Infection

Mpox virus infection and drug treatment modelled in human skin organoids

Posted on by yun
12
Oct

Abstract

Mpox virus (MPXV) primarily infects human skin to cause lesions. Currently, robust models that recapitulate skin infection by MPXV are lacking. Here we demonstrate that human induced pluripotent stem cell-derived skin organoids are susceptible to MPXV infection and support infectious virus production. Keratinocytes, the predominant cell type of the skin epithelium, effectively support MPXV infection. Using transmission electron microscopy, we visualized the four stages of intracellular virus particle assembly: crescent formation, immature virions, mature virions and wrapped virions. Transcriptional analysis showed that MPXV infection rewires the host transcriptome and triggers abundant expression of viral transcripts. Early treatment with the antiviral drug tecovirimat effectively inhibits infectious virus production and prevents host transcriptome rewiring. Delayed treatment with tecovirimat also inhibits infectious MPXV particle production, albeit to a lesser extent. This study establishes human skin organoids as a robust experimental model for studying MPXV infection, mapping virus–host interactions and testing therapeutics.

This is a preview of subscription content, access via your institution

Access options

/* style specs start */
style{display:none!important}.LiveAreaSection-193358632 *{align-content:stretch;align-items:stretch;align-self:auto;animation-delay:0s;animation-direction:normal;animation-duration:0s;animation-fill-mode:none;animation-iteration-count:1;animation-name:none;animation-play-state:running;animation-timing-function:ease;azimuth:center;backface-visibility:visible;background-attachment:scroll;background-blend-mode:normal;background-clip:borderBox;background-color:transparent;background-image:none;background-origin:paddingBox;background-position:0 0;background-repeat:repeat;background-size:auto auto;block-size:auto;border-block-end-color:currentcolor;border-block-end-style:none;border-block-end-width:medium;border-block-start-color:currentcolor;border-block-start-style:none;border-block-start-width:medium;border-bottom-color:currentcolor;border-bottom-left-radius:0;border-bottom-right-radius:0;border-bottom-style:none;border-bottom-width:medium;border-collapse:separate;border-image-outset:0s;border-image-repeat:stretch;border-image-slice:100%;border-image-source:none;border-image-width:1;border-inline-end-color:currentcolor;border-inline-end-style:none;border-inline-end-width:medium;border-inline-start-color:currentcolor;border-inline-start-style:none;border-inline-start-width:medium;border-left-color:currentcolor;border-left-style:none;border-left-width:medium;border-right-color:currentcolor;border-right-style:none;border-right-width:medium;border-spacing:0;border-top-color:currentcolor;border-top-left-radius:0;border-top-right-radius:0;border-top-style:none;border-top-width:medium;bottom:auto;box-decoration-break:slice;box-shadow:none;box-sizing:border-box;break-after:auto;break-before:auto;break-inside:auto;caption-side:top;caret-color:auto;clear:none;clip:auto;clip-path:none;color:initial;column-count:auto;column-fill:balance;column-gap:normal;column-rule-color:currentcolor;column-rule-style:none;column-rule-width:medium;column-span:none;column-width:auto;content:normal;counter-increment:none;counter-reset:none;cursor:auto;display:inline;empty-cells:show;filter:none;flex-basis:auto;flex-direction:row;flex-grow:0;flex-shrink:1;flex-wrap:nowrap;float:none;font-family:initial;font-feature-settings:normal;font-kerning:auto;font-language-override:normal;font-size:medium;font-size-adjust:none;font-stretch:normal;font-style:normal;font-synthesis:weight style;font-variant:normal;font-variant-alternates:normal;font-variant-caps:normal;font-variant-east-asian:normal;font-variant-ligatures:normal;font-variant-numeric:normal;font-variant-position:normal;font-weight:400;grid-auto-columns:auto;grid-auto-flow:row;grid-auto-rows:auto;grid-column-end:auto;grid-column-gap:0;grid-column-start:auto;grid-row-end:auto;grid-row-gap:0;grid-row-start:auto;grid-template-areas:none;grid-template-columns:none;grid-template-rows:none;height:auto;hyphens:manual;image-orientation:0deg;image-rendering:auto;image-resolution:1dppx;ime-mode:auto;inline-size:auto;isolation:auto;justify-content:flexStart;left:auto;letter-spacing:normal;line-break:auto;line-height:normal;list-style-image:none;list-style-position:outside;list-style-type:disc;margin-block-end:0;margin-block-start:0;margin-bottom:0;margin-inline-end:0;margin-inline-start:0;margin-left:0;margin-right:0;margin-top:0;mask-clip:borderBox;mask-composite:add;mask-image:none;mask-mode:matchSource;mask-origin:borderBox;mask-position:0 0;mask-repeat:repeat;mask-size:auto;mask-type:luminance;max-height:none;max-width:none;min-block-size:0;min-height:0;min-inline-size:0;min-width:0;mix-blend-mode:normal;object-fit:fill;object-position:50% 50%;offset-block-end:auto;offset-block-start:auto;offset-inline-end:auto;offset-inline-start:auto;opacity:1;order:0;orphans:2;outline-color:initial;outline-offset:0;outline-style:none;outline-width:medium;overflow:visible;overflow-wrap:normal;overflow-x:visible;overflow-y:visible;padding-block-end:0;padding-block-start:0;padding-bottom:0;padding-inline-end:0;padding-inline-start:0;padding-left:0;padding-right:0;padding-top:0;page-break-after:auto;page-break-before:auto;page-break-inside:auto;perspective:none;perspective-origin:50% 50%;pointer-events:auto;position:static;quotes:initial;resize:none;right:auto;ruby-align:spaceAround;ruby-merge:separate;ruby-position:over;scroll-behavior:auto;scroll-snap-coordinate:none;scroll-snap-destination:0 0;scroll-snap-points-x:none;scroll-snap-points-y:none;scroll-snap-type:none;shape-image-threshold:0;shape-margin:0;shape-outside:none;tab-size:8;table-layout:auto;text-align:initial;text-align-last:auto;text-combine-upright:none;text-decoration-color:currentcolor;text-decoration-line:none;text-decoration-style:solid;text-emphasis-color:currentcolor;text-emphasis-position:over right;text-emphasis-style:none;text-indent:0;text-justify:auto;text-orientation:mixed;text-overflow:clip;text-rendering:auto;text-shadow:none;text-transform:none;text-underline-position:auto;top:auto;touch-action:auto;transform:none;transform-box:borderBox;transform-origin:50% 50%0;transform-style:flat;transition-delay:0s;transition-duration:0s;transition-property:all;transition-timing-function:ease;vertical-align:baseline;visibility:visible;white-space:normal;widows:2;width:auto;will-change:auto;word-break:normal;word-spacing:normal;word-wrap:normal;writing-mode:horizontalTb;z-index:auto;-webkit-appearance:none;-moz-appearance:none;-ms-appearance:none;appearance:none;margin:0}.LiveAreaSection-193358632{width:100%}.LiveAreaSection-193358632 .login-option-buybox{display:block;width:100%;font-size:17px;line-height:30px;color:#222;padding-top:30px;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-access-options{display:block;font-weight:700;font-size:17px;line-height:30px;color:#222;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-login>li:not(:first-child)::before{transform:translateY(-50%);content:””;height:1rem;position:absolute;top:50%;left:0;border-left:2px solid #999}.LiveAreaSection-193358632 .additional-login>li:not(:first-child){padding-left:10px}.LiveAreaSection-193358632 .additional-login>li{display:inline-block;position:relative;vertical-align:middle;padding-right:10px}.BuyBoxSection-683559780{display:flex;flex-wrap:wrap;flex:1;flex-direction:row-reverse;margin:-30px -15px 0}.BuyBoxSection-683559780 .box-inner{width:100%;height:100%}.BuyBoxSection-683559780 .readcube-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:1;flex-basis:255px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:300px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox-nature-plus{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:100%;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .title-readcube,.BuyBoxSection-683559780 .title-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .title-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .asia-link{color:#069;cursor:pointer;text-decoration:none;font-size:1.05em;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:1.05em6}.BuyBoxSection-683559780 .access-readcube{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;opacity:.8px;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .price-buybox{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;padding-top:30px;text-align:center}.BuyBoxSection-683559780 .price-buybox-to{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center}.BuyBoxSection-683559780 .price-info-text{font-size:16px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-value{font-size:30px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-per-period{font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-from{font-size:14px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .issue-buybox{display:block;font-size:13px;text-align:center;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:19px}.BuyBoxSection-683559780 .no-price-buybox{display:block;font-size:13px;line-height:18px;text-align:center;padding-right:10%;padding-left:10%;padding-bottom:20px;padding-top:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .vat-buybox{display:block;margin-top:5px;margin-right:20%;margin-left:20%;font-size:11px;color:#222;padding-top:10px;padding-bottom:15px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:17px}.BuyBoxSection-683559780 .tax-buybox{display:block;width:100%;color:#222;padding:20px 16px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:NaNpx}.BuyBoxSection-683559780 .button-container{display:flex;padding-right:20px;padding-left:20px;justify-content:center}.BuyBoxSection-683559780 .button-container>*{flex:1px}.BuyBoxSection-683559780 .button-container>a:hover,.Button-505204839:hover,.Button-1078489254:hover,.Button-2496381730:hover{text-decoration:none}.BuyBoxSection-683559780 .readcube-button{background:#fff;margin-top:30px}.BuyBoxSection-683559780 .button-asia{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;margin-top:75px}.BuyBoxSection-683559780 .button-label-asia,.ButtonLabel-3869432492,.ButtonLabel-3296148077,.ButtonLabel-1651148777{display:block;color:#fff;font-size:17px;line-height:20px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center;text-decoration:none;cursor:pointer}.Button-505204839,.Button-1078489254,.Button-2496381730{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;max-width:320px;margin-top:10px}.Button-505204839 .readcube-label,.Button-1078489254 .readcube-label,.Button-2496381730 .readcube-label{color:#069}
/* style specs end */

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MPXV infection in early-stage human skin organoids.
Fig. 2: MPXV infection in late-stage human skin organoids.
Fig. 3: MPXV infection in end-stage human skin organoids.
Fig. 4: Transcriptomic analysis of MPXV-infected organoids.
Fig. 5: MPXV–host interactions and response to tecovirimat treatment.
Fig. 6: MPXV infection and antiviral treatment in skin organoids cultured in ALI.

Data availability

The data supporting the findings of this study are available within the paper, its supplementary information or its source data. RNA sequencing data are publicly available at https://doi.org/10.17026/dans-xj2-hhat. Mpox viral reads were mapped according to the reference genome (accession NC_063383.1). Source data are provided with this paper.

Code availability

The code used for transcriptomics analysis in this study is publicly available at https://doi.org/10.17026/dans-xzc-46u4

References

  1. Gessain, A., Nakoune, E. & Yazdanpanah, Y. Monkeypox. N. Engl. J. Med. 387, 1783–1793 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  2. Lum, F. M. et al. Monkeypox: disease epidemiology, host immunity and clinical interventions. Nat. Rev. Immunol. 22, 597–613 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  3. Thornhill, J. P. et al. Monkeypox virus infection in humans across 16 Countries—April–June 2022. N. Engl. J. Med. 387, 679–691 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  4. Zheng, Q. et al. Projecting the impact of testing and vaccination on the transmission dynamics of the 2022 monkeypox outbreak in the USA. J. Travel Med. 29, taac101 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  5. McCollum, A. M. & Damon, I. K. Human monkeypox. Clin. Infect. Dis. 58, 260–267 (2014).

    Article 
    PubMed 

    Google Scholar 

  6. Adler, H. et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect. Dis. 22, 1153–1162 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  7. Girometti, N. et al. Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis. Lancet Infect. Dis. 22, 1321–1328 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  8. Ogoina, D. et al. Clinical course and outcome of human monkeypox in Nigeria. Clin. Infect. Dis. 71, e210–e214 (2020).

    Article 
    PubMed 

    Google Scholar 

  9. Boesecke, C., Monin, M. B., van Bremen, K., Schlabe, S. & Hoffmann, C. Severe monkeypox-virus infection in undiagnosed advanced HIV infection. Infection 50, 1633–1634 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  10. Rosa, R. B. et al. In vitro and in vivo models for monkeypox. iScience 26, 105702 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  11. Lee, J. et al. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature 582, 399–404 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  12. Jung, S. Y. et al. Wnt-activating human skin organoid model of atopic dermatitis induced by Staphylococcus aureus and its protective effects by Cutibacterium acnes. iScience 25, 105150 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  13. Ma, J. et al. Establishment of human pluripotent stem cell-derived skin organoids enabled pathophysiological model of SARS-CoV-2 infection. Adv. Sci. 9, e2104192 (2022).

    Article 

    Google Scholar 

  14. Ma, J. et al. Application of an iPSC-derived organoid model for localized scleroderma therapy. Adv. Sci. 9, e2106075 (2022).

    Article 

    Google Scholar 

  15. Ramovs, V. et al. Characterization of the epidermal-dermal junction in hiPSC-derived skin organoids. Stem Cell Rep. 17, 1279–1288 (2022).

    Article 
    CAS 

    Google Scholar 

  16. Lee, J. et al. Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells. Nat. Protoc. 17, 1266–1305 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  17. Weisberg, A. S. et al. Enigmatic origin of the poxvirus membrane from the endoplasmic reticulum shown by 3D imaging of vaccinia virus assembly mutants. Proc. Natl Acad. Sci. USA 114, E11001–E11009 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  18. Yang, Z., Bruno, D. P., Martens, C. A., Porcella, S. F. & Moss, B. Simultaneous high-resolution analysis of vaccinia virus and host cell transcriptomes by deep RNA sequencing. Proc. Natl Acad. Sci. USA 107, 11513–11518 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  19. Wilson, S. R. et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155, 285–295 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  20. Lian, L. H., Milora, K. A., Manupipatpong, K. K. & Jensen, L. E. The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36γ. J. Invest. Dermatol. 132, 1346–1353 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  21. Subramanian, A. et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nat. Med. 28, 1706–1714 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  22. Altindis, M., Puca, E. & Shapo, L. Diagnosis of monkeypox virus—an overview. Travel Med. Infect. Dis. 50, 102459 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  23. Suner, C., et al. Viral dynamics in patients with monkeypox infection: a prospective cohort study in Spain. Lancet Infect. Dis. 23, 445–453 (2022).

  24. Gupta, A. K., Talukder, M., Rosen, T. & Piguet, V. Differential diagnosis, prevention, and treatment of mpox (Monkeypox): a review for dermatologists. Am. J. Clin. Dermatol. 24, 541–556 (2023).

  25. Holley, J. et al. Engineered promoter-switched viruses reveal the role of poxvirus maturation protein A26 as a negative regulator of viral spread. J. Virol. 95, e0101221 (2021).

    Article 
    PubMed 

    Google Scholar 

  26. Li, P. et al. Recapitulating infection, thermal sensitivity and antiviral treatment of seasonal coronaviruses in human airway organoids. EBioMedicine 81, 104132 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  27. Li, P. et al. Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver-derived organoids. Sci. Adv. 8, eabj5908 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  28. Yin, Y. et al. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antivir. Res 123, 120–131 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  29. El-Jesr, M., Teir, M. & Maluquer de Motes, C. Vaccinia virus activation and antagonism of cytosolic DNA sensing. Front. Immunol. 11, 568412 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  30. Albarnaz, J. D. et al. Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat. Microbiol. 7, 154–168 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  31. Yang, G. et al. An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J. Virol. 79, 13139–13149 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  32. Grosenbach, D. W. et al. Oral tecovirimat for the treatment of smallpox. N. Engl. J. Med. 379, 44–53 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  33. Sherwat, A., Brooks, J. T., Birnkrant, D. & Kim, P. Tecovirimat and the treatment of monkeypox—past, present, and future considerations. N. Engl. J. Med. 387, 579–581 (2022).

    Article 
    PubMed 

    Google Scholar 

  34. Desai, A. N. et al. Compassionate use of tecovirimat for the treatment of monkeypox infection. JAMA 328, 1348–1350 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  35. Frenois-Veyrat, G. et al. Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations. Nat. Microbiol 7, 1951–1955 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  36. Chinsangaram, J. et al. Pharmacokinetic comparison of a single oral dose of polymorph form i versus form V capsules of the antiorthopoxvirus compound ST-246 in human volunteers. Antimicrob. Agents Chemother. 56, 3582–3586 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  37. Mondi, A. et al. Clinical experience with use of oral tecovirimat or intravenous cidofovir for the treatment of monkeypox in an Italian reference hospital. J. Infect. 86, 66–117 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  38. Warner, B. M. et al. In vitro and in vivo efficacy of tecovirimat against a recently emerged 2022 monkeypox virus isolate. Sci. Transl. Med. 14, eade7646 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  39. O’Laughlin, K. et al. Clinical use of tecovirimat (Tpoxx) for treatment of monkeypox under an investigational new drug protocol—United States, May–August 2022. Morb. Mortal. Wkly Rep. 71, 1190–1195 (2022).

    Article 

    Google Scholar 

  40. Govind, A. et al. Severe mpox infections in people with uncontrolled human immunodeficiency virus (HIV). Clin. Infect. Dis. 76, 1843–1846 (2023).

    Article 
    PubMed 

    Google Scholar 

  41. McLean, J. et al. Tecovirimat treatment of people with HIV during the 2022 mpox outbreak: a retrospective cohort study. Ann. Intern. Med. 176, 642–648 (2023).

    Article 
    PubMed 

    Google Scholar 

  42. Hutson, C. L. & Damon, I. K. Monkeypox virus infections in small animal models for evaluation of anti-poxvirus agents. Viruses 2, 2763–2776 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  43. Xuan, D. T. M. et al. Comparison of transcriptomic signatures between monkeypox-infected monkey and human cell lines. J. Immunol. Res 2022, 3883822 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  44. Zhang, M. et al. Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange–Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc. Natl Acad. Sci. USA 111, E5383–E5392 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  45. Bajanca, F., Luz, M., Duxson, M. J. & Thorsteinsdottir, S. Integrins in the mouse myotome: developmental changes and differences between the epaxial and hypaxial lineage. Dev. Dyn. 231, 402–415 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  46. Chen, S., Zhou, Y., Chen, Y. & Gu, J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  47. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  48. UCSC Genome Browser on Human (GRCh38/hg38). UCSC https://genome.ucsc.edu/cgi-bin/hgTracks?db=hub_3471181_GCF_014621545.1 (2023).

  49. Danecek, P. et al. Twelve years of SAMtools and BCFtools. Gigascience 10, giab008 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

Download references

Acknowledgements

We thank our colleagues at the hiPSC Hotel, Leiden University Medical Center, for providing hiPS cell lines. This work was supported by a VIDI grant (grant number 91719300) from the Dutch Research Council (NWO) to Q.P., and by the Novo Nordisk Foundation Center for Stem Cell Medicine supported by the Novo Nordisk Foundation, Denmark (grant number NNF21CC0073729) to K.R. K.R. is Chargé de Recherche at the Institut National de la Santé et de la Recherche Médicale (INSERM).

Author information

Author notes

  1. These authors contributed equally: Pengfei Li, Spyridon T. Pachis.

  2. These authors jointly supervised this work: Karine Raymond, Qiuwei Pan.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

    Pengfei Li, Guige Xu, Annemarie C. de Vries, Marco J. Bruno, Maikel P. Peppelenbosch & Qiuwei Pan

  2. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands

    Spyridon T. Pachis & Karine Raymond

  3. The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands

    Spyridon T. Pachis & Karine Raymond

  4. Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

    Rick Schraauwen

  5. Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

    Roberto Incitti & Intikhab Alam

  6. University of Grenoble Alpes, CEA, Inserm, IRIG, UA13 BGE, Biomics, Grenoble, France

    Karine Raymond

Authors

  1. Pengfei Li
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  2. Spyridon T. Pachis
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  3. Guige Xu
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  4. Rick Schraauwen
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  5. Roberto Incitti
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  6. Annemarie C. de Vries
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  7. Marco J. Bruno
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  8. Maikel P. Peppelenbosch
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  9. Intikhab Alam
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  10. Karine Raymond
    View author publications

    You can also search for this author in
    PubMed Google Scholar

  11. Qiuwei Pan
    View author publications

    You can also search for this author in
    PubMed Google Scholar

Contributions

P.L., S.T.P., K.R. and Q.P. conceptualized the project. G.X., R.S., R.I. and I.A. developed the methodology. P.L., S.T.P., K.R., A.C.V. and Q.P. conducted the investigations. P.L., S.T.P., R.I., I.A. and K.R. conducted formal analysis. P.L., S.T.P., K.R. and Q.P. wrote the original draft. A.C.V., M.J.B. and M.P.P. reviewed and edited the manuscript. K.R. and Q.P. acquired funding.

Corresponding authors

Correspondence to
Karine Raymond or Qiuwei Pan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Microbiology thanks David Ulaeto, Karl Koehler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Quantification of infectious viral titers in organoids at 1 hour and 7 days post-inoculation.

a, Infectious viral titers of organoids after 55 days of differentiation (n = 2 biological replicates). b, Infectious viral titers of organoids after 90 days of differentiation (n = 2 biological replicates).

Source data

Extended Data Fig. 2 Transmission electron microscopy analysis of skin organoids.

(a) and (b) show destroyed organelles, degrading cytoplasm (black arrowheads), and irregular chromatin condensation, alteration of nucleus membrane (red frame) in end-stage skin organoids. c, Representative skin characteristics was visualized in ALI-skin organoid, including skin dermis, collagen fibers, keratin bundles, desmosomes, and basement membrane.

Extended Data Fig. 3 Gene ontology analysis of skin organoids upon MPXV infection.

Top 30 significantly up- and down-regulated pathways by gene ontology analysis at day 7 post-inoculation, compared with the uninfected group. Three independent skin organoids were used in each group, P value determined by DESeq2.

Extended Data Fig. 4 Transcriptomic analysis of skin organoids upon 7 days infection, compared with uninfected or 1 h infection group.

a, Significantly up- and down-regulated genes by volcano plot analysis at day 7 post-inoculation, compared with the uninfected group. P value determined by DESeq2. b-e, Gene set enrichment analysis (GSEA) of KEGG pathways including autophagy_other (HSA04136), apoptosis (HSA04210), necroptosis (HSA04217), and ferroptosis (HSA04216) in skin organoids.

Extended Data Fig. 5 Total reads and mapped MPXV reads in different skin organoid groups by bulk-RNA sequencing.

Skin organoids were either not infected (control), infected for 1 hour (1 hour), infected for 7 days (7 day) or infected and treated with 5 μM of tecovirimat for 7 days (Tecovirimat), n = 3 per group. Data are presented as means of biological replicates ± SEM.

Source data

Extended Data Fig. 6 Low magnification images of the mpox virion (green) and integrin β4 subunit (red) immunostaining depicted in Fig. 6g.

White * indicates the potential autofluorescent signal of the cornified layer of the epithelium, which is distinguishable from the specific staining of mpox virion observed in the conditions where MPXV had been inoculated.

Supplementary information

Supplementary Information

Supplementary table and methods.

Reporting Summary

Source data

Source Data Fig. 1

qPCR and plaque assay source data.

Source Data Fig. 2

qPCR and plaque assay source data.

Source Data Fig. 3

qPCR and plaque assay source data.

Source Data Fig. 5

qPCR and statistical source data.

Source Data Fig. 6

qPCR and statistical source data.

Source Data Extended Data Fig. 1

Plaque assay source data.

Source Data Extended Data Fig. 5

RNA-sequencing mapped reads source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, P., Pachis, S.T., Xu, G. et al. Mpox virus infection and drug treatment modelled in human skin organoids.
Nat Microbiol (2023). https://doi.org/10.1038/s41564-023-01489-6

Download citation

  • Received: 03 February 2023

  • Accepted: 04 September 2023

  • Published: 12 October 2023

  • DOI: https://doi.org/10.1038/s41564-023-01489-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

yun

Leave a Reply

Your email address will not be published. Required fields are marked *