Progressive Cognitive Impairment After Recovery from Neuroinvasive and Non-neuroinvasive Infection

Background: Neuro-cognitive impairment is a deleterious complication of bacterial infections that is difficult to treat or prevent. () is a neuroinvasive bacterial pathogen and commonly used model organism for studying immune responses to infection. Antibiotic-treated mice that survive systemic infection have increased numbers of CD8 and CD4 T-lymphocytes in the brain that include tissue resident memory (T) T cells, but post-infectious cognitive decline has not been demonstrated. We hypothesized that infection would trigger cognitive decline in accord with increased numbers of recruited leukocytes.

Methods: Male C57BL/6J mice (age 8 wks) were injected with neuroinvasive 10403s, non-neuroinvasive Δ mutants, or sterile saline. All mice received antibiotics 2-16d post-injection (p.i.) and underwent cognitive testing 1 month (mo) or 4 mo p.i. using the Noldus PhenoTyper with Cognition Wall, a food reward-based discrimination procedure using automated home cage based observation and monitoring. After cognitive testing, brain leukocytes were quantified by flow cytometry.

Results: Changes suggesting cognitive decline were observed 1 mo p.i. in both groups of infected mice compared with uninfected controls, but were more widespread and significantly worse 4 mo p.i. and most notably after 10403s. Impairments were observed in learning, extinction of prior learning and distance moved. Infection with 10403s, but not Δ, significantly increased numbers of CD8 and CD4 T-lymphocytes, including populations expressing CD69 and T cells, 1 mo p.i. Numbers of CD8, CD69CD8 T-lymphocytes and CD8 T remained elevated at 4 mo p.i. but numbers of CD4 cells returned to homeostatic levels. Higher numbers of brain CD8 T-lymphocytes showed the strongest correlations with reduced cognitive performance.

Conclusions: Systemic infection by neuroinvasive as well as non-neuroinvasive triggers a progressive decline in cognitive impairment. Notably, the deficits are more profound after neuroinvasive infection that triggers long-term retention of CD8 T-lymphocytes in the brain, than after non-neuroinvasive infection, which does not lead to retained cells in the brain. These results support the conclusion that systemic infections, particularly those that lead to brain leukocytosis trigger a progressive decline in cognitive function and implicate CD8 T-lymphocytes, including CD8T in the etiology of this impairment.