title: Severe acute respiratory syndrome-coronavirus infection in aged nonhuman primates is associated with modulated pulmonary and systemic immune responses.
abstract: BACKGROUND
  Many respiratory viruses disproportionately impact the elderly. Likewise, advanced age correlated with more adverse disease outcomes following severe acute respiratory syndrome coronavirus (SARS-CoV) infection in humans. We used an aged African green monkey SARS-CoV infection model to better understand age-related mechanisms of increased susceptibility to viral respiratory infections. Nonhuman primates are critical translational models for such research given their similarities to humans in immune-ageing as well as lung structure.
  
  
  RESULTS
  Significant age- and infection-dependent differences were observed in both systemic and mucosal immune compartments. Peripheral lymphocytes, specifically CD8 T and B cells were significantly lower in aged monkeys pre- and post- SARS-CoV infection, while neutrophil and monocyte numbers were not impacted by age or infection status. Serum proinflammatory cytokines were similar in both age groups, whereas significantly lower levels of IL-1beta, IL-18, IL-6, IL-12 and IL-15 were detected in the lungs of SARS-CoV-infected aged monkeys at either 5 or 10 days post infection. Total lung leukocyte numbers and relative frequency of CD8 T cells, B cells, macrophages and dendritic cells were greatly reduced in the aged host during SARS-CoV infection, despite high levels of chemoattractants for many of these cells in the aged lung. Dendritic cells and monocytes/macrophages showed age-dependent differences in activation and chemokine receptor profiles, while the CD8 T cell and B cell responses were significantly reduced in the aged host. In examination of viral titers, significantly higher levels of SARS-CoV were detected in the nasal swabs early, at day 1 post infection, in aged as compared to juvenile monkeys, but virus levels were only slightly higher in aged animals by day 3. Although there was a trend of higher titers in respiratory tissues at day 5 post infection, this did not reach statistical significance and virus was cleared from all animals by day 10, regardless of age.
  
  
  CONCLUSIONS
  This study provides unique insight into how several parameters of the systemic and mucosal immune response to SARS-CoV infection are significantly modulated by age. These immune differences may contribute to deficient immune function and the observed trend of higher SARS-CoV replication in aged nonhuman primates.
authors.forename: Candice C
authors.initials: CC
authors.lastname: Clay
authors.forename: Nathan
authors.initials: N
authors.lastname: Donart
authors.forename: Ndingsa
authors.initials: N
authors.lastname: Fomukong
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Knight
authors.forename: Katie
authors.initials: K
authors.lastname: Overheim
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tipper
authors.forename: Jesse
authors.initials: J
authors.lastname: Van Westrienen
authors.forename: Fletcher
authors.initials: F
authors.lastname: Hahn
authors.affiliation: Work performed at Lovelace Respiratory Research Institute (LRRI), Infectious Disease Program, Albuquerque, NM, Mexico. Kharrod@LRRI.org.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod