Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone

Julie E. Pickett, John M. Thompson, Agnieszka Sadowska, Christine Tkaczyk, Bret R. Sellman, Andrea Minola, Davide Corti, Antonio Lanzavecchia, Lloyd S Miller, Daniel Lj Thorek

Research output: Contribution to journalArticle

Abstract

Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI). In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography (PET) with [18F]FDG and [18F]NaF as well as X-ray computed tomography (CT), before being evaluated with the zirconium-89-labeled antibody specific for LTA ([89Zr]SAC55). The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater (P < 0.05) uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [89Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI.

Original languageEnglish (US)
Article number13
JournalBone Research
Volume6
Issue number1
DOIs
StatePublished - Dec 1 2018

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Joints
Bone and Bones
Infection
Monoclonal Antibodies
Prostheses and Implants
Antibodies
Diagnostic Imaging
Positron-Emission Tomography
Inflammation
Bacteria
lipoteichoic acid
Surgical Wound Infection
Molecular Probes
Molecular Imaging
X Ray Computed Tomography
Fluorodeoxyglucose F18
Anti-Idiotypic Antibodies
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Tomography

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

Cite this

Pickett, J. E., Thompson, J. M., Sadowska, A., Tkaczyk, C., Sellman, B. R., Minola, A., ... Thorek, D. L. (2018). Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. Bone Research, 6(1), [13]. https://doi.org/10.1038/s41413-018-0014-y

Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. / Pickett, Julie E.; Thompson, John M.; Sadowska, Agnieszka; Tkaczyk, Christine; Sellman, Bret R.; Minola, Andrea; Corti, Davide; Lanzavecchia, Antonio; Miller, Lloyd S; Thorek, Daniel Lj.

In: Bone Research, Vol. 6, No. 1, 13, 01.12.2018.

Research output: Contribution to journalArticle

Pickett, JE, Thompson, JM, Sadowska, A, Tkaczyk, C, Sellman, BR, Minola, A, Corti, D, Lanzavecchia, A, Miller, LS & Thorek, DL 2018, 'Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone', Bone Research, vol. 6, no. 1, 13. https://doi.org/10.1038/s41413-018-0014-y
Pickett, Julie E. ; Thompson, John M. ; Sadowska, Agnieszka ; Tkaczyk, Christine ; Sellman, Bret R. ; Minola, Andrea ; Corti, Davide ; Lanzavecchia, Antonio ; Miller, Lloyd S ; Thorek, Daniel Lj. / Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. In: Bone Research. 2018 ; Vol. 6, No. 1.
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abstract = "Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI). In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography (PET) with [18F]FDG and [18F]NaF as well as X-ray computed tomography (CT), before being evaluated with the zirconium-89-labeled antibody specific for LTA ([89Zr]SAC55). The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater (P < 0.05) uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [89Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI.",
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