Twelve years ago, cancer researchers at University of California San Diego identified a molecule that helps cancer cells survive by shutting damaging inflammatory cells into tumor tissue. In new research published in Science Transitional Medicine, show that the same molecule does the same in lung tissue infected with COVID-19, and that the molecule can be suppressed with a repurposed cancer drug. This represents a new approach in preventing irreversible damage in infectious diseases like COVID-19 and methicillin-resistant Staphylococcus aureus (MRSA).
“Our work shows that drugs that can prevent the recruitment of damaging myeloid cells into tissues that are infected with severe agents like COVID-19 or MRSA have a significant benefit in preserving tissue function if given early enough in an infection,” said Dr. Judith Varner, professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine, co-leader of the Solid Tumor Therapeutics program at UC San Diego Moores Cancer Center, and the study’s senior author in press release.
In this scenario, the two key players are inflammatory cells called myeloid cells, and an enzyme called P13K. Myeloid cells are innate to the body’s immune system, the immunity people are born with before exposed to pathogens in the environment and work quickly to kill deadly agents such as SARS-CoV-2, the virus that causes COVID-19.
Varner said myeloid cells protect us, but they can also do a lot of damage.
“If you have a little infection, myeloid cells come in, kill bacteria, release alerts that recruit even more potent killer immune cells, and produce substances that can heal the damage. But if you get an infection that’s too strong, you get overproduction of these alert signals, and the substances they release to kill these infective agents can also kill yourself. That’s what happens in COVID-19,” she said.
Using a combination of bulk RNA sequencing and bioinformatics, the scientists analyzed tissues from humans and mice to see how SARS-CoV-2 changed the cellular and molecular makeup of infected tissues. They then treated the tissue with eganelisib to see if suppressing PI3K gamma made a difference.
“We sequenced COVID-19 patient lung tissue and showed that when patients have COVID-19, a lot of their lung cells are killed and there’s a huge increase in myeloid cells. We also found the same thing in infected mice,” said Varner. “When we treated with the drug, we showed that eganelisib prevents entry of myeloid cells into tissue so they can’t do all that damage. Further studies will determine if it can actually reverse damage.” The team also had the same results in mice infected with MRSA. No similar approach has yet been approved for clinical use. Other drugs were tested early during the COVID-19 crisis for similar effects, with only modest success. Our work is significant because this is the first time this particular approach of targeting the myeloid cells specifically has been shown to be effective in COVID.”
