Global translational reprogramming in <i>Trichophyton mentagrophytes</i>-infected keratinocytes.
This study maps the translational landscape of keratinocytes during fungal infection, revealing extensive regulatory mechanisms that could inform future research.
Where it sits
this study against the rest of the survodutide (bi 456906) corpusSummary and findings
This study investigated the translational and transcriptional responses of human keratinocytes to infection by Trichophyton mentagrophytes. It identified 3,189 differentially expressed genes and 295 differentially translated genes, highlighting significant post-transcriptional regulation. The research offers insights into the translational landscape during fungal infection.
Abstract
Dermatophytosis afflicts approximately 25% of the global population, representing a critical public health burden. <i>Trichophyton mentagrophytes</i> (<i>T. mentagrophytes</i>), a predominant zoonotic dermatophyte, is a significant contributor to disease morbidity. While the transcriptomic response of keratinocytes-the primary barrier of the skin-to <i>T. mentagrophytes</i> infection is well characterized, the genome-wide translational regulatory mechanisms remain unknown. Here, we employed parallel ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) to dissect the genome-wide transcriptional and translational landscape of human keratinocytes during <i>T. mentagrophytes</i> infection. Our analysis revealed extensive but distinct reprogramming at both transcriptional (3,189 differentially expressed genes) and translational (295 differentially translated genes) levels, with only minimal overlap (5.8% of upregulated genes and 0.8% of the downregulated genes), indicating prevalent post-transcriptional control. We further identified and characterized a vast non-canonical translatome, including 17,564 upstream ORFs (uORFs), 188,357 downstream ORFs (dORFs), and 185,704 lncRNA-derived ORFs (lncORFs). Strikingly, both translatable uORFs and dORFs were associated with significantly enhanced translation efficiency (TE) of their host genes, a phenomenon conserved under infection. Moreover, we demonstrated that miRNAs coordinately repress target gene expression at both transcriptional and translational levels. Functional interactions revealed that the presence of translated uORFs or dORFs could significantly attenuate miRNA-mediated TE suppression. This study provides the first comprehensive map of the keratinocyte translatome during fungal infection, establishing uORFs and dORFs as critical dual-layer regulators in the host anti-fungal defense.
Background
This paper addresses the genomic and translational responses of keratinocytes to Trichophyton mentagrophytes infection, a common dermatophyte affecting a significant portion of the global population. Prior research has characterized the transcriptomic response, but the translational regulatory mechanisms remain largely unexplored. Understanding these mechanisms is crucial for elucidating the host's defense strategies against fungal infections.
Methods
The study utilized parallel ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) to analyze the responses of human keratinocytes during infection. The population consisted of human keratinocytes exposed to T. mentagrophytes. The analysis focused on both transcriptional and translational levels, identifying differentially expressed and translated genes.
Results
The primary endpoint revealed 3,189 differentially expressed genes and 295 differentially translated genes. The study found that only 5.8% of upregulated genes and 0.8% of downregulated genes overlapped, indicating a significant degree of post-transcriptional regulation. Additionally, a large number of upstream and downstream ORFs were identified, suggesting complex regulatory mechanisms.
Interpretation
The findings contribute to the understanding of keratinocyte responses to fungal infection, highlighting the importance of translational regulation. While the statistical significance of the results is clear, the clinical implications remain uncertain without direct evidence of functional outcomes. Limitations include the lack of longitudinal data and potential confounding factors not addressed in the study.
Key findings
- 3,189 differentially expressed genes identified.
- 295 differentially translated genes identified.
- 5.8% of upregulated genes and 0.8% of downregulated genes overlapped.
- 17,564 upstream ORFs (uORFs) identified.
- 188,357 downstream ORFs (dORFs) identified.
- 185,704 lncRNA-derived ORFs (lncORFs) identified.
Limitations
- Not reported in abstract.
- Lack of longitudinal data.
- Potential confounding factors not addressed.