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| Status |
Public on Feb 08, 2022 |
| Title |
Transcriptional atlas of the cytokine drivers and cellular contributors mediating enhanced SARS-CoV-2 lung pathology in hamsters after non-protective immunization |
| Organism |
Mesocricetus auratus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Since December 2019, the novel human Coronavirus SARS-CoV-2 has spread globally, causing millions of deaths. Unprecedented efforts have enabled development and authorization of a range of vaccines, which reduce transmission rates and confer protection against the associated disease COVID-19. These vaccines are conceptually diverse, including e.g. classical adjuvanted whole-inactivated virus, viral vectors, and mRNA vaccines. We have analysed two prototypic model vaccines, the strongly TH1-biased measles vaccine-derived candidate MeVvac2-SARS2-S(H) and a TH2-biased Alum-adjuvanted, non-stabilized Spike protein side-by-side, for their ability to protect Syrian hamsters upon challenge with a low-passage SARS-CoV-2 patient isolate. The MeVvac2-SARS2-S(H) vaccine protected the hamsters from severe disease. In contrast, the protein vaccine induced vaccine-associated enhanced respiratory disease (VAERD) with massive infiltration of eosinophils into the lungs. Global RNA-Seq analysis of hamster lungs revealed reduced viral RNA and less host dysregulation in MeVvac2-SARS2-S(H) vaccinated animals, while S protein vaccination triggered enhanced host gene dysregulation when compared to unvaccinated control animals. Of note, mRNAs encoding the major eosinophil attractant CCL-11, the TH2 response-driving cytokine IL-19, as well as TH2-cytokines IL-4, IL-5, and IL-13 were exclusively up-regulated in the lungs of S protein vaccinated animals, consistent with previously described VAERD induced by RSV vaccine candidates. IL-4, IL-5, and IL-13 were also up-regulated in S-specific splenocytes after protein vaccination. Using scRNA-Seq, T cells and innate lymphoid cells were identified as the source of these cytokines, while CCL11 and IL-19 mRNAs was found in interstitial macrophages displaying an activated phenotype. Interestingly, the amount of viral reads in this macrophage population correlated with the abundance of Fc-receptor reads. These findings suggest that VAERD is triggered by induction of TH2-type helper cells secreting IL-4, IL-5, and IL-13, together with stimulation of macrophages dependent on Fc-receptor mediated uptake of virus complexed with non-neutralizing antibodies. Via this mechanism, uncontrolled eosinophil recruitment to the infected tissue occurs, a hallmark of VAERD immunopathogenesis. These effects could effectively be treated using dexamethasone and were not observed in animals vaccinated with MeVvac2-SARS2-S(H). Taken together, our data validate the potential for, and identify the transcriptional mediators that underlie VAERD and their cellular origins, in the context of protein-based TH2-biased COVID-19 vaccines. Dexamethasone, which is already in use for treatment of severe COVID-19, may alleviate such VAERD, but in-depth scrutiny of any next-generation protein-based vaccine candidates is required, prior and after their regulatory approval.
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| Overall design |
To identify determinants underlying the differential protection or pathology arising from TH1- or TH2-biased vaccination approaches, we performed RNA-Seq profiling of hamster lung tissue. Lung transcriptomes from SARS-CoV-2 infected hamsters were compared to infected animals previously immunized with either TH1- or TH2-biased vaccines. We subjected RNA of four animals per group (four groups) to NextSeq 550 Illumina RNAseq using a single-end 86 bp setting.
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| Contributor(s) |
Ebenig A, Muraleedharan S, Kazmierski J, Todt D, Auste A, Anzaghe M, Gömer A, Postmus D, Gogesch P, Niles M, Plesker R, Miskey C, Serra MG, Breithaupt A, Hörner C, Kruip C, Ehmann R, Ivics Z, Waibler Z, Pfaender S, Wyler E, Landthaler M, Kupke A, Nouailles G, Goffinet C, Brown RJ, Mühlebach MD |
| Citation(s) |
35952673 |
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| Submission date |
Feb 01, 2022 |
| Last update date |
Aug 16, 2022 |
| Contact name |
Daniel Todt |
| E-mail(s) |
daniel.todt@rub.de
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| Phone |
+492343222463
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| Organization name |
Ruhr University Bochum
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| Department |
Molecular & Medical Virology
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| Street address |
Universitätsstr. 150
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| City |
Bochum |
| ZIP/Postal code |
44801 |
| Country |
Germany |
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| Platforms (1) |
| GPL29592 |
NextSeq 550 (Mesocricetus auratus) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA802668 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE195939_RAW.tar |
20.3 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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