Unknown,Transcriptomics,Genomics,Proteomics

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CYP19A1 mediated sex hormone metabolism promotes severe disease outcome in SARS-CoV-2 infected male golden hamsters

ABSTRACT: Male sex belongs to one of the risk factors for severe COVID-19 outcome. However, underlying mechanisms that could affect sex dependent disease outcome are yet unknown. Here, we identified the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (alias aromatase) as a host factor that contributes to worsened disease outcome in male hamsters. SARS-CoV-2 infection increases CYP19A1 transcription most prominently in the lungs of male animals, which correlates with reduced circulating testosterone and increased circulating estradiol levels. Dysregulated sex hormone levels in male golden hamsters are associated with reduced lung function compared to females. Treatment of SARS-CoV-2 infected hamsters with letrozole, a clinically approved CYP19A1 inhibitor, supported recovery of dysregulated sex hormone levels and was associated with improved lung function in male but not female animals compared to placebo controls. Whole-lung transcriptome analysis in letrozole treated versus placebo treated control groups revealed key pathways associated with improved lung health in males. To seek translation of these findings into humans, we analyzed autopsy-derived lung samples of COVID-19 cases from three independent study sites. We found that CYP19A1 transcription and protein expression is strongly elevated in the lungs of men who died with COVID-19 as compared to females or non-COVID-19 controls. Our findings highlight the role of the lung as a yet unrecognized but critical organ involved in metabolic responses against respiratory virus infections. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may pose a new therapeutic strategy to reduce poor long-term COVID-19 outcome.

INSTRUMENT(S): NextSeq 550

ORGANISM(S): Mesocricetus auratus

SUBMITTER: Daniel Wibberg

PROVIDER: E-MTAB-11162 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Translating findings from animal models to human disease is essential for dissecting disease mechanisms, developing and testing precise therapeutic strategies. The coronavirus disease 2019 (COVID-19) pandemic has highlighted this need, particularly for models showing disease severity-dependent immune responses. Single-cell transcriptomics (scRNAseq) is well poised to reveal similarities and differences between species at the molecular and cellular level with unprecedented resolution. However, computational methods enabling detailed matching are still scarce. Here, we provide a structured scRNAseq-based approach that we applied to scRNAseq from blood leukocytes originating from humans and hamsters affected with moderate or severe COVID-19. Integration of COVID-19 patient data with two hamster models that develop moderate (Syrian hamster, Mesocricetus auratus) or severe (Roborovski hamster, Phodopus roborovskii) disease revealed that most cellular states are shared across species. A neural network-based analysis using variational autoencoders quantified the overall transcriptomic similarity across species and severity levels, showing highest similarity between neutrophils of Roborovski hamsters and severe COVID-19 patients, while Syrian hamsters better matched patients with moderate disease, particularly in classical monocytes. We further used transcriptome-wide differential expression analysis to identify which disease stages and cell types display strongest transcriptional changes. Consistently, hamster’s response to COVID-19 was most similar to humans in monocytes and neutrophils. Disease-linked pathways found in all species specifically related to interferon response or inhibition of viral replication. Analysis of candidate genes and signatures supported the results. Our structured neural network-supported workflow could be applied to other diseases, allowing better identification of suitable animal models with similar pathomechanisms across species.

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CYP19A1 mediated sex hormone metabolism promotes severe disease outcome in SARS-CoV-2 infected male golden hamsters

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