Immune Activated Cellular Therapy for Drug Resistant Infections: Rationale, Mechanisms, and Implications for Veterinary Medicine

Abstract

Antimicrobial resistance and biofilm formation both present challenges to treatment of bacterial infections with conventional antibiotic therapy and serve as the impetus for development of improved therapeutic approaches. Mesenchymal stromal cell (MSC) therapy exerts an antimicrobial effect as demonstrated in multiple acute bacterial infection models. This effect can be enhanced by pre-conditioning the MSC with Toll or Nod-like receptor stimulation, termed activated cellular therapy (ACT). The purpose of this review is to summarize the current literature on mechanisms of antimicrobial activity of MSC with emphasis on enhanced effects through receptor agonism, and data supporting use of ACT in treatment of bacterial infections in veterinary species including dogs, cats, and horses with implications for further treatment applications. This review will advance the field's understanding of the use of activated antimicrobial cellular therapy to treat infection, including mechanisms of action and potential therapeutic applications.

Keywords: antibiotic resistance; antimicrobial; cell; mesenchymal; stem; stromal.

Figure 1

Immune mechanisms for antimicrobial properties of MSC against biofilms. Direct antimicrobial activity of MSC via secreted factors including antimicrobial peptides and indirect immunomodulatory activity of MSC are illustrated. Directly, cationic antimicrobial peptides (e.g., cathelicidin, lipocalin-2, ß-defensin 2), induce damage to bacterial membranes or alter bacterial function either directly or indirectly. Indirectly, MSC activate host immune cells, modulate local inflammation and induce angiogenesis and fibrogenesis, targeting several different cell types including T cells, macrophages, neutrophils, and dendritic cells. This activity is primarily mediated by up-regulation or inhibition of immunomodulatory cytokines and chemokines that in turn augment the immune system either to a pro-inflammatory or an anti-inflammatory state.

Figure 2

Evaluation of TLR poly I:C activated bone marrow derived MSC therapy in an equine model of multi-drug resistant USA300 methicillin resistant Staphylococcus aureus [25]; original unpublished images presented with permission from the authors]. Representative images of horses at day 7 following intra-articular inoculation of the left tarsocrural joint treated with three intra-articular injections of (A) MSC and antibiotics, or (B) antibiotics alone. Quantitative bacterial cultures were significantly reduced in horses treated with (C) MSC and antibiotics versus (D) antibiotics alone. Synovial fluid parameters serum amyloid A, lactate, and inflammatory biomarkers IL-6 and IL-18 were significantly improved in horses treated with MSC and antibiotics (left) versus antibiotics alone (right) (D).