A Structural Model for the Ligand Binding of Pneumococcal Serotype 3 Capsular Polysaccharide-Specific Protective Antibodies

Ozdilek, Ahmet; Huang, Jenq‐Kuen; Babb, Rachelle; Paschall, Amy V.; Middleton, Dustin R.; Duke, Jeremy A.; Pirofski, Liise Anne; Mousa, Jarrod J.; Avci, Fikri Y.

doi:10.1128/mbio.00800-21

Cited by 13 publications

(7 citation statements)

References 65 publications

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“…These data indicate that mAb PhtD3 can bind to encapsulated bacteria for both serotypes 19A and 4. We attempted this study using a previously described anti-serotype 3 mAb (33) and pneumococcal serotype 3 strain WU2, however, we could not obtain consistent binding of this mAb to bacteria likely due to capsule shedding upon mAb binding as previously described (34), since the capsule of pneumococcal serotype 3 is not covalently attached to the surface. However, we have previously demonstrated binding of mAb PhtD3 to serotype 3 bacteria, although it is unclear if the capsule is present or not (26).…”

Section: Resultsmentioning

confidence: 98%

Synergistic protection against secondary pneumococcal infection by human monoclonal antibodies targeting distinct epitopes

Gingerich

Royer

McCormick

et al. 2022

Preprint

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Streptococcus pneumoniae persists as a leading cause of bacterial pneumonia despite the widespread use of polysaccharide-based vaccines. The limited serotype coverage of current vaccines has led to increased incidence of non-vaccine serotypes, as well as an increase in antibiotic resistance among these serotypes. Pneumococcal infection often follows a primary viral infection such as influenza virus, which hinders host defense and results in bacterial spread to the lungs. We previously isolated human monoclonal antibodies (mAbs) against the conserved surface antigen pneumococcal histidine triad protein D (PhtD), and we demonstrated that mAbs to this antigen are protective against lethal pneumococcal challenge prophylactically and therapeutically. In this study, we elucidated the mechanism of protection of a protective anti- pneumococcal human mAb, PhtD3, which is mediated by the presence of complement and macrophages in a mouse model of pneumococcal infection. Treatment with mAb PhtD3 reduced blood and lung bacterial burden in mice, and mAb PhtD3 is able to bind to bacteria in the presence of the capsular polysaccharide, indicating exposure of surface PhtD on encapsulated bacteria. In a mouse model of secondary pneumococcal infection, protection mediated by mAb PhtD3 and another mAb targeting a different epitope, PhtD7, was reduced, however, robust protection was restored by combining mAb PhtD3 with mAb PhtD7, indicating a synergistic effect. Overall, these studies provide new insights into anti-pneumococcal mAb protection and demonstrate for the first time that mAbs to pneumococcal surface proteins can protect against secondary pneumococcal infection in the mouse model.Author SummaryThe persistence of Streptococcus pneumoniae as a leading cause of bacterial pneumonia despite numerous approved pneumococcal vaccines is a serious threat to public health globally. Currently, prophylactic and therapeutic options for Streptococcus pneumoniae are constrained by the limited serotype coverage of vaccines and the emergence of antibiotic resistant strains. An additional hurdle to overcome is the incidence of secondary pneumococcal infection following a viral infection, which leads to increased mortality. Here, we determined the mechanism of action of a monoclonal antibody (mAb) that targets Streptococcus pneumoniae. We found that mAb PhtD3 operates through macrophage and complement mediated functions. mAb PhtD3 was also discovered to reduce bacterial titers in the lungs and blood and bind to a related antigen PhtE. We also tested additional mAbs and discovered that two unique mAbs to the antigen PhtD conferred protection in a pneumococcal-influenza virus co-infection model. Our study provides new insights into the mechanisms and therapeutic potential of mAbs targeting conserved proteins of Streptococcus pneumoniae.

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Section: Resultsmentioning

confidence: 98%

Synergistic protection against secondary pneumococcal infection by human monoclonal antibodies targeting distinct epitopes

Gingerich

Royer

McCormick

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Obtaining the crystal structure of the complex between oligos and the Fab fragment, not obvious in the presence of very flexible structures such as sugars, was fundamental to obtaining high-resolution information about binding interactions. Indeed, despite the power of the technique, relatively few crystal structures of carbohydrate-antibody complexes have been solved so far, with the majority of them describing interactions with murine or rabbit antibodies. − To the best of our knowledge, only five X-ray complexes including human antibodies have been reported to date . None of these involved anti-Hib antibodies.…”

Section: Discussionmentioning

confidence: 99%

A Multidisciplinary Structural Approach to the Identification of the Haemophilus influenzae Type b Capsular Polysaccharide Protective Epitope

Nonne,

Iacono,

Bertuzzi

et al. 2024

ACS Cent. Sci.

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Glycoconjugate vaccines so far licensed are generally composed of a native or size-reduced capsular polysaccharide conjugated to carrier proteins. Detailed information on the structural requirements necessary for CPS recognition is becoming the key to accelerating the development of next-generation improved glycoconjugate vaccines. Structural glycobiology studies using oligosaccharides (OS) complexed with functional monoclonal antibodies represent a powerful tool for gaining information on CPS immunological determinants at the atomic level. Herein, the minimal structural epitope of Haemophilus influenzae type b (Hib) CPS recognized by a functional human monoclonal antibody (hmAb) is reported. Short and well-defined Hib oligosaccharides originating from the depolymerization of the native CPS have been used to elucidate saccharide−mAb interactions by using a multidisciplinary approach combining surface plasmon resonance (SPR), saturation transfer differencenanomagnetic resonance (STD-NMR), and X-ray crystallography. Our study demonstrates that the minimal structural epitope of Hib is comprised within two repeating units (RUs) where ribose and ribitol are directly engaged in the hmAb interaction, and the binding pocket fully accommodates two RUs without any additional involvement of a third one. Understanding saccharide antigen structural characteristics can provide the basis for the design of innovative glycoconjugate vaccines based on alternative technologies, such as synthetic or enzymatic approaches.

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“…For example, Streptococcus pneumoniae, a common cause of pneumonia and meningitis, produces a capsule composed of exopolysaccharides. This capsule is crucial for the bacterium's virulence and its ability to evade the host's immune system [76]. The composition and structure of this exopolysaccharide capsule vary among different serotypes of S. pneumoniae.…”

Section: Shortcomings and Future Prospects Of Antibacterial Monoclona...mentioning

confidence: 99%

Monoclonal Antibodies as a Therapeutic Strategy against Multidrug-Resistant Bacterial Infections in a Post-COVID-19 Era

Chen,

Pan,

Chen

et al. 2024

Life

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The development of severe multidrug-resistant bacterial infections has recently intensified because of the COVID-19 pandemic. According to the guidelines issued by the World Health Organization (WHO), routine antibiotic administration is not recommended for patients with supposed or confirmed mild SARS-CoV-2 infection or pneumonia, unless bacterial infection is clinically suspected. However, recent studies have pointed out that the proportion of non-essential antibiotic use in patients infected with SARS-CoV-2 remains high. Therefore, the silent pandemic of antibiotic resistance remains a pressing issue regardless of the present threats presented by the COVID-19 pandemic. To prevent or delay entry into the postulated post-antibiotic era, the long-term advocacy for the rational use of antibiotics, the optimization of infection control procedures, and the development of new antibacterial agents and vaccines should be underscored as vital practices of the antibacterial toolbox. Recently, the development of vaccines and monoclonal antibodies has gradually received attention following the advancement of biotechnology as well as enhanced drug discovery and development in cancer research. Although decent progress has been made in laboratory-based research and promising results have been obtained following clinical trials of some of these products, challenges still exist in their widespread clinical applications. This article describes the current advantages of antibacterial monoclonal antibodies, the development of associated clinical trials, and some perceived future perspectives and challenges. Further, we anticipate the development of more therapeutic agents to combat drug-resistant bacterial infections as well as to increase the resilience of current or novel agents/strategies.

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A Structural Model for the Ligand Binding of Pneumococcal Serotype 3 Capsular Polysaccharide-Specific Protective Antibodies

Cited by 13 publications

References 65 publications

Synergistic protection against secondary pneumococcal infection by human monoclonal antibodies targeting distinct epitopes

Synergistic protection against secondary pneumococcal infection by human monoclonal antibodies targeting distinct epitopes

A Multidisciplinary Structural Approach to the Identification of the Haemophilus influenzae Type b Capsular Polysaccharide Protective Epitope

Monoclonal Antibodies as a Therapeutic Strategy against Multidrug-Resistant Bacterial Infections in a Post-COVID-19 Era

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