers report, have "evolved diverse strategies for targeting the MHC class I pathway to evade host immunity," including Epstein Barr, HIV, and herpes simplex viruses. But how SARS-CoV-2 hijacks the MHC class I pathway is "poorly understood," they add. The researchers sought to discover exactly how SARS-CoV-2 disabled the MHC Class I pathway.
An important pathway
Texas A&M immunologist Koichi Kobayashi, who led the study, stresses the importance of the MHC class I pathway.
"The MHC class I is very important," he said. "It's a sort of warning sign for human immune system. If there are antigens inside cells, for example antigens from invading viruses or cancers, then those antigens would be carried by the MHC class I to cell surface."
"Then 'killer T cells' recognize those foreign antigens and kill cells infected by viruses or cancerous cells. This leads to removal of infected cells together with viruses inside," Kobayashi added. "If this system does not work properly, viruses can stay in the human body longer and can cause higher risk of severity of the disease."
The researchers discovered a specific viral protein, ORF6, in the SARS-CoV-2 virus prevents a key signaling factor from reaching its target. Because ORF6 prevents key signaling transcription factors from reaching the nucleus, the invading virus can remain undetected.
Kobayashi's team also identified the "master co-activator of MHC Class I genes," NLRC5, which is "critical for the expression of not only MHC class I genes but also essential components of the MHC Class I pathway."
"Human cells can make MHC class I and other parts used in the MHC Class I pathway because of the function of NLRC5," Kobayashi said. "If NLRC5 function is impaired, we would become susceptible to cancer and infectious diseases."
Discovering new possibilities for therapeutics
“Without the activation of the MHC Class I pathway, viruses in the infected cells are essentially hidden from the immune system," Kobayashi said in the press release. "That helps to explain why SARS-CoV-2 virus persists in the body and why it keeps infecting others, leading to the pandemic.”
Kobayashi suggests that by targeting the molecular system the researchers found, "new therapeutic drugs can be developed."
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Ji-Seung Yoo et al. "SARS-CoV-2 inhibits induction of the MHC Class I pathway by targeting the STAT1-IRF1-NLRC5 axis," Nature Communications, Nov. 15, 2021.
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