New insights into the immune response to SARS-CoV-2 infections could bring better treatment for COVID-19 cases.
An international team of researchers unexpectedly discovered that the virus in biological cells triggers a biochemical pathway, known as the immune complement system, which could explain why the disease is so difficult to treat. The research was published this week in the journal Scientific immunology.
Researchers suggest that combining antiviral drugs with drugs that inhibit this process could be more effective. Using an in vitro model using human lung cells, they found that the antiviral drug Remdesivir, in combination with Ruxolitinib, inhibited this complement response.
This is despite recent evidence that trials of the use of ruxolitinib alone for the treatment of COVID-19 are not promising.
To identify possible drug targets, Majid Kazemian, an assistant professor in the Department of Computing and Biochemistry at Purdue University, said the research team examined more than 1,600 drugs previously approved by the FDA with known targets.
“We reviewed genes that are regulated by COVID-19, but with certain drugs, and Ruxolitinib was the main drug with that property,” he said.
In recent years, scientists have discovered that the immune complement system – a complex system of small proteins produced by the liver that help or supplement the body’s antibodies to fight blood-borne pathogens – can work inside cells and not just in the bloodstream.
Surprisingly, the study found that this response is triggered in cells of small structures in the lungs known as alveoli, Kazemian said.
“We have noticed that SARS-CoV2 infection of these lung cells causes the expression of an activated complement system to unprecedented levels,” said Kazemian. “It was completely unexpected to us because we didn’t think about activating this system inside the cells, or at least not the lung cells. Usually we think of the source of complement as the liver.”
Claudia Kemper, senior researcher and head of the Department of Complementary Diseases and Inflammation Research at the National Institutes of Health, was among the first to characterize the new roles of the complement system in the immune system. She agreed that these latest findings were surprising.
“The complement system is traditionally considered a sentinel system derived from the liver and circulating blood that protects the host from infections with bacteria, fungi and viruses,” she said. “Unexpectedly, in an environment of SARS-CoV2 infection, this system prefers to turn against the host and contribute to the harmful tissue inflammation observed in severe COVID-19. We need to consider modulating this intracellular, local complement when fighting COVID-19.”
Dr. Ben Afzali, an Earl Stadtman investigator with the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, said there are now indications that this has implications for difficulties in treating COVID-19.
“These findings provide important evidence showing not only that complement-related genes are among the most significant pathways induced by SARS-CoV2 in infected cells, but also that complement activation occurs within lung epithelial cells, i.e., locally where infection is present,” he said. said.
“This may explain why targeting the complement system outside the cells and in the circulation is generally disappointing for COVID-19. We should probably consider using inhibitors of complement gene transcription or activation of complement proteins that are permeable to cells and act intracellularly instead.”
Afzali warns that appropriate clinical trials should be conducted to determine whether combined treatment brings survival benefits.
“Another finding that I think is important is that the data suggest a potential benefit for patients with severe COVID-19 from the combined use of an antiviral agent along with an agent that broadly targets complement production or activation in infected cells,” he said. “These data are promising, but it’s important to recognize that we’ve conducted drug treatment experiments on SARS-CoV2-infected cell lines. So, by themselves, they shouldn’t be used to guide patient treatment.”
Kemper added that the unexpected findings raise more questions.
“Currently, an unexplored and perhaps therapeutically interesting aspect of our observations is whether the virus uses the creation and activation of local complement to its advantage, for example, for the processes underlying infection and cell replication,” she said.