Human Metapneumovirus Reinfection in Aged Mice Recapitulates Increased Disease Severity in Elderly Humans Infected
Olivia B Parks1, Taylor Eddens2, Yu Zhang1
1Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Abstract:
Human metapneumovirus (HMPV) is a leading cause of respiratory infection in adults >65 y. Nearly all children worldwide are seropositive for HMPV by age 5 y, but reinfections occur throughout life, and there is no licensed vaccine. Recurrent HMPV infection is mild and self-resolving in immunocompetent individuals. However, elderly individuals develop severe respiratory disease on HMPV reinfection that leads to a high risk for morbidity and mortality. In this study, we developed a mouse model to mirror HMPV reinfection in elderly humans. C57BL/6J mice were infected with HMPV at 6-7 wk old, aged in-house, and rechallenged with high-dose virus at 70 wk. Aged rechallenged mice had profound weight loss similar to primary infected mice, increased lung histopathology, and accumulated cytotoxic CD8+CD44+CD62L-CD69+CD103+ memory cells despite having undetectable lung virus titer. When aged mice 14 mo postinfection (p.i.) or young mice 5 wk p.i. were restimulated with HMPV cognate Ag to mimic epitope vaccination, aged mice had an impaired CD8+ memory response. Convalescent serum transfer from young naive or 5 wk p.i. mice into aged mice on day of infection did not protect. Aged mice vaccinated with UV-inactivated HMPV also exhibited diminished protection and poor CD8+ memory response compared with young mice. These results suggest aged individuals with HMPV reinfection have a dysregulated CD8+ memory T cell response that fails to protect and exacerbates disease. Moreover, aged mice exhibited a poor memory response to either epitope peptide or UV-inactivated vaccination, suggesting that aged CD8+ T cell dysfunction presents a barrier to effective vaccination strategies.
Insights
Elderly individuals experience severe respiratory illness from human metapneumovirus (HMPV) reinfection due to a dysregulated CD8+ T cell response. This dysfunction impairs vaccine effectiveness in older adults, highlighting a barrier to HMPV prevention strategies.
Area of Science:
- Immunology
- Virology
- Gerontology
Background:
- Human metapneumovirus (HMPV) causes mild illness in children but severe respiratory disease and mortality in the elderly.
- Reinfection with HMPV occurs throughout life, with no currently licensed vaccine available.
- Elderly individuals exhibit increased susceptibility to severe HMPV-related respiratory illness.
Purpose of the Study:
- To develop and utilize a mouse model that replicates HMPV reinfection in elderly humans.
- To investigate the immunological mechanisms underlying severe HMPV disease in aged populations.
- To evaluate the efficacy of vaccination strategies in aged mice with HMPV reinfection.
Main Methods:
- C57BL/6J mice were infected with HMPV, aged, and subsequently rechallenged with a high virus dose.
- Lung histopathology, weight loss, and immune cell populations (specifically CD8+ T cells) were analyzed in aged and young mice.
- The response to epitope peptide stimulation and UV-inactivated HMPV vaccination was assessed in aged and young mice.
Main Results:
- Aged, rechallenged mice exhibited significant weight loss and increased lung pathology, similar to primary infection, despite undetectable viral loads.
- Accumulation of cytotoxic CD8+ T cells was observed in aged mice, but these cells showed impaired memory responses upon restimulation.
- Both convalescent serum transfer and vaccination with UV-inactivated HMPV provided diminished protection in aged mice compared to young controls, correlating with poor CD8+ T cell memory.
Conclusions:
- HMPV reinfection in aged individuals is associated with a dysregulated CD8+ T cell response that fails to protect and may exacerbate disease.
- Aged CD8+ T cell dysfunction presents a significant barrier to developing effective HMPV vaccination strategies for the elderly.
- The developed mouse model provides a valuable platform for studying age-related HMPV immunopathogenesis and testing interventions.
