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Home / Equine Research Bank / Ann Transl Med / TLR-activated mesenchymal stromal cell therapy and antibioti...
Annals of translational medicine2022; 10(21); 1157; doi: 10.21037/atm-22-1746

TLR-activated mesenchymal stromal cell therapy and antibiotics to treat multi-drug resistant Staphylococcal septic arthritis in an equine model.

Abstract: Rapid development of antibiotic resistance necessitates advancement of novel therapeutic strategies to treat infection. Mesenchymal stromal cells (MSC) possess antimicrobial and immunomodulatory properties, mediated through antimicrobial peptide secretion and recruitment of innate immune cells including neutrophils and monocytes. TLR-3 activation of human, canine and equine MSC has been shown to enhance bacterial killing and clearance in vitro, in rodent Staphylococcal biofilm infection models and dogs with spontaneous multi-drug-resistant infections. The objective of this study was to determine if intra-articular (IA) TLR-3-activated MSC with antibiotics improved clinical parameters and reduced bacterial counts and inflammatory cytokine concentrations in synovial fluid (SF) of horses with induced septic arthritis. Unassigned: Eight horses were inoculated in one tarsocrural joint with multidrug-resistant Staphylococcus aureus (S. aureus). Bone marrow-derived MSC from three unrelated donors were activated with TLR-3 agonist polyinosinic, polycytidylic acid (pIC). Recipient horses received MSC plus vancomycin (TLR-MSC-VAN), or vancomycin (VAN) alone, on days 1, 4, 7 post-inoculation and systemic gentamicin. Pain scores, quantitative bacterial counts (SF, synovium), SF analyses, complete blood counts, cytokine concentrations (SF, plasma), imaging changes (MRI, ultrasound, radiographs), macroscopic joint scores and histologic changes were assessed. Results were reported as mean ± SEM. Unassigned: Pain scores (d7, P=0.01, 15.2±0.2 vs. 17.9±0.5), ultrasound (d7, P=0.03, 9.0±0.6 vs. 11.8±0.5), quantitative bacterial counts (SF d7, P=0.02, 0±0 vs. 3.4±0.4; synovium P=0.003, 0.4±0.4 vs. 162.7±18.4), systemic neutrophil (d4, P=0.03, 4.6±0.6 vs. 7.8±0.6) and serum amyloid A (SAA) (d4, P=0.01, 1,106.0±659.0 vs. 2,858.8±141.3; d7, P=0.02, 761.8±746.2 vs. 2,357.3±304.3), and SF lactate (d7, P<0.0001, 5.4±0.2 vs. 15.0±0.3), SAA (endterm, P=0.01, 0.0 vs. 2,094.0±601.6), IL-6 (P=0.03, 313.0±119.2 vs. 1,328.2±208.9), and IL-18 (P=0.02, 11.1±0.5 vs. 13.3±3.8) were improved in TLR-MSC-VAN vs. VAN horses. Study limitations include the small horse sample size, short study duration, and lack of additional control groups. Unassigned: Combined TLR-activated MSC with antibiotic therapy may be a promising approach to manage joint infections with drug resistant bacteria.
2022 Annals of Translational Medicine. All rights reserved.
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Publication Date: 2022-12-06 PubMed ID: 36467344PubMed Central: PMC9708491DOI: 10.21037/atm-22-1746Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study investigated the use of TLR-activated mesenchymal stromal cell (MSC) therapy together with antibiotic treatment to combat multi-drug resistant Staphylococcal septic arthritis in horses. The research found that the combination of TLR-MSC therapy with antibiotics led to improved clinical parameters and reduced bacterial counts and inflammation in horses than when using antibiotics alone.

Introduction and Objectives

  • The study addresses the urgency of finding new treatments for infections due to rapid development of antibiotic resistance.
  • Mesenchymal stromal cells (MSC) have shown antimicrobial and immunomodulatory properties largely because they secrete antimicrobial peptides and attract innate immune cells like neutrophils and monocytes.
  • TLR-3 activation on human, canine, and equine MSC has been demonstrated to enhance bacterial killing and clearance, even in rodent biofilm infection models and dogs with spontaneous multi-drug-resistant infections.
  • The goal of the study was to find out if combined treatment of intra-articular (IA) TLR-3-activated MSC with antibiotics could improve clinical parameters, reduce bacterial counts, and decrease inflammatory cytokine concentrations in horses suffering from induced septic arthritis.

Methodology

  • An experiment was conducted on eight horses. One tarsocrural joint of each horse was inoculated with multidrug-resistant Staphylococcus aureus.
  • MSCs derived from the bone marrow of three unrelated donors were activated by a TLR-3 agonist called polyinosinic-polycytidylic acid (pIC).
  • The recipient horses were treated either with MSC plus the antibiotic vancomycin (TLR-MSC-VAN group) or only with vancomycin (VAN group).
  • Pain scores, bacterial counts, blood counts, cytokine concentrations, and imaging changes were among the parameters assessed to evaluate the impact of combined therapy.

    Results

    • Compared to the VAN group, horses in the TLR-MSC-VAN group showed improvement in several parameters, such as pain scores, ultrasound imaging, bacterial counts in the synovial fluid and synovium, systemic neutrophil count and serum amyloid A (SAA) levels.
    • The TLR-MSC-VAN horses also exhibited reduced lactate, SAA, IL-6, and IL-18 in synovial fluid.
    • The study, however, mentions limitations, including small sample size, short duration, and unavailability of additional control groups.

    Conclusion

    • The findings suggest that TLR-activated MSC therapy combined with antibiotic treatment can be a promising strategy to manage joint infections caused by drug-resistant bacteria.

Cite This Article

APA
Pezzanite LM, Chow L, Phillips J, Griffenhagen GM, Moore AR, Schaer TP, Engiles JB, Werpy N, Gilbertie J, Schnabel LV, Antczak D, Miller D, Dow S, Goodrich LR. (2022). TLR-activated mesenchymal stromal cell therapy and antibiotics to treat multi-drug resistant Staphylococcal septic arthritis in an equine model. Ann Transl Med, 10(21), 1157. https://doi.org/10.21037/atm-22-1746

Publication

Annals of translational medicine
ISSN: 2305-5839
NlmUniqueID: 101617978
Country: China
Language: English
Volume: 10
Issue: 21
Pages: 1157

Researcher Affiliations

Pezzanite, Lynn M
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Chow, Lyndah
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Phillips, Jennifer
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Griffenhagen, Gregg M
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Moore, A Russell
  • Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Schaer, Thomas P
  • Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA.
Engiles, Julie B
  • Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA.
  • Department of Pathobiology, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA.
Werpy, Natasha
  • Ocala Equine Hospital, Ocala, FL, USA.
Gilbertie, Jessica
  • Department of Microbiology and Immunology, Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.
Schnabel, Lauren V
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.
Antczak, Doug
  • Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Miller, Donald
  • Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Dow, Steven
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
  • Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Goodrich, Laurie R
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.

Conflict of Interest Statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1746/coif). LMP, LC, SD, and LRG declare that a patent application has been filed covering the antimicrobial cellular therapy technology described here. LMP reports that support for this work was provided by the Grayson Jockey Club Research Foundation, ACVS Zoetis Dual Training Grant, NIH/NCATS CTSA 5TL1TR002533-02, NIH 5T32ODO010437-19, Verdad Foundation, Charles Shipley Family Foundation and Carolyn Quan and Porter Bennett. The StableLab serum amyloid A testing material was kindly provided by Zoetis. LMP reports that she holds stock options in eQCell Inc. SD reports that he holds stock options in eQCell Inc. LRG reports that she holds stock options in eQCell and Advanced Regenerative Therapies. The other authors have no conflicts of interest to declare.

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