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Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Anthony Fernández-Castañeda, Peiwen LuiD, Anna C. GeraghtyiD, Eric SongiD, Myoung-Hwa Lee, Jamie WoodiD, Belgin YalçıniD, Kathryn R. TayloriD, Selena DuttoniD, Lehi Acosta-AlvareziD, Lijun Ni, Daniel Contreras-Esquivel, Jeff R. GehlhauseniD, Jon KleiniD, Carolina Lucas, Tianyang MaoiD, Júlio Dos Santos SilvaiD, Mario A. Peña-Hernández, Alexandra TabachnikovaiD, Takehiro TakahashiiD, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy KontorovichiD, Dayna McCarthy, , Michelle MonjeiD

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In-depth summary

Claude Sonnet 4.6 · max effort · 8 Nov 2026 · from the full text of version 1 (10 Jan 2022) · CC BY 4.0

Respiratory-restricted SARS-CoV-2 infection in mice, without brain virus, drives white matter microglial reactivity, impaired neurogenesis, oligodendrocyte depletion and myelin loss lasting at least 7 weeks.

Persistent cognitive symptoms after COVID-19 occur even after mild infection, and the cellular basis is unclear. This work tests whether neuroinflammatory and glial changes seen in cancer therapy-related cognitive impairment also arise after mild respiratory infection without neuroinvasion.

Key results

  1. ShownMild respiratory infection in mice caused microglial reactivity (IBA1+CD68+) in subcortical white matter but not in cortical gray matter. This held in two strains and persisted to 7 weeks.

    Cingulum, CD1 and BALB/c, unpaired t-tests. 7 days: CD1 n=5 control vs n=4 infected; BALB/c n=3 vs n=5. 7 weeks: CD1 n=7 vs n=7; BALB/c n=5 vs n=5. Cortex showed no reactivity. No virus detected in brain. · Mild respiratory SARS-CoV-2 infection causes…; Figure legends

  2. SuggestedAutopsy brain from people with SARS-CoV-2 infection showed higher CD68+ microglial reactivity in subcortical white matter than in cortex and than in uninfected controls, mirroring the mouse pattern.

    9 SARS-CoV-2-positive individuals (7 male, 2 female, age 24-73; only one needed ICU admission) vs 5 controls (5 male, age 43-70); 2-way ANOVA with multiple comparisons. · Mild respiratory SARS-CoV-2 infection causes…; Figure legends

  3. ShownCSF chemokines stayed elevated in infected mice for weeks, including CCL11, which fell back to normal in serum. Plasma CCL11 was higher in long-COVID patients with cognitive symptoms than in those without.

    Mouse CSF (n=7 CD1 per group): CXCL10, CCL7 and CCL11 remained elevated at 7 weeks. Human plasma: n=48 with cognitive symptoms (mean age 46.1±14.6 years) vs n=15 without (46.7±14.1 years); unpaired t-test. · Mild respiratory SARS-CoV-2 infection causes…; Mild respiratory SARS-CoV-2 infection impairs…; Figure legends

  4. ShownHippocampal neurogenesis dropped after infection at both timepoints, and new-neuron counts correlated inversely with reactive microglial load in the dentate gyrus.

    DCX+ neuroblasts in CD1 dentate gyrus: 7 days n=5 control vs n=4 infected; 7 weeks n=6 control vs n=7 infected. Correlation (7 days) by simple linear regression, n=5 and n=4. P values are shown only on figure panels. · Mild respiratory SARS-CoV-2 infection impairs…; Figure legends

  5. ShownMature oligodendrocytes were depleted early and persistently, OPCs fell modestly only at 7 weeks, and electron microscopy showed lower myelinated axon density from 7 days onward.

    Cingulum, CD1: about one third of ASPA+ oligodendrocytes lost by 7 days; OPC (PDGFRa+) decrease of ~10% at 7 weeks; myelinated axon density n=4 mice per group. G-ratio differences were not conclusive. · Mild respiratory SARS-CoV-2 infection impairs…; Figure legends

Methods, data and reproducibility

Mice received intratracheal AAV-hACE2 and then intranasal SARS-CoV-2 or mock. Brain and CSF were assessed at 7 days and 7 weeks by immunofluorescence cell counts, electron microscopy and multiplex cytokine assays, with human autopsy and long-COVID plasma comparisons.

  • Mock-infected vs SARS-CoV-2-infected mice (AAV-hACE2) for cytokines, microglia, neurogenesis, oligodendrocyte lineage and EM · mouse (CD1 and BALB/c, female) · n = n=3 to 7 per group for most assays; n=24 per group for body weight
  • Human autopsy brain (cortex and subcortical white matter) from SARS-CoV-2-positive individuals and uninfected controls · human · n = 9 COVID vs 5 controls
  • Plasma CCL11 in long-COVID patients with vs without cognitive symptoms · human · n = 48 with vs 15 without cognitive symptoms
  • Mouse CSF and serum multiplex cytokine profiles at 7 days and 7 weeks · mouse (CD1) · n = n=7 per group
Methods & tools
AAV9-CMV-hACE2, Luminex Procarta 48-plex mouse panel, Eve Technologies Human Cytokine/Chemokine Array HD71, Zeiss LSM700/LSM800 confocal microscopy, FIJI, Imaris (Spots function), ImageJ, Transmission electron microscopy, GraphPad Prism, Aperio AT2 slide scanner
Reagents & environment
Female CD1 and BALB/c mice aged 6 to 12 weeks; AAV-CMV-hACE2 delivered intratracheally; SARS-CoV-2 isolate USA-WA1/2020 (NR-52281). Antibodies with catalog numbers include IBA1 (Wako 019-19741), CD68 (Abcam ab53444), DCX (Abcam ab18723).
Experimental conditions
Imaging on Zeiss LSM700 or LSM800 confocal at 20X; EM images at 6000X; human slides scanned on Aperio AT2; multiplex assay read on an FM3D FlexMap instrument, with a minimum of 50 beads per sample per cytokine.
Reproducibility gaps
No code or data repository is given; counts are shown in figure panels and no accession is reported. Human subject characteristics are in a supplementary table.
Limitations (6)
  • Working at biosafety level 3 limited behavioral assessment, so cognitive consequences of the cellular changes were not tested in the infected mice. · stated by the authors
  • Whether the microglial reactivity induces neurotoxic astrocyte reactivity after mild respiratory infection, which could explain the oligodendrocyte loss, remains undetermined. · stated by the authors
  • Whether microglial depletion strategies that help in cancer therapy models would also benefit cognitive impairment after COVID-19 has not yet been established. · stated by the authors
  • Effects after newer variants such as Omicron, or breakthrough infection in vaccinated individuals, remain to be determined. · stated by the authors
  • Group sizes are small (n=3 to 7 mice; 9 vs 5 human brains), and the associations are not tested causally, for example by microglial depletion, so the link to neurogenesis and myelin loss is correlative. · noted in this summary
  • The human autopsy controls were all male (5 male) while cases included 2 female, and the long-COVID CCL11 comparison has no uninfected control group, limiting inference from human data. · noted in this summary

Read this if you study post-COVID cognitive symptoms or neuroinflammation and want mouse and human evidence for white matter microglial reactivity, CCL11 and myelin loss after mild infection.

Citations
100

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.

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