Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain
Abstract
Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 10, 2022
- Source ID
- 10.1101/2022.01.07.475453
Entities
People
- Akiko Iwasaki
- Alexandra Tabachnikova
- Amy Kontorovich
- Anna C. Geraghty
- Anthony Fernández-castañeda
- Avindra Nath
- Belgin Yalçın
- Carolina Lucas
- Daniel Contreras-esquivel
- Daniel Perl
- David F Putrino
- Dayna Mccarthy
- Eric Song
- Erica Breyman
- Jamie Wood
- Jeff R. Gehlhausen
- Jenna Tosto-mancuso
- Jon Klein
- Julio Silva
- Kathryn R. Taylor
- Laura Tabacof
- Lehi Acosta-alvarez
- Lijun Ni
- Marco M Hefti
- Mario A. Peña-hernández
- Martha Quezado
- Michelle Monje
- Myoung-hwa Lee
- Peiwen Lu
- Rebecca Folkerth
- Selena Dutton
- Takehiro Takahashi
- Tianyang Mao