Assistant Professor Colorado State University Fort Collins, Colorado
TLR-3-Activated Allogeneic Mesenchymal Stromal Cell Therapy Reduces Bioburden and Pro-Inflammatory Biomarkers in an Equine Model of Multidrug-Resistant Staphylococcal Septic Arthritis. Pezzanite L1, Dow S1, Chow L1, Phillips JN1, Griffenhagen GM1, Hendrickson D1, McIlwraith CW1, Johnson S1, Moore AR1, Stoneback J2, Johnson V3, Engiles JB4, Werpy N5, Schnabel L6, Gilbert J6, Daniels J1, Schaer T4, Goodrich L1. 1Colorado State University, Fort Collins, CO; 2University of Colorado, Denver, CO; 3Michigan State University, Lansing, MI; 4University of Pennsylvania, Philadelphia, PA; 5Ocala Equine Hospital, Ocala, FL; 6North Carolina State University, Raleigh, NC.
Mesenchymal stromal cells (MSCs) are antimicrobial and immunomodulatory through peptide secretion and paracrine recruitment of immune cells. Toll-like-receptor (TLR-3) activation of human, canine, and equine MSCs enhanced bacterial killing in vitro, and increased bacterial clearance in rodent Staphylococcal biofilm infection. Objectives were to determine if intra-articular (IA) TLR-3-activated equine MSC administration improved clinical outcomes and reduced bacterial burden and pro-inflammatory biomarkers in equine septic arthritis. Eight horses were inoculated in one tarsocrural joint with multidrug-resistant S. aureus (1 × 104 CFU). Bone marrow-derived MSCs from three donors were activated with TLR-3 agonist polyI:C (10 µg/mL, 2 × 106 MSC/mL, 2 h). Recipient horses received IA TLR-3 MSCs and vancomycin or vancomycin alone. Inflammation/pain scoring, complete blood counts, synovial fluid (SF) analyses, quantitative bacterial counts, inflammatory biomarkers, imaging, macroscopic scoring and histology were assessed. Inflammation/pain scores (P = 0.0002), quantitative bacterial counts (SF D4 P = 0.03, D7 P = 0.02; synovium P = 0.003) and peripheral blood neutrophil counts (D4 P = 0.03, D7 P = 0.06) were lower in treated horses. SF (D7) from treated horses had lower total nucleated cell counts (P = 0.09), total protein (P = 0.08), neutrophils% (P = 0.006), lactate (P < 0.0001), and higher glucose (P = 0.009). SF IL-6 (P = 0.02) and IL-18 (P = 0.02) were lower in treated horses. Intra-articular TLR-3 MSCs inhibited bacterial growth and improved clinical parameters in multidrug-resistant septic arthritis. Study limitations included small sample size, lack of later data collection time points, lack of control group receiving non-activated MSC therapy. TLR-3 MSC therapy mitigated inflammation and infection due to multidrug resistant S. aureus.