Bone marrow–derived mesenchymal stem cells transplantation alters the course of experimental paracoccidioidomycosis by exacerbating the chronic pulmonary inflammatory response

Abstract

Several studies have shown the potential use of bone marrow mesenchymal stem cells (BM-MSCs) as a therapeutic approach to infectious diseases. Since BM-MSCs can exert antimicrobial properties and influence the immune response against pathogens, our aim was to study the antimicrobial therapeutic potential of BM-MSCs in an experimental model of paracoccidioidomycosis (PCM). BM-MSCs were isolated from BALB/c donor mice. Paracoccidioides brasiliensis-infected male BALB/c mice were injected with purified BM-MSCs at 8th week post-infection. Mice were sacrificed at 12th week post-infection. Homing of BM-MSCs was confirmed by cellular labeling with fluorescent lipophilic dye and detected by flow cytometry. We found that, in comparison with nontransplanted infected animals, BM-MSCs-treated and P. brasiliensis-infected mice showed a significant increase in (i) fungal burdens, (ii) neutrophils, eosinophils and M2 macrophages counts, and (iii) interleukin (IL)-6, IL-9, GM-CSF, CXCL1, CXCL9, and CCL5 levels, while presenting a decrease in M1 macrophages and Treg cells in lungs. In addition, the histopathological analysis of the lungs showed an increased inflammatory process. This is the first study to our knowledge that evaluates the effects of BM-MSCs treatment in PCM. Our results indicate that the immunoregulatory function of BM-MSCs may be triggered by the interaction with P. brasiliensis, which exacerbates chronic pulmonary inflammatory response.

Gene expression of Paracoccidioides virulence factors after interaction with macrophages and fibroblasts

“…They may interact with host cells and establish the colonisation and dissemination of fungi in the host organism, (17,41) interacting with components of the host extracellular matrix (ECM) and lung cells. (41) Most adhesins are enzymes of the glycolytic pathway, tricarboxylic acid (TCA), and glyoxylate cycle of Paracoccidioides spp. They have adhesive properties that facilitate the interaction with the host ECM and act as 'moonlighting' proteins.…”

Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

“…Downregulation of PGE 2 levels indirectly enhanced the immune response, leading to higher bacterial clearance[ 26 , 83 ]. Further, injection of BM-MSCs in Paracoccidioides brasiliensis -infected mice led to increased fungal levels and exaggerated immune responses, with increased accumulation of neutrophils, eosinophils, and M2 macrophages, leading to congestion and edema in lungs[ 84 ]. Similarly, treatment with BM-MSCs in mice with latent M. bovis infection resulted in significantly higher mycobacterial number and granuloma formation[ 85 ].…”

Newer Horizon of Mesenchymal Stem Cell–Based Therapy in the Management of SARS-CoV-2–Associated Mucormycosis: A Safe Hope for Future Medicine

“…In a previously conducted study on COVID-19 patients, injection of MSCs to lungs in pulmonary disease showed a protective effect on the endothelial cells ( Liang et al, 2020 ). In another study published recently, it is quoted that MSC transplantation significantly reduced neutrophil-mediated inflammation of the airways by inhibiting the Th17 signaling pathway in a mouse model of asthma triggered by the fungus Aspergillus fumigatus hyphal extract ( Arango et al, 2018 ). Bone marrow–derived MSCs show an immunomodulatory effect on macrophages stimulated by Aspergillus fumigatus conidia that further lowers the expression of tumor necrosis factor-α (TNF-α) and increases the expression of IL-10 ( Arango et al, 2018 ).…”