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Typhoid toxin causes neuropathology by disrupting the blood–brain barrier

Nature Microbiology volume 10, pages 1340–1351 (2025)Cite this article

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Abstract

Typhoid fever, primarily caused by Salmonella Typhi, can result in severe life-threatening complications such as encephalopathy. Here we elucidate the mechanisms by which typhoid toxin, a unique virulence factor of S. Typhi, mediates the neuropathology associated with typhoid fever. Utilizing mice engineered to have specific tissues protected from toxin action and an in vitro model of the blood–brain barrier (BBB), we demonstrate that, rather than direct action on neuronal or glial cells, typhoid toxin causes neuropathology by disrupting the BBB. Intravenous tracer studies confirmed significant BBB permeability changes following toxin exposure, an effect we found to be mediated by typhoid toxin’s CdtB catalytic subunit. We demonstrate that corticosteroids are effective at mitigating BBB disruption in vivo, supporting their use for managing typhoid fever neurological complications. Our data reveal mechanistic insight into how typhoid toxin causes encephalopathy and suggest targeted therapeutic interventions to alleviate the severe neurological manifestations of typhoid fever.

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Fig. 1: Preventing typhoid toxin neuronal and glial cell targeting does not prevent intoxication.
Fig. 2: Typhoid toxin disrupts the blood–brain barrier.
Fig. 3: Encephalopathy is associated with typhoid toxin disruption of the blood–brain barrier.
Fig. 4: Direct administration of typhoid toxin into the central nervous system causes no pathologies.
Fig. 5: Typhoid toxin disruption of the blood–brain barrier is mediated by its CdtB subunit.
Fig. 6: Typhoid toxin directly targets blood–brain barrier endothelial cells.

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All data are provided within the main paper, Supplementary Information and Source data files.

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Acknowledgements

We thank J. Hansen, Yale University, for the generous gift of the hCMEC/D3 cell line; M. Shanabrough, Yale University, for help with the electron microscopy experiments; and T. Nottoli at the Yale Genome Editing Center for assistance in the construction of the Cmahfl mouse. This work was supported by NIH Grants R01AI114618 to J.E.G.

Author information

Author notes

  1. Jonatas Catarino

    Present address: Max Plank Institute for Metabolic Research, Cologne, Germany

  2. Gabrielle Stack

    Present address: Elly Lilly and Company, Cork, Ireland

Authors and Affiliations

  1. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA

    Heng Zhao, Gabrielle Stack, Maria Lara-Tejero & Jorge E. Galán

  2. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA

    Jonatas Catarino, Ashley Kristant Albizu & Tamas L. Horvath

  3. Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary

    Tamas L. Horvath

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Contributions

H.Z. conducted most of the experiments. J.C. assisted with BBB experiments. G.S. constructed the Cmahfl mouse. A.K.A. assisted with the electron microscopy experiments. M.L.-T. provided intellectual input in the project and assisted in the design of the Cmahfl mouse model. T.L.H. provided intellectual input in the project in all aspects related to the BBB and brain pathology. J.E.G. conceived and directed the project. H.Z. and J.E.G wrote the paper with comments from all authors.

Corresponding author

Correspondence to Jorge E. Galán.

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Extended data

Extended Data Fig. 1 Survival and weight changes in different mouse lines following administration of various doses of typhoid toxin.

Survival (a, c and e) or weight change (b, d and f) of the indicated mice after receiving 0.1, 0.5, or 1 μg of typhoid toxin via the retro-orbital route. n = 4 animals per category. Weight change data are normalized using the initial weight as 100% and represent the mean ± SD for 4 independent measurements.

Source data

Extended Data Fig. 2 Typhoid toxin directly targets blood-brain barrier endothelial cells.

(a) Coronal sections of Cmahfl or Cmahfl/Tek-cre mouse brains (as indicated), 24 and 48 h after receiving 5 μg of Alexa 488-labeled typhoid toxin via the retro-orbital route. (b) Representative fluorescence images of ex vivo toxin binding to brain sections of Cmahfl or Cmahfl/Tek-cre mouse brains (as indicated). Brain sections were fixed and stained with 1 μg Alexa 488-conjugated typhoid toxin (green). Whole brain fluorescence images taken with a 4 x objective were stitched together using the Fusion software package. Scale bar, 1500 μm.

Extended Data Fig. 3 In vivo tropism of typhoid toxin in different mouse lines.

Immunofluorescence images of brain sections of indicated mice 1 h after receiving 5 µg Alexa 488-labeled typhoid toxin (green) via the retro-orbital route. The left panels show whole brain images taken with a 4 x objective and stitched together using the Fusion software package. DAPI (blue) was used to visualized nuclei. The right panels show insets of close-up areas (20 x objective) of the brain sections on the left. To visualize blood vessel endothelial cells, brain sections were stained with a primary rat antibody against mouse CD31 followed by Alexa 568-labeled goat anti-rat antibody (red).

Extended Data Fig. 4 Schematic of the microfluidic device-based 3D BBB in vitro model.

Immortalized human cerebral microvascular endothelial cells hCMEC/D3 are seeded in the apical chamber to form a 3D single-layer vessel, with medium flow to mimic sheer stress from blood flow in vivo to induce expression of tight junction proteins. The slits between the apical chamber and the inner and outer chambers are 3 μm wide and allow measurement of transendothelial electric resistance through the electrode ports (labeled as ‘E’ in the schematic). The device is symmetrical and allows a biological replicate.

Extended Data Fig. 5 Typhoid toxin disrupts the blood-brain barrier tight junctions.

Immunofluorescence images of hCMEC/D3 human brain microvascular endothelial cells cultured in a 3D in vitro system after growing in medium with or without 10 nM wild-type typhoid toxin (a) or its derivatives assembled with its CdtBH160Q (b) or PltAE133A (c) catalytic mutant subunits. Cells were stained with primary mouse antibody against Zonula occludens (ZO-1) followed by Alexa Fluor 488-labeled goat anti-mouse antibody (green) and DAPI (blue) to stain the nuclei. The left panels show a low magnification (4 x objective) image of the entire device and the right panels an inset of a close-up area (20 x objective).

Extended Data Fig. 6 Typhoid toxin induces cell death and activates caspase-3/7 through the Dnase activity of the CdtB subunit.

(a) Cell death and (b) relative caspase-3/7 activity in hCMEC/D3 cells following intoxication with wild-type typhoid toxin or toxoid containing the catalytically inactive CdtBH160Q mutant. Toxin and toxoid concentrations (nM) are indicated. Cell death was quantified by flow cytometry of propidium iodide (PI)-stained cells at the specified time points post-intoxication. Caspase-3/7 activity was measured using the Caspase-Glo® 3/7 luminescence assay, with values normalized to vehicle treated control cells. Data represent the mean ± SD of four biological replicates.

Source data

Extended Data Fig. 7 Effect of dexamethasone on the typhoid toxin-mediated disruption of the blood-brain barrier.

C57BL/6 mice received a sublethal dose of typhoid toxin (500 ng) delivered via the retro-orbital route. Starting 4 days post-intoxication, animals received subcutaneously either dexamethasone (3 μg/g body weight) or eluent (PBS) daily until the end of the experiment. Survival (a), weight change (b), relative Evans blue tracer leakage across the blood-brain barrier (c), or water content of the brain (d) were monitored over time in all the animals. Weight change data were normalized using initial weight as 100% and represent the mean ± SD for measurements in 6 animals (b). For the measurement of Evans blue tracer leakage (c) or the brain water content (d), SD are shown (n = 4 animals per data point before day 4, and n = 3 per category per data point afterwards). Statistically analysis was performed using unpaired two-tailed Student’s t test; *, p < 0.05. The p values were as follows: (c) 0.033453, 0.014107, 0.044075, and 0.026804; (d) 0.027178, and 0.041198. (e) mRNA levels of proinflammatory cytokines in mouse brains 9 days after receiving typhoid toxin (500 ng) through the retro-orbital route. Starting 4 days post-intoxication, animals received subcutaneously either dexamethasone (3 μg/g body weight) or eluent (PBS) daily (n = 5 animals per group). Values were normalized using Gapdh and represent fold induction over mock-treated animal controls. The mean ± SD and p values of the indicated comparison (unpaired two-tailed Student’s t test) are shown.

Source data

Extended Data Fig. 8

Map of plasmid pSB8922 used for the construction of mice with floxed Cmah for tissue specific expression.

Extended Data Table 1 Neurological symptoms in animals following toxin administration
Full size table

Supplementary information

Supplementary Information

Supplementary Table 1.

Reporting Summary

Supplementary Movie 1

Human brain microvascular hCMEC/D3 cells grown on a microfluidic device to model the blood–brain barrier. Cells were stained with primary mouse antibody against Zonula occludens (ZO-1), followed by Alexa 488-labelled goat anti-mouse antibody (green) and DAPI (blue) to visualize nuclei.

Supplementary Movie 2

Human brain microvascular hCMEC/D3 cells grown on a microfluidic device 24 h after typhoid toxin treatment. Cells were stained with primary mouse antibody against ZO-1, followed by Alexa 488-labelled goat anti-mouse antibody (green) and DAPI (blue) to visualize nuclei.

Supplementary Movie 3

Human brain microvascular hCMEC/D3 cells grown on a microfluidic device 48 h after typhoid toxin treatment. Cells were stained with primary mouse antibody against ZO-1, followed by Alexa 488-labelled goat anti-mouse antibody (green) and DAPI (blue) to visualize nuclei.

Supplementary Movie 4

C57BL/6 mouse exhibiting lethargy 4 days post administration of 5 µg of typhoid toxin via the retro-orbital route.

Supplementary Movie 5

C57BL/6 mouse exhibiting ataxia 4 days post administration of 5 µg of typhoid toxin via the retro-orbital route.

Supplementary Movie 6

C57BL/6 mice exhibiting hyperexcitability 4 days post administration of 5 µg of typhoid toxin via the retro-orbital route.

Supplementary Movie 7

C57BL/6 mouse exhibiting seizure-like behaviour 4 days post administration of 5 µg of typhoid toxin via the retro-orbital route.

Source data

Source Data Figs. 1–6 and Extended Data Figs. 1, 6 and 7.

Raw data and statistical analysis for Figs. 1–6 and Extended Data Figs. 1, 6 and 7.

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Zhao, H., Catarino, J., Stack, G. et al. Typhoid toxin causes neuropathology by disrupting the blood–brain barrier. Nat Microbiol 10, 1340–1351 (2025). https://doi.org/10.1038/s41564-025-02000-z

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