tetano
Editor, Senior Moderator
Aging Cell
. 2024 Nov 17:e14409.
doi: 10.1111/acel.14409. Online ahead of print. Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment
Katie L Reagin[SUP] 1 [/SUP], Rae-Ling Lee[SUP] 1 [/SUP], Luke A Williams[SUP] 1 [/SUP], Loren Cocciolone[SUP] 1 [/SUP], Kristen E Funk[SUP] 1 [/SUP]
Affiliations
Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8[SUP]+[/SUP] T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8[SUP]+[/SUP] T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103[SUP]+[/SUP] resident memory cells (T[SUB]RM[/SUB]), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8[SUP]+[/SUP] T cells retained within the adult brain post-infection, but also that adult CD8[SUP]+[/SUP] cells expressed lower levels of T[SUB]RM[/SUB] marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8[SUP]+[/SUP] T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8[SUP]+[/SUP] T cells are recruited to the aged brain and cause broad neuronal death without establishing a T[SUB]RM[/SUB] phenotype that confers lasting protection against a secondary infection.
Keywords: CD8+ T cells; aging; cognitive dysfunction; murine hepatitis virus; neuroinflammation; resident memory T cells; respiratory infection.
. 2024 Nov 17:e14409.
doi: 10.1111/acel.14409. Online ahead of print. Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment
Katie L Reagin[SUP] 1 [/SUP], Rae-Ling Lee[SUP] 1 [/SUP], Luke A Williams[SUP] 1 [/SUP], Loren Cocciolone[SUP] 1 [/SUP], Kristen E Funk[SUP] 1 [/SUP]
Affiliations
- PMID: 39550693
- DOI: 10.1111/acel.14409
Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8[SUP]+[/SUP] T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8[SUP]+[/SUP] T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103[SUP]+[/SUP] resident memory cells (T[SUB]RM[/SUB]), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8[SUP]+[/SUP] T cells retained within the adult brain post-infection, but also that adult CD8[SUP]+[/SUP] cells expressed lower levels of T[SUB]RM[/SUB] marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8[SUP]+[/SUP] T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8[SUP]+[/SUP] T cells are recruited to the aged brain and cause broad neuronal death without establishing a T[SUB]RM[/SUB] phenotype that confers lasting protection against a secondary infection.
Keywords: CD8+ T cells; aging; cognitive dysfunction; murine hepatitis virus; neuroinflammation; resident memory T cells; respiratory infection.