Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Aberrant immune cell number and function underpins increased mortality in respiratory viral infected bone marrow transplant recipients (#163)

Sophie C Hamann 1 , Alika D Collinge 1 , Rachel D Kuns 1 , Cassandra Pegg 2 , Andrew D Clouston 3 , Kirsten M Spann 4 , Seweryn Bialasiewicz 2 5 , Simon Phipps 4 5 6 , Mariapia Degli-Esposti 7 , Geoffrey R Hill 8 9 , Benjamin Schulz 2 5 , Antiopi Varelias 1 4 5 10
  1. Transplantation Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  2. School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, St Lucia, QLD, Australia
  3. Envoi Specialist Pathologists, Brisbane, QLD, Australia
  4. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
  5. Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, QLD, Australia
  6. Respiratory Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  7. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  8. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  9. Division of Medical Oncology, University of Washington, Seattle, WA, USA
  10. Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia

Allogeneic haematopoietic stem cell transplantation is the curative treatment for patients with high-risk haematological malignancies and provides alloimmunity to eliminate malignant cells and prevent relapse. However this elicits graft-versus-host disease (GVHD), a life-threatening complication that limits treatment success. Use of immunosuppressive agents to minimise GVHD increases the risk of opportunistic infections. Respiratory syncytial virus (RSV) is a common infection that is fatal in up to 50% of infected transplant recipients. Given the immunological determinants that underpin respiratory failure are not well understood, the aim of this study was to utilize a novel preclinical model which we have developed and shown recapitulates the outcome seen in patients, to define the cellular immune response. Recipients of allogeneic bone marrow grafts (alloBMT) were infected with pneumonia virus of mice (PVM; murine homologue of RSV), and the immune response in lung and lymphoid tissues assessed by flow cytometry one week post-infection, when fulminant pneumonia typically develops. This revealed a reduced number and/or frequency of the donor conventional dendritic cell type-2 subset (cDC2), polyclonal effector memory CD4+ and CD8+ T-cells and B-cells in lung and spleen of PVM-infected compared to uninfected alloBMT recipients, suggesting broad virus-induced immune suppression. Analysis of the lung-derived donor CD45.2+ IA/IE+ CD11c+ dendritic cell proteome by mass spectrometry demonstrated a significant enrichment in proteins involved in antigen processing within MHC class II (e.g. cathepsin S [CatS]) in PVM-infected versus uninfected alloBMT recipients, consistent with enhanced antigen presentation in response to virus. In contrast, the donor CD45.2+ CD3+ T-cell proteome revealed a significant enrichment in proteins involved in regulation of gene expression (e.g. DEAD-box RNA helicase 5 [DDX5], elongation factor 2 [EF2]) and macromolecule metabolic processes (e.g. α-enolase [ENOA], C-terminal Src kinase [Csk]) in PVM-infected versus uninfected alloBMT recipients, consistent with T-cell dysfunction. Mechanistic studies to interrogate PVM antigen-specific responses and cellular protein interactions that lead to pneumonitis in PVM-infected alloBMT recipients are warranted.