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Vaccination reduces central nervous system IL-1β and memory deficits after COVID-19 in mice

Abstract

Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1β and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1β during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1β as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.

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Fig. 1: Respiratory B.1.351 infection causes memory deficits in C57BL/6J mice.
Fig. 2: B.1.351 infection induces microglial activation and monocyte infiltration in the CNS.
Fig. 3: Activated myeloid cells produce IL-1β during acute B.1.351 infection.
Fig. 4: Hippocampal neuroblast proliferation and synapse number decrease after B.1.351 infection.
Fig. 5: IL-1R1 signaling on NSCs promotes acute loss of neurogenesis and memory deficits.
Fig. 6: Vaccination lowers hippocampal IL-1β expression after breakthrough infection.
Fig. 7: Vaccination prevents loss of neurogenesis and cognitive deficits after breakthrough SARS-CoV-2 infection.

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Acknowledgements

We thank M. S. Diamond (Washington University in St. Louis) for the ChAd-S vaccine, WNV stock and Vero cells. We thank M. S. Suthar for the B.1.351 variant of SARS-CoV-2. We thank W. Beatty from the Washington University in St. Louis Microscopy Core Facility for her assistance and technical expertise. Imaging and Imaris analyses were performed, in part, through the use of Washington University Center for Cellular Imaging supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). Flow cytometry analysis was supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University, Immunomonitoring Laboratory. This work was supported by F32NS128065 (to A.V.), R01NS104471, R35 NS122310 and R01 AI160188 (all to R.S.K.) and R01-AI139251 (to A.C.M.B.).

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Contributions

A.V. and R.S.K. conceived and designed the study and wrote the paper. A.V., J.H., X.J., B.D., G.B., N.S., A.J. and M.D.C. contributed to the acquisition of data. A.V., J.H., M.D.C., A.C.M.B. and R.S.K. contributed to data analysis and interpretation.

Corresponding author

Correspondence to Robyn S. Klein.

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Nature Immunology thanks Changyoun Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team.

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Extended data

Extended Data Fig. 1 Sex does not impact B.1.351 infection.

Mice were intranasally infected with B.1.351 (5 ×105 pfu). a) Weight loss curves for mice infected at 8, 10, or 20 weeks of age (all male, n = 5-6). b) Weight loss curves for 16-week-old male or female mice infected with B.1.351 (n = 6-8). c) Viral titer in the Nasal turbinates and lung from 2 (n = 9), 4 (n = 8), 6 (n = 9), 8 (n = 12), 12 (n = 6) dpi measured via plaque assay. d) RNA transcript levels of Ifnb, Ifng, Il1b, Tnf at 4 and 6 dpi represented as fold change over mock (6 dpi) in the lung (n = 4). e) Representative image of Spike RNA in situ hybridization for an entire sagittal section of the brain from 4 dpi counterstained with hematoxylin. f) Indicated Open field measurement for combined sexes at 30 dpi (n = 19). g) Representative image of Novel Object apparatus set-up. On the right the percentage of investigations of each object during a preference test (n = 4). h) Selected open field measurements for male vs female mice at 30 dpi (n = 9). i) The discrimination index for the NOR test for B.1.351 infected male (n = 18) vs female mice (n = 20) is displayed on the left at 30 dpi. On the right, the discrimination index plotted vs the maximum weight lost during infection. Linear regression was used to calculate the R-squared and p-value are displayed on chart (n = 19). Data is represented as mean with SEM and was pooled (F-I) or representative (A-E) of 2-4 independent experiments. Statistical significance was determined using an unpaired, two-tailed, student’s t-test (F, I) or Welch’s one-way ANOVA with Dunnett’s multiple comparisons test (F), ordinary two-way ANOVA with Sidak’s multiple correction test (A, H), or simple linear regression (I).

Source data

Extended Data Fig. 2 T cells are increased in the cortex after SARS-CoV-2 infection.

Mice were intranasally infected with B.1.351 and euthanized at the indicated timepoint. a) Representative plots of the cortex at 30 dpi showing gating strategy for blood, cortex, and hippocampus. b) Frequency of the indicated population as a percentage of the total CD45+ cells in the blood at 6 dpi and c) 30 dpi d) Frequency of Ly6CLo or Hi cells in the total CD45HiCD11b+ population at 6 and 30 dpi in the blood. e) The count per gram of tissue for the indicated cell population in the cortex (top) or hippocampus (bottom) at 6 dpi or f) 30 dpi. 6 dpi: Mock n = 9, B.1.351 n = 8, 30 dpi: mock n = 8, B.1.351 n = 9. Data is represented as mean with SEM and was pooled from 2 independent experiments. Statistical significance was determined using an unpaired, two-tailed, student’s t-test (A-F).

Source data

Extended Data Fig. 3 Microglia are activated in the hippocampus after B.1.351 infection.

a) Representative pseudocolor flow plots showing expression of P2RY12 or Ly6C on CD45MidCD11b+ cells from the cortex at 6 dpi from B.1.351 infected mice. b) Representative images of IBA-1 expression in the DG after B.1.351 infection or mock at 6 and 30 dpi (40X magnification). Below is the percentage of IBA-1+ area in the indicated hippocampal region at mock (n = 6), 2 (n = 3), 4 (n = 3), 6 (n = 6), 8 (n = 4) dpi and 30 dpi (n = 10). c) Morphological measurements of IBA-1 or total IBA-1 count in the DG from mock and B.1.351 infected animals at the indicated timepoint (6 dpi n = 8, 30 dpi n = 6). All image analysis and acquisition were performed blinded and quantification was averaged from 2-4 slices for each mouse. Scale bar is 20 μM. Data is represented as mean with SEM and was representative of 2 independent experiments. Statistical significance was determined using an unpaired, two-tailed, student’s t-test (C) or Welch’s one-way ANOVA with Dunnett’s multiple comparisons test (B).

Source data

Extended Data Fig. 4 B.1.351 does not induce higher serum cytokine levels compared to PR8 infection.

C57Bl/6J mice at 14 weeks of age were intranasally infected with B.1.351, PR8 (2000 TCID50) or mock infected with PBS. a) The percent of original weight for mock and PR8 infected mice (n = 8). b) qRT-PCR was performed for the M gene of PR8 lung, cortex, and hippocampus. Values are represented as delta CT normalized to GAPDH. Dotted line indicates the limit of detection. c) qRT-PCR was performed for the indicated gene on mock, 3, and 6 dpi samples from the lung (n = 4). Multiplex analysis of serum cytokines was performed on mock (n = 8), B.1.351 (n = 5) and PR8 (n = 4) animals at 6 dpi. d) Cytokine levels represented as fold change over mock levels. e) concentration of the indicated cytokine in the serum at 7 dpi (IFNg). Data is represented as mean with SEM and was pooled or representative of 2 independent experiments. Statistical significance was determined using a Welch’s one-way ANOVA with Dunnett’s multiple comparisons test (B-C, E) for A this test was performed on the area under the curve.

Source data

Extended Data Fig. 5 PR8 infection does not induce hippocampal IL-1β.

C57Bl/6J mice at 14 weeks of age were intranasally infected with B.1.351, PR8 (2000 TCID50) or mock infected with PBS. a) qRT-PCR was performed for the indicated gene on mock, 3, and 6 dpi samples from the cortex and hippocampus (n = 4). b) Representative images of Isotype control for IL-1β (Goat IgG) from 6 dpi B.1.351 mice on the left. On the right, mice were intracranially infected with WNV-E218A, harvested at 7 dpi and hippocampal slices were stained for IL-1β expression. c) Representative images of IL-1β staining in the DG (40X magnification) with quantification of the total percent IL-1β + are on the right for the DG, CA3, and CA1 for mock (n = 7) and 6 dpi PR8 (n = 7) or B.1.351 (n = 4). d) Representative images of IBA-1 staining in the DG (40X magnification) with the total % IBA-1 area quantified on the right for mock (n = 7) and 6 dpi PR8 (n = 7) or B.1.351 (n = 4). All image analysis and acquisition were performed blinded and quantification was averaged from 2-4 slices for each mouse. Scale bar is 20 μM. Data is represented as mean with SEM and was pooled from 2 independent experiments. Statistical significance was determined using Welch’s one-way ANOVA with Dunnett’s multiple comparisons test (A, C-D).

Source data

Extended Data Fig. 6 Inhibition of neurogenesis begins at neuroblast stage and does not occur during PR8 infection.

C57Bl/6 mice were intranasally infected with B.1.351 or PR8. a) Quantification of the total number of DCX+ (o.p.=0.03) or Ki67+ cells per arbitrary unit (A.U.) of DG length. Samples from 2 (n = 3), 4 (n = 2), 6 (n = 7), 8 (n = 4) dpi are compared to a mock (M) from 6 dpi (n = 5) and representative of 2 independent experiments b) Representative image of TBR2 and Ki67 staining in the DG in mock (n = 4) or 6 dpi (n = 5), with quantification of cell number/ A.U. on the right (20X magnification). c) Representative images of Ki67 and DCX staining in the SGZ of the DG at 6 dpi from mock and PR8 infected animals (20X magnification). Quantified on the right is the number of DCX + , Ki67 + , and Ki67+ DCX+ (n = 8). Mice were intranasally infected with B.1.351 and harvested at the indicated timepoints. d) Number of synaptophysin+ puncta or homer+ puncta represented as the % of the number of average mock puncta in the indicated sub-region of the hippocampus at 8 (n = 7) and 15 dpi (n = 5) are compared to 8 dpi mock (n = 8). Or at e) 30 dpi (n = 9) is compared to a day 30 mock (n = 8). f) Representative images of the DG showing staining for NeuN, TUNEL, and DAPI (20X magnification). Below, quantification of the total number of TUNEL+ NeuN+ cells per mm2 for each subregion of the hippocampus (n = 5). All image analysis and acquisition were performed blinded and quantification was averaged from 2-4 slices for each mouse. Scale bar is 20 μM. Data is represented as mean with SEM and was pooled from 2 independent experiments. Statistical significance was determined using an unpaired, two-tailed, student’s t-test (B-D) or Welch’s one-way ANOVA with Dunnett’s multiple comparisons test (A, E-G).

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Extended Data Fig. 7 IL-1R1 signaling on NSCs does not impact synapse formation.

Nestin-CreERT2 x IL-1R1fl/fl littermates (Cre+ and Cre-) were intraperitoneally (I.P.) injected with Tamoxifen for 5 days. 10 days after the last tamoxifen injection, mice were intranasally infected with B.1.351. a) Weight loss curves for Mock and B.1.351 infected Nestin-Cre- and Nestin-Cre+ mice (n = 6). b) Representative z-stacks of DCX and Ki67 staining in the DG (20X) with enlarged regions below. c) Quantification of number of DCX+ or Ki67+ cells per arbitrary unit (A.U.) of DG at 6 (n = 6, Cre+ B.1.351 n = 9), or 30 dpi (mock, n = 5, B.1.351 n = 8, I.P.=n.s.). d) Representative z-stacks of Synaptophysin and Homer in the DG at 30 dpi (63X). e) Number of puncta for each marker and the number of overlapping (synapse) puncta was quantified as the total number of puncta per mm2 and represented as a percentage of the number of puncta in mock samples for each region (Mock: Cre- n = 7, Cre+ n = 4, B.1.351: n = 8, I.P.= n.s.). f) Mice were trained for the NOR test and the percentage of total investigations of identical Object 1a and 1b is shown for Mock and B.1.351 Nestin-Cre- and Nestin-Cre+ mice at 31 dpi. g) Selected open field measurements at 30 dpi (I.P.=n.s.). For F and G: Mock: Cre- n = 10, Cre+ n = 6, B.1.351: Cre- n = 11, Cre+ n = 11. h) Simple linear regressions between the discrimination index calculated from the Novel object test and the # of Ki67+DCX+ cells, the # of BrdU+ GFAP+ Cells, or the # of Synapse puncta for B.1.351 infected mice for Nestin-Cre- mice at 30 dpi (n = 11). All image analysis and acquisition was performed blinded and quantification was averaged from 3-5 slices for each mouse. Scale bar is 20 μM. Data is represented as mean with SEM and was pooled from 2 independent experiments. Statistical significance was determined via two-way ANOVA with Sidak’s multiple correction test (C, E-G) or simple linear regression (H).

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Extended Data Fig. 8 Vaccination provides neutralizing antibodies in C57Bl/6 mice.

a) Experimental schematic: Mice were intranasally vaccinated with 108 ChAd-Spike (S) or empty vector ChAD-Control (CTL) at day -30 p.i. At day -7, a cheek bleed was performed. At day 0, mice were intranasally infected with 5 ×105 pfu B.1.351. Mice were harvested at the indicated timepoint. b) FRNTs were performed to measure the % of B.1.351 neutralized by serum collected at - 21 days post vaccination from ChAd-CTL or ChAd-S inoculated animals (n = 8). c). The total number of CD3+ cells (I.P.= n.s.), CD45mid CD11b+, or CD45high CD11b+ Ly6Clo cells per gram of tissue was quantified for mock and 6 dpi ChAd-CTL or ChAd-S animals via flow cytometry (n = 7). Data is represented as mean with standard error of the mean and either representative of or pooled from 2 independent experiments. Statistical significance was determined by two-way ANOVA with Sidak’s multiple correction test (C).

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Extended Data Fig. 9 Vaccination does not impact open field performance after breakthrough infection.

Mice were intranasally vaccinated with 108 ChAd-S or ChAd-CTL, then challenged with B.1.351 30 days later. a) The number of DCX+ or Ki67+ cells per A.U. of DG in mock (n = 5) or 30 dpi (n = 6) in ChAd-CTL or ChAd-S mice (I.P.=n.s.). b) Selected open field test parameters measured at 30 dpi from ChAd-CTL or ChAd-S mice (n = 5-10, I.P.=n.s.). c) At 31 dpi, mice underwent training for the Novel Object test. On the left, the % of total investigations (nose pokes) spent with identical Object 1 A or 1B. On the right, the discrimination index for mock and 30 dpi ChAd-CTL and ChAd-S mice (I.P.=n.s.). For B-C: Mock: CTL n = 8, S = 9, B.1.351: CTL n = 12, S n = 14. Data is represented as mean with standard error of the mean and pooled from 2 independent experiments. Statistical significance was determined by two-way ANOVA with Sidak’s multiple correction test (A-C).

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Vanderheiden, A., Hill, J.D., Jiang, X. et al. Vaccination reduces central nervous system IL-1β and memory deficits after COVID-19 in mice. Nat Immunol 25, 1158–1171 (2024). https://doi.org/10.1038/s41590-024-01868-z

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