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Structural study of mucosal antibody reveals unexpected host-pathogen interactions

January 24, 2024
By: Quang Nguyen, School of MCB Communications

Secretory Immunoglobulin A (SIgA), the predominant human mucosal antibody, can bind to bacterial surface proteins and trigger an immune response to improve infection outcomes, but these interactions are poorly understood. In a new study, University of Illinois researchers found distinct host-pathogen interaction through unexpected binding of SIgA, the pathogen streptococcus M4, and CD89, an immune cell receptor.

Qianqiao Liu, Graduate Student, with Beth Stadtmueller, Assistant Professor of Biochemistry
Qianqiao Liu, Graduate Student, with Beth Stadtmueller, Assistant Professor of Biochemistry

Group A streptococcus (GAS) causes infectious diseases like strep throat and impetigo in approximately 660,000 cases each year worldwide. Many of these bacteria are covered in a surface protein called M4. Researchers have known about the pathogenic M4 protein for decades, and that it interacts with many antibodies, but little is known about the outcomes or host-pathogen interactions with predominantly mucosal antibody SIgA.

“Understanding the [host-pathogen interaction] could lead to therapy that prevents or limits the virulence of GAS infection,” said Beth Stadtmueller (MMG), an assistant professor in the Biochemistry in the School of Molecular & Cellular Biology and principal investigator. In the Stadtmueller laboratory, researchers study the structure and function of mucosal antibody SIgA with focus on pathogen clearance and commensal microbe homeostasis.

Previous research identified the region of M4 that binds antibodies, but not how it binds SIgA or the outcome. The authors wondered if it is evolutionary beneficial for these bacteria to develop M4 protein to bind SIgA.

IgA has two forms: monomeric (m) IgA (single unit) and SIgA (two units and two additional proteins). mIgA is found in the blood stream while SIgA is predominantly in the mucosa (e.g. oral lining) and each form is thought to have overlapping and unique functions. For example, SIgA is known to crosslink mucosal antigens, promoting clearance via peristalsis. A lot of research has focused on studying the role of mIgA in the context of GAS infection. However, GAS enters the host through mucosal routes and scientists are still wondering how SIgA binds to pathogens and host factors. Additionally, the binding of SIgA to CD-89, a receptor on immune cells, is poorly understood.

“[By understanding this interaction], we will know how bacteria can invade our body and how humans evolved to counteract these invasions. This information is important for us to understand the host-pathogen interaction,” said first author Qianqiao Liu (PhD, Biochemistry, ’23), past member of the Stadtmueller laboratory and now postdoctoral research fellow at Stanford University.

Proteins are bound in a surprising way
In the recent published article, “SIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions,” the authors reported the molecular structure of M4-SIgA and CD-89-SIgA binding complexes which revealed unexpected binding orientation of these two proteins to SIgA.

“By using cryoelectron microscopy to determine a 3D molecular structure, we can clearly see the 29-residue region on M4 contacting SIgA,'' Liu said. “There are two binding sites on SIgA predicted to bind proteins such as M4 or CD89; however unexpectedly we saw only one copy of M4 bound, and it was bound in an unexpected orientation. When we used the structure to model what might happen on a bacterial surface, we could see that M4 may effectively hold SIgA in a fixed orientation at the bacterial surface.” Interestingly, this leaves the second site open and perhaps able to bind to other proteins, such as host CD89.

The authors were not expecting to see one-to-one binding of M4 to SIgA. Based on previously published data, the two M4 or CD89 binding sites on SIgA should be structurally identical. This led them to also determine the structure SIgA bound to CD89, which revealed two copies of CD89 bound to SIgA. So why can only one copy of M4 bind but two copies of CD89 can bind? Liu discovered that the answer lies in the asymmetric shape of the SIgA structure, which causes M4 to selectively bind to just one binding site.

This unexpected binding of M4 to SIgA may prevent immune cells from engulfing the streptococcus during an immune response or provide advantage to microbes in the mucosa. “I would like to figure out what binding of the SIgA does to the or for the bacteria. The orientation of SIgA binding in our model is intriguing, and we suspect may provide advantages for the bacteria other than just immune evasion - perhaps adhesion to host factors in the mucosa and we are working to understand that,” Stadtmueller said.

Nonetheless, there are still many factors to consider. In a lab setting, scientists often use only a subset of cells to study host-pathogen interactions in the mucosa or think about one molecular interaction at a time. However, the mucosa is a dynamic and complex system including immune cells, proteins, carbohydrates, commensal, and pathogenic microbes.

“Moving forward we need to integrate our molecular model for SIgA interactions with M4 and CD89 into a broader biological context,” Stadtmueller said. “The structural data we have provides a foundation to consider host interactions with GAS and that empowers us to think about disease and therapeutics strategies in new light.”

The work was funded by the National Institutes of Health and the University of Illinois Urbana-Champaign.


January 24, 2024
By: Quang Nguyen, School of MCB Communications
Photos By: School of MCB Communications


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