Scientists have discovered a surprising reaction in lung cells infected with the SARS-CoV-2 virus, which could explain why the disease is so difficult to treat. “That was completely unexpected,” says Purdue scientist Majid Kazemian, who led the research. The researchers suggest testing a new drug pair to fight the disease. Photo credit: Purdue University / Rebecca McElhoe

New insights into the immune response to SARS-CoV-2 infections could lead to better treatments for COVID-19 cases.

An international team of researchers unexpectedly found that a biochemical pathway known as the immune complement system is triggered in lung cells by the virus, which could explain why the disease is so difficult to treat. The research is published this week in the journal Science Immunology.

The researchers suggest that pairing antiviral drugs with drugs that inhibit this process might be more effective. Using an in vitro model using human lung cells, they found that the antiviral drug remdesivir in combination with the drug ruxolitinib inhibited this complement reaction.

This is despite recent evidence that studies using ruxolitinib alone to treat COVID-19 have not shown promise.

To identify potential drug targets, Majid Kazemian, assistant professor in the computer science and biochemistry departments at Purdue University, said the research team examined more than 1,600 previously FDA-approved drugs with known drugs.

“We looked at the genes that are upregulated by COVID-19 but downregulated by certain drugs, and ruxolitinib was the top drug with that trait,” he said.

In recent years, scientists have discovered that the immune complement system – a complex system of small proteins produced by the liver that aid or supplement the body’s antibodies in fighting blood-borne pathogens – can act not only in cells, but also in cells in the bloodstream.

Surprisingly, the study found that this response is triggered in cells in the small structures in the lungs known as alveoli, Kazemian said.

“We observed that SARS-CoV2 infection of these lung cells caused the expression of an activated complement system in an unprecedented way,” said Kazemian. “This was completely unexpected to us, as we didn’t think about activating this system within the cells, or at least not about lung cells. We usually consider the source of complement to be the liver.”

Claudia Kemper, Senior Researcher and Head of Complement and Inflammation Research at the National Institutes of Health, was one of the first to characterize new roles for the complement system in the immune system. She agreed that this latest finding is surprising.

“The complement system has traditionally been viewed as a liver-derived, perfused sentinel system that protects the host from bacterial, fungal, and viral infections,” she said. “It is unexpected that in SARS-CoV2 infection this system would be more likely to turn against the host and contribute to the harmful tissue inflammation seen in severe COVID-19. We need to think about the modulation of this intracellular, local complement when combating from COVID-19. “

Dr. Ben Afzali, an Earl Stadtman investigator with the National Institute of Health’s National Institute of Diabetes and Digestive and Kidney Diseases, said there is now evidence that this is affecting difficulties in treating COVID-19.

“These results provide important evidence that not only complement-related genes are among the most important signaling pathways induced by SARS-CoV2 in infected cells, but also that activation of the complement occurs within lung epithelial cells, ie locally where there is an infection.” He said.

“This could explain why targeting the complement system outside the cells and in the circulatory system has been generally disappointing in COVID-19. We should probably consider using inhibitors of complement gene transcription or complement protein activation that are cell permeable and instead act intracellularly. “

Afzali warns that appropriate clinical trials should be conducted to determine whether combination treatment offers a survival benefit.

“The second finding that I think is important is that the data suggests a potential benefit for patients with severe COVID-19 from the combinatorial use of an antiviral agent along with an agent that acts largely on complement production or activation in infected people Targets cells, “he said. “These data are promising, but it is important to recognize that we have conducted the drug treatment experiments in SARS-CoV2 infected cell lines. Therefore, they should not in and of themselves be used to treat patients directly.”

Kemper added that the unexpected results raise further questions.

“Another currently unexplored and potentially therapeutically interesting aspect of our observations is whether the virus uses local complement generation and activation to its advantage, for example for the processes that underlie cell infection and replication,” she said.

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More information:
Bingyu Yan et al., SARS-CoV-2, control JAK1 / 2-dependent local complement hyperactivation, Science Immunology (2021). DOI: 10.1126 / sciimmunol.abg0833 Provided by Purdue University

Quote: COVID-19 causes an “unexpected” cellular response in the lungs, Research Results (2021, April 8), accessed April 9, 2021 from -response-lungs .html

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