Model shows how antibodies navigate pathogen surfaces like a child at play

Antibodies aim to establish a foothold on two separate antigens, in much the same way a child might try navigating stepping stones in a stream. Credit: Ian Hoffecker

A new study shows how antibodies select the antigens that they bind to, as they navigate the surface of pathogens like coronaviruses. Researchers from KTH Royal Institute of Technology and Karolinska Institutet have created a model that suggests the migration of these pathogen hunters may be akin to the random movements of a child playing on a stream laden with stepping stones.

Ian Hoffecker, a researcher at KTH Royal Institute of Technology in Stockholm, says the model raises new ways to consider the evolution of viruses and immune systems, and that the new study yields insights that may be useful in vaccine engineering.

Antibodies are often thought of as Y-shaped proteins. But recent studies have shown that perhaps a more accurate way to envision them is to flip the picture upside down and regard as walking stick figures, stepping on antigens. Those two characteristic “Y” branches function as legs of sorts, Hoffecker says.

Paraphrasing Nancy Sinatra’s 1966 hit recording, he says: “These antibodies are made for walking.”

These stalking pathogen hunters mark their prey by planting their “feet” on antigens— scattered like stepping stones in various patterns on the surfaces of viruses. They rely on what’s called multivalence—or establishing a foothold with both “Y” branches, typically on two separate antigens—which allows them to bind as strongly as possible to their targets. Once in place, antibodies participate in a series of interactions with other signaling proteins to neutralize or kill the pathogen.

Using a nano-fabricated model of a pathogen’s antigen pattern, the researchers set out to determine how this behavior is influenced by pathogen surfaces, Hoffecker says. “What if antigens are really close together or what if they’re kind of far apart? Do the antibodies’ molecules stretch out, do they compress?”

To find out, Björn Högberg from Karolinska Institutet’s Division of Biomaterials Research says the team simulated a pathogen and antigen scenario using a method called DNA origami, in which DNA self-assembles into nanostructures with a programmable geometry that allowed them to control the distance between antigens.

“This tool has enabled us to investigate how this distance between two antigens impacts binding strength,” Högberg says. “In our new work we took this data and plugged it into a model that lets us ask interesting questions about how antibodies behave in more complex environments—without straying too far from reality.”

Hoffecker says the model reveals that antibodies behave not much differently from another well-known bipedal organism—namely, human beings.

“The process could be likened to a child playing on a river laden with stepping stones just large enough to accommodate a single foot,” Hoffecker says. “So to stand in place, the child would have to straddle two rocks or else balance on one foot.”

The antibodies in the seemed to favor antigens that are closer together and easier to stand on. And if are too far apart, they have a statistical tendency to migrate to an area where they stand closer together, he says.

Such observations raise the question of whether the flexibility and structure of antibodies is influenced by their antagonists, the pathogens. “We are asking the question, is this relevant to evolution, or co-evolution, where you have this constant arms race between the and pathogens, and this control system that basically says how antibodies move and where they go?” he says.

Hoffecker says the next steps are to observe how this property of antibodies manifests itself in , and to incorporate these findings into rationally-designed vaccines that account for the antigen spatial organization factor.

The research was published in Nature Computational Science.

More information:
Ian Hoffecker et al, Stochastic modeling of antibody binding predicts programmable migration on antigen patterns, Nature Computational Science (2022). DOI: 10.1038/s43588-022-00218-z.

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Hexbyte Glen Cove New research sets stage for development of salmonella vaccine thumbnail

Hexbyte Glen Cove New research sets stage for development of salmonella vaccine

Hexbyte Glen Cove

Salmonella forms a biofilm. Credit: CDC

With the COVID-19 vaccines on many people’s minds, some may be surprised to learn that we do not yet have vaccines for many common infectious diseases.

Take , for example, which can infect people through contaminated food, water and animals. According to the World Health Organization, non-typhoidal salmonella infection affects more than 95 million people globally each year, leading to an estimated 2 million deaths annually. There is no approved vaccine for salmonella in humans, and some strains are antibiotic-resistant.

But just as scientists spent decades doing the basic research that made the eventual development of the COVID-19 vaccines possible, University of Florida researchers led by Mariola Edelmann in the department of microbiology and cell science, UF/IFAS College of Agricultural and Life Sciences, are laying the groundwork for an effective vaccine for salmonella and other hard-to-treat bacterial infections. In their study supported by the National Institutes of Health and published in PLOS Pathogens, the UF/IFAS scientists demonstrate a novel approach to triggering immunity against salmonella.

This approach takes advantage of how cells communicate with each other, said Winnie Hui, first author of the study, which was conducted while she was a doctoral candidate in microbiology and cell science.

“Cells communicate with each other through particles called extracellular vesicles or EVs. Think of these like molecular telephones that let cells talk to each other. We wanted to know if some of those messages included information related to immune response,” said Hui, who graduated from the UF/IFAS College of Agricultural and Life Sciences in 2019 and is now a postdoctoral researcher in the UF College of Medicine, division of rheumatology and clinical immunology.

“Host EVs have not been previously studied in the context of fighting enteric bacterial infections, so that is part of what makes our approach new and adds to the field,” said Edelmann, senior author on the study, Hui’s dissertation director and an assistant professor of microbiology and .

Edelmann hypothesized that a specific type of EVs called exosomes were part of the immune response against salmonella and may one day hold the key to developing a vaccine.

To test their idea, the research team took exosomes from white blood cells infected with salmonella. Inside those exosomes, which measure just a few dozen nanometers across, they found salmonella antigens, which are bits of salmonella protein known to trigger an .

Next, the researchers wanted to know if these exosomes might function as a vaccine, helping the body build up its defenses against salmonella, said Lisa Emerson, one of the study’s co-authors and a doctoral student in Edelmann’s laboratory.

“We put the exosomes in ‘nanobubbles’ that the mice inhaled. Later, we ran tests to see how their immune systems responded,” said Emerson, who is in the UF/IFAS College of Agricultural and Life Sciences.

The researchers found that after they introduced the exosomes containing salmonella antigens, the exosomes localized to tissues that produce mucous, activating specific cells at these sites. Weeks later, mice developed antibodies against salmonella and specific cellular immune responses, which typically target this bacterium for elimination. For the researchers, this is a promising result.

“There are two types of immune responses generated when our bodies encounter a pathogen. The first one is called innate immunity, which is an immediate response to an , but it is also less specific. The other response is called adaptive immunity, and this protective response is specifically tailored to a given pathogen, but it also takes longer to develop. Exosomes generated by infected white blood stimulated both of these responses in animals,” said Hui.

While these results show promise, more research will be needed before we have a salmonella that works in humans, Hui said.

“Our study has identified a novel role of exosomes in the protective responses against salmonella, but we also think that exosomes can find broader applications for other intestinal infections and beyond,” Edelmann said.

“Exosomes have this unique capability to encapsulate precious cargo while enabling its targeted delivery to tissue of interest. For many conditions and infections, this precise delivery of therapeutic payload is what makes a difference, and we are currently also evaluating exosomes in delivering cargo to other tissues of choice,” said Edelmannn whose work is supported by several federal funds focused on the roles of extracellular vesicles in bacterial infections and disease and host-directed therapies against intestinal infections.

More information:
Winnie W. Hui et al, Antigen-encapsulating host extracellular vesicles derived from Salmonella-infected cells stimulate pathogen-specific Th1-type responses in vivo, PLOS Pathogens (2021). DOI: 10.1371/journal.ppat.1009465

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