Researchers at the University of Washington School of Medicine have identified new ways that antibodies can prevent E. coli bacteria, which cause urinary tract infections (UTIs), from attaching to bladder cells. The study describes several distinct mechanisms by which antibodies interfere with bacterial adhesion, including forming molecular wedges, conformational traps, and pocket locks in the proteins that bacteria use to bind to human cells.
One newly recognized class of antibodies mimics molecules on cell surfaces. These antibodies deceive the bacteria into binding to them instead of bladder cells. "All of these antibody mechanisms found in studying urinary tract infecting E. coli are likely applicable in defending against other bacterial and viral pathogens as well," said Dr. Evgeni V. Sokurenko, a physician-scientist and professor of microbiology at the UW School of Medicine.
The findings were published in Nature Communications. Pearl N. Magala, acting instructor of biochemistry who initiated the study, and Justin M. Kollman, professor and chair of biochemistry at UW School of Medicine, served as co-senior and corresponding authors.
The research team observed that E. coli’s cell-adhesion system could be tricked by a decoy molecule attached to a key region on one antibody studied. This antibody contained a glycan—a complex carbohydrate structure common on cell surfaces—that mimicked the receptor E. coli targets on human cells. As a result, bacteria bound mistakenly to these antibodies rather than live cells, blocking their attachment and marking them for destruction by the immune system.
"This class of antibodies are likely to be broadly produced in response to bacterial and viral antigens, or with immunization with vaccines," Sokurenko noted.
Kollman added: "While many antibodies are known to carry various forms of glycans, surprisingly, existence of antimicrobial antibodies with the cell receptor-mimicking glycans were not documented before."
He also pointed out that certain microbial glycan-binding proteins might interact with some cancerous B cells in lymphomas and promote tumor growth or persistence.
Additionally, since normal B cells play a role in immunity, antigens from infectious microbes may contribute to autoimmune disorders by stimulating B cell receptors.
The researchers suggest their results provide groundwork for developing immune therapies targeting glycan-binding proteins used by bacteria causing UTIs; this approach could also be explored for other disease-causing organisms such as viruses or fungi.
However, they caution that anti-adhesion antibody actions may not always benefit people or animals; potential side effects should be considered when selecting vaccine components for testing.
To conduct this research, scientists used cryo-electron microscopy, mass spectrometry, adhesion assays and molecular dynamics simulations on the Expanse supercomputer located in San Diego.
Funding was provided through grants from the U.S. National Institutes of Health (F32 AI145111, R00 GM147304, K99 GM141364, R01 AI119675 R21 AI178593, R01 AI171570, R35 GM149542 and S10 OD023476).
