Late-breaking Poster Asia-Pacific Vaccine and Immunotherapy Congress 2024

PVM infection after bone marrow transplantation leads to increased mortality which is associated with impaired viral antigen-specific T cell responses and IL-6-mediated pathogenic Th17 differentiation in the lung (#174)

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

Respiratory viral infections are a major global public health problem. RSV-induced bronchiolitis and pneumonia are the leading cause of hospitalization in infants and young children worldwide, while in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients, the incidence of progression from upper to lower respiratory tract infection is 40-60%, with mortality rates as high as 80%. The effectiveness of antivirals or immunoglobulins to curb RSV infection in HSCT recipients remains controversial and represents an unmet clinical need. Given the paucity of mechanistic data to guide clinical studies or define the basis of disease, we established a unique murine model of RSV infection after bone marrow transplantation (BMT) using pneumonia virus of mice (PVM), the murine homologue of human RSV, to address this. B6.WT grafts were transplanted into lethally irradiated B6D2F1 (alloBMT) or B6.WT (synBMT) mice and infected with PVM on day 21 post-BMT. In contrast to syngeneic BMT, alloBMT recipients displayed a high incidence of mortality after PVM infection with fulminant lung pathology, recapitulating the outcome seen in patients. Notably, IL-6 levels in lung tissue were significantly elevated in PVM infected alloBMT recipients compared to uninfected alloBMT and synBMT recipients at day 12 post-infection and correlated with lung pathology. We hypothesized the elevated IL-6 levels would trigger activation of the Th17/Tc17 differentiation program. We performed transplants using grafts comprised of T cells from B6.IL-17eYFP fate-map reporter mice with PVM infection at day 21 post-BMT. This revealed an increase in the frequency and number of Th17 cells, but not Tc17 cells, in lung tissue of PVM-infected alloBMT recipients compared to uninfected alloBMT and synBMT recipients, suggesting that blockade of the IL-6/Th17 axis may serve as a logical therapeutic pathway. Furthermore, to identify PVM-specific T cell responses, we designed MHC-I and MHC-II tetramers directed to epitopes of PVM matrix (M37-47) and RNA polymerase (L1052-1060) proteins. A reduction in the frequency and number of PVM-specific CD4+ and CD8+ T cells was observed in lung and lymphoid tissues of PVM-infected alloBMT recipients versus synBMT recipients at days 9-12 post-infection. Taken together, these data suggest that in the presence of GVHD impaired antiviral T cell responses may lead to a lack of viral control and thereby exacerbate disease. Ongoing mechanistic experiments are focussed on interrogating the relationship between elevated IL-6 levels, defective antiviral T cell responses and viral control in PVM-infected alloBMT recipients.