by Okayama University

Researchers from Okayama University, Japan, uncover novel pathogenic role of a surface collagen-binding protein "Cnm," on Streptococcus mutans, a dental caries-causing bacteria, in the development of IgAN. Their findings open avenues for novel therapeutic interventions targeting dental caries to improve kidney health in patients with IgAN. Credit: Dr. Shuhei Naka, Okayama University https://www.nature.com/articles/s42003-024-06826-x

IgA nephropathy (IgAN) is an immune response disease affecting the filtering units of the kidneys. It is an intractable disease with a complex physiological process. Streptococcus mutans, a dental caries-causing bacterial pathogen, has been linked to IgAN disease progression. Now, researchers from the Okayama University, Japan, have uncovered a virulent role of Cnm—a surface collagen-binding protein expressed on S. mutans in IgAN development—highlighting a potential link between dental caries and renal lesions.

The kidneys act as a filtering system in the human body that help in the removal of excess fluids and unwanted wastes from the bloodstream. Inflammation of glomeruli or the tiny filtering units within the kidneys, also known as glomerulonephritis, results in the alteration to the functioning of kidneys. IgAN is the most common type of primary glomerulonephritis with deposition of the antibody—immunoglobulin A (IgA) in the glomerular region.

The underlying disease progression is complex and multifactorial, and 30–40% of patients develop terminal kidney failure. Given the intractable nature of the disease, there is a need to understand specific pathological mechanisms contributing to IgAN, and develop targeted treatments.

Tonsillitis (inflammation or immune response of the tonsils) and bacteria related to dental caries and periodontal disease have been implicated in IgAN pathogenesis. This is likely due to the entry of the pathogen into circulation during invasive dental procedures.

Streptococcus mutans is one such bacterial caries-causing pathogen, known to cause bacterial sepsis (extreme response of immune system to an infection leading to death) and infective endocarditis (inflammation of the inner lining of the heart). Moreover, S. mutans expressing a surface collagen-binding protein (Cnm) has been found more frequently in patients with IgAN than in healthy individuals. The precise role in IgAN development is, however, unclear.

A research team led by Dr. Shuhei Naka, including co-first author, Professor Michiyo Matsumoto-Nakano from Department of Pediatric Dentistry, Okayama University, Professor Kazuhiko Nakano from the Department of Pediatric Dentistry, Osaka University, Dr. Taro Misaki from the Seirei Hamamatsu General Hospital, and Assistant Professor Daiki Matsuoka from the Department of Pediatric Dentistry, Okayama University, Japan, were involved in this study.

The team of researchers sought to uncover the potential virulent role of Cnm from S. mutans in the progression of IgAN disease.

"Until now, oral pathogens and kidney disease have been studied independently. We have been able to obtain useful research results over 10 years by establishing a collaboration between clinicians and researchers in oral pathogens and kidney diseases," says Dr. Naka.

The team has previously shown that injection of a Cnm-expressing S. mutans strain in rats induces the formation of IgA-like renal lesions following intensive caries and simulation of invasive dental procedures. The potential link between the oral pathogen and renal lesions prompted the researchers to assess the role of the Cnm protein itself.

Explaining the rationale behind their current work published in Communications Biology, on 14 September, 2024, Dr. Naka, the corresponding author of the article, says, "Collagen-binding protein, one of the proteins present on the surface of dental caries, may be associated with the development of IgA nephropathy. Future development of research through medical-dental collaborations may lead to the development of a fundamental treatment for IgA nephropathy."

They injected a Cnm-positive strain of S. mutans isolated from the oral cavity of a patient with severe IgAN, a Cnm-deficient strain, a complementation strain (with a similar genetic makeup as Cnm positive), and recombinant Cnm protein ([rCnm], a genetically modified variant), intravenously in rats. Next, they went on to assess the clinical features of IgAN, namely proteinuria (presence of protein in urine), hematuria (presence of blood in urine), and renal function in the animals.

Notably, while there was no change in proteinuria and renal function across the experimental animals, hematuria was significantly higher in the Cnm-positive, Cnm complementation groups, and rCnm groups, compared to the negative controls. This finding suggests that Cnm protein or Cnm-expressing S. mutans may induce hematuria in the early stages of IgAN.

Next, the researchers evaluated stained tissue sections of kidneys isolated from the treated animals. Mesangial cell and matrix proliferation (types of cells in the kidney tissue which are altered in IgAN present in the supporting medium known as mesangial matrix) were significantly higher in the Cnm-positive and rCnm groups compared to Cnm-negative groups.

Furthermore, tissue sections obtained from Cnm-positive rats showed higher deposition of IgA, complement C3, and IgG (a prominent feature of IgAN) in the mesangial region of the glomerulus. The researchers also noted the presence of Cnm protein in the mesangial region—another hallmark feature of IgAN—in animals injected with rCnm. Given that both Cnm-expressing S. mutans and rCnm induce IgA-like nephropathy, the Cnm protein by itself may have a pathogenic role in the development of IgAN.

The researchers also highlight that the amount of Cnm protein present in one milligram of dental plaque is equivalent to the amount injected in the rat model. Therefore, invasive dental procedures which allow the entry of Cnm-expressing S. mutans can trigger IgAN-like nephropathy. Furthermore, Cnm deposition may independently, or in combination with IgA and/or IgG, contribute to the development of an IgAN.

Talking to us about the long-term implications of these findings, Dr. Naka says "Our findings suggest that the kidneys' condition may be improved by reducing carious bacteria through a preventive dental approach in patients with IgAN. We intend to further advance this project and obtain results that can be delivered to clinical settings."

More information: Shuhei Naka et al, Contribution of collagen-binding protein Cnm of Streptococcus mutans to induced IgA nephropathy-like nephritis in rats, Communications Biology (2024). DOI: 10.1038/s42003-024-06826-x

Journal information: Communications Biology 

Provided by Okayama University