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Infection with mpox virus via the genital mucosae increases shedding and transmission in the multimammate rat (Mastomys natalensis)

Nature Microbiology volume 9, pages 1231–1243 (2024)Cite this article

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A preprint version of the article is available at bioRxiv.

Abstract

The 2022 mpox virus (MPXV) outbreak was sustained by human-to-human transmission; however, it is currently unclear which factors lead to sustained transmission of MPXV. Here we present Mastomys natalensis as a model for MPXV transmission after intraperitoneal, rectal, vaginal, aerosol and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Virus shedding and tissue replication were route dependent and occurred in the presence of self-resolving localized skin, lung, reproductive tract or rectal lesions. Mucosal inoculation via the rectal, vaginal and aerosol routes led to increased shedding, replication and a pro-inflammatory T cell profile compared with skin inoculation. Contact transmission was higher from rectally inoculated animals. This suggests that transmission might be sustained by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release.

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Fig. 1: Robust, non-lethal infection of M. natalensis through mucosal and respiratory, but not skin, inoculation.
Fig. 2: Mpox antigen and RNA in skin, urogenital or respiratory tract lesions.
Fig. 3: Exposure-route-dependent MPXV shedding profile of M. natalensis.
Fig. 4: Significant T cell activation and effector function after rectal, but not aerosol and transdermal, inoculation with MPXV.
Fig. 5: Contact transmission in M. natalensis after rectal and transdermal inoculation.
Fig. 6: Contact transmission in M. natalensis after aerosol inoculation.

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Data availability

Data were deposited in figshare: https://doi.org/10.6084/m9.figshare.25105940. Source data are provided with this paper.

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Acknowledgements

We want to thank Z. Wiener, T. Smith, N. Baird, C. Hutson, F. Atif and I. Damon of the CDC for rapidly sharing the MPXV strain used in this study, A. Chowdhury and D. Douek of the Vaccine Research Center for sharing protein used in the ELISA, and X. Zeng of the United States Army Medical Research Institute of Infectious Diseases for sharing positive control tissues for histology. We would also like to thank B. Moss, P. Earl, E. Haddock, R. Fischer, the RML Institutional Biosafety Committee and the biosafety office for helpful suggestions and support. We would like to thank the animal caretakers for their assistance during the study. We want to thank A. Athman, R. Perry-Gottschalk and A. Mora from the VMA for assisting with image compilation. Lastly, we want to thank N. van Doremalen for helpful feedback on the paper.

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (1ZIAAI001179-01). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. This paper has been deposited as a preprint with bioRxiv under a CC0 license for government authors.

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Author notes

  1. These authors contributed equally: Kyle Rosenke, Vincent J. Munster.

Authors and Affiliations

  1. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA

    Julia R. Port, Jade C. Riopelle, Samuel G. Smith, Franziska K. Kaiser, Matthew C. Lewis, Shane Gallogly, Atsushi Okumura, Trent Bushmaker, Jonathan E. Schulz, Heinz Feldmann, Kyle Rosenke & Vincent J. Munster

  2. Research and Technologies Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA

    Lara Myers & Aaron Carmody

  3. Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA

    Rebecca Rosenke, Jessica Prado-Smith, Brian J. Smith & Greg Saturday

  4. International Center of Excellence in Research (ICER-Mali), University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali

    Sidy Bane

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Contributions

J.R.P. and K.R. designed the studies. J.R.P., J.C.R., S.G.S., F.K.K., M.C.L., S.G., A.O., T.B., J.E.S., R.R., J.P.-S., A.C., S.B., B.J.S. and K.R. performed the experiments. J.R.P., K.R., J.C.R., S.G.S., L.M., F.K.K. and G.S. analysed results. J.R.P., K.R. and V.J.M. wrote the paper. V.J.M. and H.F. secured funding for the study. All co-authors reviewed the paper.

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Correspondence to Kyle Rosenke or Vincent J. Munster.

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Extended data

Extended Data Fig. 1 Lesion formation after inoculation of Mastomys natalensis with MPXV.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using one of the transdermal, rectal, vaginal, or intraperitoneal routes (N = 8; 4 males and 4 females). (a-c) Exemplary skin lesions. (d-f) Exemplary irritation of the vagina and the rectum.

Source data

Extended Data Fig. 2 Representative gating strategy for flow cytometric analysis of splenocytes.

In the first experiment with rectal and transdermal infection, splenocytes were first gated on SSC-A vs FSC-A (a), followed by a Time gate to exclude possible erratic sample flow (b), followed by a single cell gate using FSC-H vs FSC-A (c), which was followed by a dead cell exclusion gate using Fixable Blue vs Time (d). In the second experiment with aerosol infection, counting beads were included and first EDF3excluded from the analysis (e), followed by a lymphocyte gate (f), followed by a single cell gate (g), which was followed by a dead cell and Time gate (h). This population was further analyzed by gating on B cells or T cells using CD19 PE-CF594 vs CD3 FITC as represented in Fig. 4a. CD19+ and CD3+ cells were then further analyzed for expression of Ki-67 R718, Granzyme B APC, MHCII PE, TNFα eF450 and IFNγ PE as represented in Fig. 4e.

Source data

Extended Data Fig. 3 Polyfunctionality of T-cell response after rectal, aerosol, or transdermal inoculation.

M. natalensis were inoculated with MPXV by the rectal, aerosol, or transdermal route. Uninfected age-matched animals served as controls. Splenocytes were analyzed by flow cytometry at day 14. Splenocytes were cultured in vitro for 24 hours in the presence of IL-2. a CD3+ T-cells were then analyzed by intracellular flow cytometry for expression of Ki-67, Granzyme B, TNFα, and IFNγ. Boolean gating was performed. Bar graph depicting median, 95% CI, and individuals. Rectal N = 6, transdermal N = 6, aerosol N = 8. b Comparison of expression of Ki-67, Granzyme B, TNFα, and IFNγ after in vitro culture in the presence of IL-2 alone and when stimulated by MPXV-specific peptides. Rectal N = 6, transdermal N = 6, control N = 11, aerosol N = 8. Bar graph depicting median, 95% CI, and individuals. Two-way ANOVA, followed by Šídák’s multiple comparisons test. P-values indicated where significant.

Source data

Extended Data Fig. 4 Cell infiltration to the lesion sites after transdermal, aerosol, and rectal inoculation.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using one of the transdermal, aerosol, or rectal routes and tissues were collected on day 8 (N = 4). Immunohistochemical staining for CD3 as a marker for T-cells. PAX5 as a marker for B-cells, IBA-1 as a marker for macrophages. Transdermal (skin) (a, b, c), aerosol (nasal turbinates) (j, k, l) & rectal (rectum) (d, e, f) 40x: bar = 200 µm; vaginal (vagina and uterus) (g, h, i) 20x: bar = 500 µm; aerosol (lungs) (m, n, o) 200x: bar = 50 µm.

Source data

Extended Data Fig. 5 Rectal shedding dynamics of individual contact transmission pairs after rectal and transdermal inoculation.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using either the rectal (a) or transdermal (b) route (N = 8; 4 males and 4 females). On day 2, eight donor animals were co-housed with eight naïve sentinels (sex-matched, 2:2 ratio) and co-housed for 12 days. Rectal swabs were collected on days 3, 5, 7, 9, 11, and 14 post-inoculation/-exposure. Median of N = 2 swabs collected per time point (dark continuous = donors, light dotted = sentinels). M = male, F = female.

Source data

Extended Data Fig. 6 Oral shedding dynamics of individual contact transmission pairs after rectal and transdermal inoculation.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using either the rectal (a) or transdermal (b) route (N = 8; 4 males and 4 females). On day 2, eight donor animals were co-housed with eight naïve sentinels (sex-matched, 2:2 ratio) and co-housed for 12 days. Oral swabs were collected on days 3, 5, 7, 9, 11, and 14 post-inoculation/-exposure. Median of N = 2 swabs collected per time point (dark continuous = donors, light dotted = sentinels). M = male, F = female.

Source data

Extended Data Fig. 7 Rectal shedding dynamics of individual contact transmission pairs after rectal and transdermal inoculation.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using the aerosol route and exposure occurred either continuously (a) or was limited to the peak oral shedding phase of the donors (b). (N = 8; 4 males and 4 females). On day 2, eight donor animals were co-housed with eight naïve sentinels (sex-matched, 2:2 ratio) and co-housed for 12 days for continuous exposure. For the limited exposure window, sentinels were exposed between day 3 and 6. Rectal swabs were collected on days 3, 5, 7, 9, 11, and 14- post inoculation/-exposure. Median of N = 2 swabs collected per time point (dark continuous = donors, light dotted = sentinels). M = male, F = female.

Source data

Extended Data Fig. 8 Oral shedding dynamics of individual contact transmission pairs after continues or limited exposure to aerosol inoculated donors.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using the aerosol route and exposure occurred either continuously (a) or was limited to the peak oral shedding phase of the donors (b). (N = 8; 4 males and 4 females). On day 2, eight donor animals were co-housed with eight naïve sentinels (sex-matched, 2:2 ratio) and co-housed for 12 days for continuous exposure. For the limited exposure window, sentinels were exposed between day 3 and 6. Oral swabs were collected on days 3, 5, 7, 9, 11, and 14- post inoculation/-exposure. Median of N = 2 swabs collected per time point (dark continuous = donors, light dotted = sentinels). M = male, F = female.

Source data

Extended Data Fig. 9 Contact transmission in Mastomys natalensis.

M. natalensis were challenged with 105 PFU MPXV (2022 isolate, Clade IIb) using either the transdermal, rectal, or aerosol route (N = 8; 4 males and 4 females). On day 2, eight donor animals were co-housed with eight naïve sentinels (sex-matched, 2:2 ratio) for 12 days. a Oral and rectal swabs were collected on days 3, 5, 7, 9, 11, and 14 post-inoculation/-exposure. Averaged percentage of swabs positive for each group depicted as pie charts. Black = positive PCR result, white = negative PCR result. b, c Correlation between the number of positive rectal and oral donors swab samples and the total of positive sentinel swabs. Median individual values for each cage are depicted, as well as simple linear regression line across all transmission cages. Spearman r values are depicted. Teal = rectal, black = transdermal, and orange = aerosol inoculated donors. d Correlation between the number of all positive donor swabs and all positive sentinel swabs, separated by sex. Median individual values for each cage are depicted, as well as simple linear regression lines across all transmission cages. Spearman r values are depicted. Black = males, pink = females. e M. natalensis were challenged using one of the transdermal, rectal, vaginal, intraperitoneal, or aerosol routes. Viral genetic copies (left) and infectious virus (right) measured in oral, rectal, or urogenital skin swabs on days 1, 3, 5, 7, 9, 11, and 14 post-inoculation. Cumulative shedding (day 1 to day 14) across all routes, separated by sex, calculated as area under the curve (AUC), N = 16. Bar chart, mean and SEM, and individuals are depicted. Light grey = vaginally inoculated females.

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Port, J.R., Riopelle, J.C., Smith, S.G. et al. Infection with mpox virus via the genital mucosae increases shedding and transmission in the multimammate rat (Mastomys natalensis). Nat Microbiol 9, 1231–1243 (2024). https://doi.org/10.1038/s41564-024-01666-1

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