T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory. Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-γ (IFN-γ) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms. Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini. Accordingly, animals deficient in CD8+ T cells or IFN-γ signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection. Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses.
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The data from this study are tabulated in the main paper and supplementary materials. All reagents are available from R.S.K. under a material transfer agreement with Washington University. The data that support the findings of this study are also available from the corresponding author upon request.
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The authors acknowledge M. Diamond, J. Miner, A. Smith, L. Thackray, and K. Funk for helpful discussions and technical support. They also thank W. Beatty at the Molecular Microbiology Imaging facility at Washington University School of Medicine. This work was supported by NIH grants U19 AI083019, R01 NS052632, and R01 AI101400 to R.S.K.
The authors declare no competing interests.
Journal peer review information: Nature Neuroscience thanks Ryuta Koyama, Susanna Rosi, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Integrated supplementary information
(a, b) ZIKV preferentially targets the hippocampus (white box). Additional representative images of in situ hybridization for viral RNA (RNA-ISH) at 7 dpi as in Fig 1e, (n=4 mice per group). (c, d) Neither WNV nor ZIKV targets astrocytes (GFAP+) or microglia (IBA1+) in the CA3 region of the hippocampus. (e, f) Neither WNV nor ZIKV targets neural progenitor cells (DCX+) but does infect NeuN+ cells in the dentate gyrus of the hippocampus. Data from one independent experiment. Scale bar 20 µm.
Cx3CR1GFPCCR2RFP reporter animals were infected with WNV or ZIKV at 8 weeks old. Cells were isolated from the hippocampus at indicated dpi. (a) Gating strategy to identify putative microglia (P1: CD45midCD11b+), macrophage (P2: CD45hiCD11b+), and lymphocyte (P3: CD45hiCD11b-) populations. (b, c) Quantification of indicated populations at 0, 7, and 25 dpi revealed infiltration of putative macrophage and lymphocyte populations by 7 dpi, the latter of which persisted in the hippocampus at 25 dpi. Data are representative of two independent experiments (n=3 mice per group, mean ± SD, b: p<0.0001, =0.0006, <0.0001 c: p<0.0001, =0.0020, 0.0140, <0.0001). (d) Additional gates were applied to P1 and P3 populations to assess MHC-II expression in CD45midCD11b+Cx3CR1+CCR2- microglia populations and CD103 expression in CD45hiCD11b- CD8+ T cells (quantification in main Figure 2). (e, f) CD45hiCD11b- CD8+ T cells (identified by gating strategy in a,d) enter the hippocampus by 7 dpi and persist to 25 dpi (n=3 mice per group, mean ± SD, e: p=0.0018, <0.0001, =0.0001, 0.0017 f: p=0.0012, 0.0043). Data was analyzed by two-way (b,c) or one-way (e,f) ANOVA, and corrected for multiple comparisons. *,P<0.05, **, P<0.005, ***, P<0.001, ****, P<0.0001.
Most of the IFNg+ cells in the hippocampus during recovery are CD8+ T cells, and these persist in the hippocampus for at least a month after viral clearance. IFNγ-Thy1.1 reporter mice were infected with ZIKV or WNV and cells were isolated from the hippocampus at 25 or 52 dpi for flow cytometric analysis. (a) Representative gating strategy to identify CD45+IFNg+ cells, which were further analyzed according to the gating strategy shown in main Fig. 3. (b, c) Data from main Fig. 3f, g represented as number of cells (n=4 mice per group, mean ± SD, b: p<0.0001, =0.0289, 0.0038, 0.0015 c: p=0.0106, 0.0052, 0.0056). (d, e) Analysis of CD45+IFNγ+ cells at 52 dpi showed that CD45hiCD11b- CD8+ T cells persist in the hippocampus at least one month after viral clearance. Data are representative of two independent experiments (d: n=4 mice per group; e: n=3 mice per group, mean ± SD, d: p=0.0001, 0.0107, <0.0001 e: p<0.0001, =0.0001, 0.0108). Data was analyzed by one-way ANOVA, and corrected for multiple comparisons. *,P<0.05, **, P<0.005, ***, P<0.001, ****, P<0.0001.
(a-f) Loss of IFNγ signaling does not affect survival, weight loss, or clinical score. (a,d) Survival analysis (n indicated in the figure). (b,e) No difference in weight loss following infection, expressed as % of day 0 body weight (b: n=4 (WT Mock), 10 (WT WNV), 5 (Ifngr1-/- WNV) mice per group; e: n=20 (WT mock), 15 (WT ZIKV), 16 (Ifngr1-/- ZIKV) mice per group, mean ± SD, b: p=0.0001, 0.0002 e: p=0.0002, 0.0001). (c,f) No difference in clinical score following infection (n as in b,e, mean ± SD). (g-i) Loss of IFNγ signaling does not influence replication or clearance of infectious virus, with the exception of slight delay in the cerebellum. Viral burden was quantified via standard plaque assays. Data are pooled from two independent experiments (n=10 mice per group; mean ± SD, i: p=0.0040). Data was analyzed by log rank (Mantel-Cox) test (a,d) or two-way ANOVA (b,c,e-i) and corrected for multiple comparisons. **, P<0.005.
Supplementary Figure 5 Ifngr1-/- mice have slight decrease in CD103+CD8+ T cells, which express high levels of CCR2.
(a, b) Loss of IFNγ signaling led to a small but significant decrease in CD103 expression of CD45hiCD11b-CD8+ T cells isolated from the hippocampus at 25 dpi. Flow cytometric analysis of cells isolated from the hippocampus of Cx3CR1GFPCCR2RFP or Ifngr1-/-Cx3CR1GFPCCR2RFP animals as in Fig. 2e, f (gating strategy in Supplementary Fig 2). Data are pooled from two independent experiments (a: n=8 mice per group; b: n=3 (WT Mock, Ifngr1-/- Mock), 8 (WT WNV, Ifngr1-/- WNV) mice per group, mean ± SD, a: p<0.0001, =0.0060 b: p<0.0001, =0.0004). (c, d) Loss of IFNγ signaling did not influence CCR2 expression, which was high increased in CD45hiCD11b-CD8+ T cells isolated from the hippocampus at 25 dpi. Flow cytometric analysis of cells isolated from the hippocampus of Cx3CR1GFPCCR2RFP or Ifngr1-/-Cx3CR1GFPCCR2RFP animals as in Fig. 2e, f (gating strategy in Supplementary Fig 2). Data are pooled from two independent experiments (n=3 mice per group, mean ± SD, c: p<0.0001, d: p<0.0001). Data was analyzed by two-way ANOVA and corrected for multiple comparisons (a-d). **, P<0.005, ***, P<0.001, ****, P<0.0001.
Supplementary Figure 6 Decreases in post-synaptic terminals and increase in apoptotic neurons are observed during ZIKV acute infection and long-term recovery.
(a, c) ZIKV infection does not target glutamatergic termini (Vglut1) or GABAergic (GAD67) neurons at 25 dpi. Data are pooled from two independent experiments (n=7 mice per group, mean ± SD). (b) No difference in new neurons within the DG during recovery. Representative images of recovered hippocampus at 52 dpi, assessed after BrdU labeling during acute infection; BrdU (red), NeuN (green), DAPI (blue). Data from one experiment (n=4 mice, mean ± SD). Scale bar 50 µm. (d) ZIKV infection leads to decreased number of neurons at 52 dpi. More neurons were found in Ifngr1-/- recovered mice. Representative images of the recovered hippocampus, NeuN (green). Data are pooled from two independent experiments (n=4 (WT Mock, WT ZIKV, Ifngr1-/- ZIKV), 5 (Ifngr1-/- Mock) mice per group, mean ± SD, p<0.0001, =0.0094). Scale bar 20 µm. (e) WNV infection leads to the acute loss of synaptophysin+ pre-synaptic terminals. Data are pooled from 2 independent experiments (n=4 mice per group, mean ± SD). Scale bar 20 µm. (f-g) ZIKV infection leads to acute loss of homer1+ post-synaptic terminals, but preservation of synaptophysin+ pre-synaptic terminals (f) Representative immunostaining in the hippocampus at 7 dpi; Synaptophysin (red), DAPI (blue). Data are pooled from 2 independent experiments (n=4 mice per group, mean ± SD). Scale bar 10 µm. (g) Representative immunostaining in the hippocampus at 7 dpi; Homer1 (green), DAPI (blue). Data are pooled from 2 independent experiments (n=4 mice per group, mean ± SD, p=0.0199, 0.0367). Scale bar 10 µm. Data was analyzed by two-way ANOVA and corrected for multiple comparisons (a-g). *,P<0.05, **, P<0.005, ***, P<0.001.
Supplementary Figure 7 Significant differences in numbers of microglia in the hippocampus of WT and Ifngr1-/- WNV and ZIKV-recovered mice.
(a) Astrocyte expression of IL-1β was similarly elevated in WT and Ifngr1-/- mice. Representative immunostaining in the hippocampus; GFAP (green), IL-1β (red), DAPI (blue). Data are pooled from 3 independent experiments (n=9 (WT Mock), 4 (WT ZIKV, Ifngr1-/- Mock, Ifngr1-/- ZIKV) mice per group, mean ± SD, p<0.0001). Scale bar 50 µm. (b-e) ZIKV- and WNV-recovered animals demonstrate similar numbers of microglia in the hippocampus at 25 dpi. (b,c) No differences in the number of CD45midCD11b+Cx3CR1+CCR2- microglia were observed in cells isolated from the ZIKA- or WNV-recovered hippocampus of reporter mice at 25 dpi. Representative plots of CD45midCD11b+ cells. Data are representative of two independent experiments (n=3 mice per group, mean ± SD). (d,e) No differences in the number of Tmem119+ microglia were observed in the hippocampus of WT and Ifngr1-/- infected animals at 25 dpi. Representative immunostaining of Tmem119 (green) and DAPI (blue) in the hippocampus. Data are pooled from two independent experiments (d: n=5 (WT), 4 (Ifngr1-/-) mice per group; e: n=6 (WT), 8 (Ifngr1-/-) mice per group, mean ± SD). Data was analyzed by unpaired two-sided t test (a-d). (f,g) WNV or ZIKV infection induces increased expression of MHC-II in hippocampal microglia at 25 dpi. Representative plots from flow cytometric analysis of MHC-II expression in CD45midCD11b+Cx3CR1+CCR2- microglia isolated from the recovered hippocampus of infected WT and Ifngr1-/- animals. Data are pooled from two independent experiments (n=8 mice per group, mean ± SD, p<0.0001). Data was analyzed by two-way ANOVA and corrected for multiple comparisons (f,g). *,P<0.05, ***, P<0.001, ****, P<0.0001.
Specific deletion of IFNgR in microglia was achieved as in Fig. 8a–g. (a, b) Flow cytometric analysis of CD45midCD11b+ microglia isolated from the hippocampus of Cx3CR1CreERIfngrfl/fl (Cre+) mice and Cx3CR1Cre-Ifngrfl/fl (Cre-) littermate controls after behavioral testing demonstrated significant deletion of IFNgR in Cre+ mice. Data are pooled from two independent experiments (a: n=4 (Cre- Mock, Cre+ ZIKV), 5 (Cre- ZIKV), 7 (Cre+ Mock) mice per group; b: n=5 (Cre- Mock, Cre+ Mock), 6 (Cre- WNV, Cre+ WNV) mice per group, mean ± SD, p<0.0001). (c) Analysis of peripheral myeloid cells isolated from the blood (PBMCs) and spleen revealed no difference in IFNgR expression between Cre+ and Cre- mice. Data are representative of two independent experiments (n=4 mice per group, mean ± SD). (d) Tamoxifen treatment did not alter IFNgR expression in CD45hiCD11b-CD8+ or CD45hiCD11b-CD4+ T cells isolated from the hippocampus of Cre+ and Cre- mice. Data are representative of two independent experiments (n=4 mice per group, mean ± SD). (e, f) Conditional deletion of IFNgR in microglia during recovery led to significant attenuation of MHC-II expression in microglia isolated from the hippocampus of Cre+ but not Cre- mice after behavioral testing. Data are pooled from two independent experiments (e: n=4 (Cre- Mock, Cre+ ZIKV), 5 (Cre- ZIKV, Cre+ Mock) mice per group; f: n=5 (Cre- Mock, Cre+ Mock, Cre+ WNV), 6 (Cre- WNV) mice per group, mean ± SD, e: p=0.0060, 0.0367 f: p=0.0182, 0.0369). Data was analyzed by two-way ANOVA and corrected for multiple comparisons (a,b,e,f) or by unpaired two-sided t test (c,d). *,P<0.05, **, P<0.005, ****, P<0.0001.
Supplementary Figure 9 T cell-derived IFNγ targets microglia to mediate neurocognitive dysfunction during recovery from WNV and ZIKV infection.
(a) WNV infects neurons throughout the CNS. Anti-viral T cells that persist in the CNS after viral recovery produce IFNγ. IFNγ targeting of microglia leads to the elimination of presynaptic termini, most prominently in the CA3 region of the hippocampus, and the development of spatial learning and memory deficits. (b) ZIKV preferentially targets neurons in the hippocampus. Like WNV, IFNγ producing T cells persist in the CNS after ZIKV recovery. Targeting microglia, IFNγ induced apoptosis of neurons and the elimination of post-synaptic termini throughout the hippocampus. ZIKV inflicted mice subsequently develop spatial learning and memory deficits.
3D reconstruction from confocal Z-stack images of immunostaining of microglia engulfment of homer+ postsynaptic termini at 25 dpi: This video shows a 3D reconstruction from confocal Z-stack images of immunostaining of the postsynaptic marker, homer, and the microglia marker, IBA1, in hippocampus of ZIKV-infected mouse at 25 dpi.
3D reconstruction from confocal Z-stack images of immunostaining of microglia engulfment of NeuN+ perikarya at 25 dpi: This video shows a 3D reconstruction from confocal Z-stack images of immunostaining of the neural cell body marker, NeuN, and the microglia marker, IBA1, in hippocampus of ZIKV-infected mouse at 25 dpi.
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Garber, C., Soung, A., Vollmer, L.L. et al. T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses. Nat Neurosci 22, 1276–1288 (2019). https://doi.org/10.1038/s41593-019-0427-y
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