Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations
Background: Leukocytes recruited into the central nervous system after infection help clear pathogens and provide long-lasting immune surveillance, but also can contribute to harmful post-infectious neuroinflammation. Listeria monocytogenes (Lm) is a neuroinvasive bacterial pathogen of humans and a...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Journal of Affective Disorders Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666915323000756 |
| _version_ | 1797854469998772224 |
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| author | Benjamin R. Cassidy Sreemathi Logan Julie Farley Daniel Owen William E. Sonntag Douglas A. Drevets |
| author_facet | Benjamin R. Cassidy Sreemathi Logan Julie Farley Daniel Owen William E. Sonntag Douglas A. Drevets |
| author_sort | Benjamin R. Cassidy |
| collection | DOAJ |
| description | Background: Leukocytes recruited into the central nervous system after infection help clear pathogens and provide long-lasting immune surveillance, but also can contribute to harmful post-infectious neuroinflammation. Listeria monocytogenes (Lm) is a neuroinvasive bacterial pathogen of humans and a commonly used model organism for studying immune responses to infection. Post-infectious cognitive decline in Lm infected mice has not been demonstrated. We hypothesized that neuroinvasive Lm infection would trigger cognitive decline in accord with persistence of increased numbers of recruited leukocytes in the brain. Methods: Male C57BL/6J mice (age 8 wks) were injected intraperitoneally with neuroinvasive Lm strain 10403s, avirulent non-neuroinvasive Δhly 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 Ethovision PhenoTyper with Cognition Wall (Noldus), a food reward-based discrimination procedure using automated home cage based observation and data analysis with continuous monitoring. Brain leukocytes were analyzed flow cytometry. Results: Mice infected with neuroinvasive Lm 10403s, but not Δhly Lm, had significantly worse cognitive outcomes than did uninfected mice 4 mo p.i. but not 1 mo p.i. Changes included decreased movement, delayed success in criterion achievement, and impaired extinguishing of prior learning. Numbers of CD8+ and CD4+ T-lymphocytes, and subpopulations expressing CD69 and tissue resident memory (TRM) cells were significantly increased 1 mo after infection with Lm 10403s, but not Δhly Lm. By 4 mo p.i., CD8+, CD69+CD8+T-lymphocytes and CD8+ TRM remained significantly elevated, but CD4+ cells were not different from uninfected mice. Greater numbers of CD8+ cells, particularly CD8+ TRM, and lower CD4/CD8 ratio correlated significantly with reduced movement and increased time to criterion success. Conclusions: Cognitive impairment follows recovery from neuroinvasive Lm infection but not by Lm Δhly mutants that do not induce brain inflammation. Identification of dynamic shifts in brain CD8+ and CD4+ T-lymphocyte populations coupled with cognitive assessments suggest CD8+ cells, e.g. CD8+ TRM, promote neuroinflammation and injury whereas CD4+ cells may have regulatory activity. Cognitive decline manifests as initial influxes of CD4+ cells regress towards homeostatic levels while numbers of CD8+ cells remain significantly elevated. |
| first_indexed | 2024-04-09T20:07:38Z |
| format | Article |
| id | doaj.art-73b569590005497b97fb745142124d06 |
| institution | Directory Open Access Journal |
| issn | 2666-9153 |
| language | English |
| last_indexed | 2024-04-09T20:07:38Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Affective Disorders Reports |
| spelling | doaj.art-73b569590005497b97fb745142124d062023-04-01T08:51:38ZengElsevierJournal of Affective Disorders Reports2666-91532023-04-0112100536Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populationsBenjamin R. CassidySreemathi LoganJulie FarleyDaniel OwenWilliam E. SonntagDouglas A. Drevets0Presenting author: Prof. Douglas A. Drevets, MD, DTM&H, FIDSA, Regents’ Professor and Chief, Section of Infectious Diseases, University of Oklahoma Health Sciences Center, 800 Stanton L. Young, Suite 7300, Oklahoma City, OK 73104, USA, Phone 405-271-6122; FAX 405-271-1570Background: Leukocytes recruited into the central nervous system after infection help clear pathogens and provide long-lasting immune surveillance, but also can contribute to harmful post-infectious neuroinflammation. Listeria monocytogenes (Lm) is a neuroinvasive bacterial pathogen of humans and a commonly used model organism for studying immune responses to infection. Post-infectious cognitive decline in Lm infected mice has not been demonstrated. We hypothesized that neuroinvasive Lm infection would trigger cognitive decline in accord with persistence of increased numbers of recruited leukocytes in the brain. Methods: Male C57BL/6J mice (age 8 wks) were injected intraperitoneally with neuroinvasive Lm strain 10403s, avirulent non-neuroinvasive Δhly 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 Ethovision PhenoTyper with Cognition Wall (Noldus), a food reward-based discrimination procedure using automated home cage based observation and data analysis with continuous monitoring. Brain leukocytes were analyzed flow cytometry. Results: Mice infected with neuroinvasive Lm 10403s, but not Δhly Lm, had significantly worse cognitive outcomes than did uninfected mice 4 mo p.i. but not 1 mo p.i. Changes included decreased movement, delayed success in criterion achievement, and impaired extinguishing of prior learning. Numbers of CD8+ and CD4+ T-lymphocytes, and subpopulations expressing CD69 and tissue resident memory (TRM) cells were significantly increased 1 mo after infection with Lm 10403s, but not Δhly Lm. By 4 mo p.i., CD8+, CD69+CD8+T-lymphocytes and CD8+ TRM remained significantly elevated, but CD4+ cells were not different from uninfected mice. Greater numbers of CD8+ cells, particularly CD8+ TRM, and lower CD4/CD8 ratio correlated significantly with reduced movement and increased time to criterion success. Conclusions: Cognitive impairment follows recovery from neuroinvasive Lm infection but not by Lm Δhly mutants that do not induce brain inflammation. Identification of dynamic shifts in brain CD8+ and CD4+ T-lymphocyte populations coupled with cognitive assessments suggest CD8+ cells, e.g. CD8+ TRM, promote neuroinflammation and injury whereas CD4+ cells may have regulatory activity. Cognitive decline manifests as initial influxes of CD4+ cells regress towards homeostatic levels while numbers of CD8+ cells remain significantly elevated.http://www.sciencedirect.com/science/article/pii/S2666915323000756 |
| spellingShingle | Benjamin R. Cassidy Sreemathi Logan Julie Farley Daniel Owen William E. Sonntag Douglas A. Drevets Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations Journal of Affective Disorders Reports |
| title | Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations |
| title_full | Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations |
| title_fullStr | Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations |
| title_full_unstemmed | Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations |
| title_short | Systemic infection of mice with neuroinvasive Listeria monocytogenes triggers cognitive decline and persistent increases in brain CD8+ T-lymphocyte populations |
| title_sort | systemic infection of mice with neuroinvasive listeria monocytogenes triggers cognitive decline and persistent increases in brain cd8 t lymphocyte populations |
| url | http://www.sciencedirect.com/science/article/pii/S2666915323000756 |
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