Institute researchers discover that blocking CD47 signaling protects against cerebral malaria in mice.

Irv Weissman, MD

March 8, 2021

By Christopher Vaughan

Researchers in the laboratory of institute director Irv Weissman, MD, working with scientists the Food and Drug Administration, have discovered that a treatment currently in clinical trials as a cancer therapy is effective in combating the most deadly form of malaria in a mouse model. The research is being published today in the Proceedings of the National Academy of Sciences.

Malaria is currently one of the deadliest infectious diseases worldwide. This is partly due to the fact that malaria is endemic in many parts of the world, and partly due to the fact that there are few good treatments for severe forms of the disease. Every year, there are over 200 million cases and over 400,000 deaths worldwide. Cerebral malaria, when the parasite Plasmodium falciparum attacks the brain, is one of the deadliest forms of malaria.

The researchers in the Weissman lab had studied CD47, a don’t eat me signal that keeps immune cells from attacking and devouring abnormal cancer cells. Anti-CD47 antibodies will block the CD47 signal on cancer cells and allow the immune cells called macrophages to attack the cancer. Such antibodies are currently in clinical trials as an anti-cancer therapy. But the researchers also had data indicating that CD47 signals would also stop the immune system from attacking cells infected by a pathogen. They decided to see what effect blocking CD47 signaling would have on an actual disease.

“Because there are naturally high levels of CD47 molecules on red blood cells, we wanted to start with a disease that targeted red blood cells,” said Laughing Bear Torrez Dulgeroff, PhD, who is the first author on the research paper. “The obvious choice was the malaria parasite, which attacks by infecting those cells.” When they looked at red blood cells infected by the malarial parasite in the lab, they found that the infected blood cells carried more CD47 protein, which was a good sign, indicating that infected cells might be removed better once the CD47 signal was blocked.

Laughing Bear Torrez Dulgeroff, PhD

The results were promising. When mice with a highly infectious case of cerebral malaria were given anti-CD47 antibodies, 80 percent of them survived, compared with no mice surviving in the control group. 

They also found something surprising. They expected that these mice were surviving because the immune cells were killing the malarial infected red blood cells, but in fact the parasite load was not different between treated and untreated mice. “If the mice that were treated and survived have the same parasite load as those didn’t get the treatment and died, what is the difference between them?” Torrez Dulgeroff said.

On closer inspection, the researchers discovered several important distinctions between the anti-CD47 treated and untreated mice, particular in the brain. For example, the blood brain barrier was disrupted on untreated mice, while it was much better preserved in the mice treated with CD47-blocking antibodies. “Once you get significant vascular leakage across the blood brain barrier, that leads to brain inflammation, and death. Anti-CD47 is able to reduce the inflammatory effects in the brain during infection.” Torrez Dulgeroff said. 

It is not clear exactly how blocking CD47 signaling would lead to better integrity of the blood-brain barrier and less brain inflammation. “Cerebral malaria is a complex disease and there are several of between the treated and untreated mice, so we can’t say it’s any one thing that is the reason why the treated mice are surviving,” Torrez Dulgeroff said. But the results are exciting. “Going from zero to 80 percent survival is very promising,” she said.

"It was surprising that a complex, multicellular parasite like malaria could also find protection from macrophages (via CD47)

The researchers say that further investigation might uncover important biological mechanisms underlying the protective effect of blocking CD47 signaling, For instance, researchers in the Weissman lab had shown before that virus-infected cells protected themselves from macrophages by producing higher levels of CD47.  “But it was surprising that a complex, multicellular parasite like malaria could also find protection from macrophages in a similar way” said Weissman. “Now we wonder if the malarial parasite first infects red blood cell precursors in the bone marrow first, which could open new avenues to study the disease.”

There is also the potential to test anti-CD47 antibodies or other drugs that act in similar was as treatments for cerebral malaria in clinical trials at some point in the future.

Other Stanford researchers involved in the project were instructor Michal Tal, PhD; graduate student Ying Ying Yiu; MD-PhD student Joy Q. He; and medical student Maia Shoham.

Coinvestigators from FDA include: Miranda Oakley, Ph.D.; Victoria Majam, M.S.; Winter Okoth, M.S.; Pallavi Malla, B.S.;  and Sanjai Kumar, Ph.D.