Viruses and bacteria take advantage of immunological brakes, raising hopes for new treatments, researchers say.
June 23, 2020
Immunologists have long focused on how the body revs up the immune system to fight invading bacteria and viruses. But researchers at the Stanford University School of Medicine, along with their colleagues at the National Institutes of Health, have discovered that after viruses and bacteria first invade, they are assisted by a particular molecule that acts as a natural immunological brake, dampening the immune response. Strategies that make the body ease up on that brake may make us better able to fight infectious disease, the researchers say.
The researchers showed that within 24 hours of a viral or bacterial infection, infected cells start expressing more of a molecule called CD47, a “don’t eat me” signal that keeps those cells from being engulfed by immune cells called macrophages. Stanford researchers previously discovered that cancer cells increase their expression of CD47, thereby evading control by the immune system.
“We wondered whether the mechanism activated by all cancer cells to avoid being destroyed could also be used by persistent infections, so that the microbes can hide inside cells to evade immune cells,” said professor Irv Weissman, MD. “Amazingly, we found that to be true, and blocking the CD47 signal helped the body get rid of more infected cells,” said Irv Weissman, MD, director of the Institute for Stem Cell Biology and Regenerative Medicine and the Virginia and DK Ludwig Professor for Clinical Investigation in Cancer Research. The paper describing this research was published June 23, 2020 in the journal mBio. Weissman and Kim Hasenkrug, PhD of the National Institute of Health are co-senior authors on the paper.
It has been known for some time that the response to infection by the adaptive immune system, which includes T and B- cells, includes a mix of immune boosters and immune suppressors that rein in the immune system so that it doesn’t overreact and cause more damage than the invading pathogen when the pathogen is gone. For instance, some flu or coronavirus patients are killed not by the activity of the viruses themselves, but by a “cytokine storm,” a flood of pro-inflammatory immune signals released when the body can’t eliminate the virus. This is a scorched earth defense by the immune system that can cause severe damage to healthy tissues.
In this paper, the researchers showed that the very early response of the innate immune system, a more primitive but still important immunological system involving cells like macrophages, is also regulated the immunologically suppressive CD47 molecule. Both mouse and human cells showed increased expression of cell surface CD47 when infected by a pathogen, they said. SARS CoV 2, the coronavirus variant responsible for COVID-19, is one of the viruses that causes increased production of CD47, they showed.
“It’s probably important for the innate immune system to have a balance of activating and suppressing forces, but pathogens seem to have co-opted this mechanism for their own purposes. we showed that if we play with that balance a little bit, we can clear some pathogens faster,” said Michal Caspi Tal, PhD, an in instructor in the Weissman lab and a co-first author on the mBio paper. The other co-first authors are former Stanford graduate student Laughing Bear Torrez Dulgeroff, PhD; and NIH staff scientist Lara Myers, PhD
To test whether negating the CD47 signal could boost the immune response to viruses, the scientists infected mice with a meningitis-causing virus called LCMV, and also gave some of them an anti-CD47 antibody. The mice in the group given the antibody had significantly lower viral loads in their bodies at all timepoints in the experiment compared to the control group, which did not get the anti-CD47 antibody. The researchers also exposed a mouse missing the gene for CD47 to tuberculosis-causing bacteria. CD47-deficient mice showed significantly more resistance to infection by the bacteria and better survival compared to mice that could make CD47.
The researchers hope that manipulating the CD47 response to infection could be another tool to fight viruses and bacteria. “In some cases it might be better to ease up on this particular immunological brake by blocking CD47,” Tal said.
Such an approach is already being tried to fight cancers such as leukemias, lymphomas, and the preleukemic condition myelodysplastic syndrome. Cancer cells also upregulated CD47 as a way of suppressing the immune response that would attack them, and an anti-cancer therapeutic using anti-CD47 antibodies is already in clinical trials.
This research was supported by the National Institutes of Health (RO1CA0806017, 5T32AI007290, F32AI124558-01, F30DK099017), the Virginia and DK Ludwig Fund for Cancer Research, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, and the Bay Area Lyme Foundation
Other Stanford scientists involved in the research include professor of Immunology Mark Davis, Phd; professor of medicine Jeffrey Glenn, MD, PhD; graduate student Ying Ying Yiu; postdoctoral fellow Ed Pham MD, PhD; pathology instructor Eric Gars, MD; graduate student Maxim Markovic; life sciences research professional Paige Hansen; CIRM scholar Sarah Galloway; postdoctoral fellow Raja Sab Kalluru, PhD; professor of pathology Niaz Banaei MD; Assistant professor of medicine Jayakumar Rajadas, MD; professor of microbiology and immunology Denise Monack, PhD; and professor of medicine Aijaz Ahmed, MD, PhD