Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis
Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-03-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.651515/full |
| _version_ | 1818850812390014976 |
|---|---|
| author | Gowrishankar Muthukrishnan Alexandra Wallimann Alexandra Wallimann Javier Rangel-Moreno Karen L. de Mesy Bentley Karen L. de Mesy Bentley Maria Hildebrand Karen Mys H. Mark Kenney Eric T. Sumrall John L. Daiss Stephan Zeiter R. Geoff Richards Edward M. Schwarz Edward M. Schwarz T. Fintan Moriarty |
| author_facet | Gowrishankar Muthukrishnan Alexandra Wallimann Alexandra Wallimann Javier Rangel-Moreno Karen L. de Mesy Bentley Karen L. de Mesy Bentley Maria Hildebrand Karen Mys H. Mark Kenney Eric T. Sumrall John L. Daiss Stephan Zeiter R. Geoff Richards Edward M. Schwarz Edward M. Schwarz T. Fintan Moriarty |
| author_sort | Gowrishankar Muthukrishnan |
| collection | DOAJ |
| description | Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)–scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination. |
| first_indexed | 2024-12-19T06:55:05Z |
| format | Article |
| id | doaj.art-1c26744227374a40a0b800dfcdf3a279 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T06:55:05Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1c26744227374a40a0b800dfcdf3a2792022-12-21T20:31:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.651515651515Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus OsteomyelitisGowrishankar Muthukrishnan0Alexandra Wallimann1Alexandra Wallimann2Javier Rangel-Moreno3Karen L. de Mesy Bentley4Karen L. de Mesy Bentley5Maria Hildebrand6Karen Mys7H. Mark Kenney8Eric T. Sumrall9John L. Daiss10Stephan Zeiter11R. Geoff Richards12Edward M. Schwarz13Edward M. Schwarz14T. Fintan Moriarty15Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, United StatesAO Research Institute Davos, Davos, SwitzerlandSwiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, SwitzerlandDivision of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United StatesCenter for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United StatesAO Research Institute Davos, Davos, SwitzerlandAO Research Institute Davos, Davos, SwitzerlandCenter for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, United StatesAO Research Institute Davos, Davos, SwitzerlandCenter for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, United StatesAO Research Institute Davos, Davos, SwitzerlandAO Research Institute Davos, Davos, SwitzerlandCenter for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, United StatesDivision of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United StatesAO Research Institute Davos, Davos, SwitzerlandStaphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)–scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination.https://www.frontiersin.org/articles/10.3389/fimmu.2021.651515/fullhumanized miceStaphylococcus aureusbone infectionosteolysisstaphylococcal abscess communitiesT cells |
| spellingShingle | Gowrishankar Muthukrishnan Alexandra Wallimann Alexandra Wallimann Javier Rangel-Moreno Karen L. de Mesy Bentley Karen L. de Mesy Bentley Maria Hildebrand Karen Mys H. Mark Kenney Eric T. Sumrall John L. Daiss Stephan Zeiter R. Geoff Richards Edward M. Schwarz Edward M. Schwarz T. Fintan Moriarty Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis Frontiers in Immunology humanized mice Staphylococcus aureus bone infection osteolysis staphylococcal abscess communities T cells |
| title | Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis |
| title_full | Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis |
| title_fullStr | Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis |
| title_full_unstemmed | Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis |
| title_short | Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis |
| title_sort | humanized mice exhibit exacerbated abscess formation and osteolysis during the establishment of implant associated staphylococcus aureus osteomyelitis |
| topic | humanized mice Staphylococcus aureus bone infection osteolysis staphylococcal abscess communities T cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.651515/full |
| work_keys_str_mv | AT gowrishankarmuthukrishnan humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT alexandrawallimann humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT alexandrawallimann humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT javierrangelmoreno humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT karenldemesybentley humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT karenldemesybentley humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT mariahildebrand humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT karenmys humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT hmarkkenney humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT erictsumrall humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT johnldaiss humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT stephanzeiter humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT rgeoffrichards humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT edwardmschwarz humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT edwardmschwarz humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis AT tfintanmoriarty humanizedmiceexhibitexacerbatedabscessformationandosteolysisduringtheestablishmentofimplantassociatedstaphylococcusaureusosteomyelitis |