Faehnrich, A. | bioRxiv Science

bioRxiv2024

scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome

Post-COVID syndrome (PCS) currently affects approximately 3-17% of people following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has the potential to become a significant global health burden. PCS presents with various symptoms, and methods for improved PCS assessment are presently developed to guide therapy. Nevertheless, there are few mechanistic insights and treatment options. Here, we performed single-cell RNA transcriptomics on nasal biopsies from 33 patients suffering from PCS with mild, moderate, or severe symptoms. We identified 17 different cell clusters representing 12 unique cell populations, including all major epithelial cell types of the conducting airways and basal, secretory, and ciliated cells. Severe PCS was associated with decreased numbers of ciliated cells and the presence of immune cells. Ensuing inflammatory signaling upregulated TGF{beta} and induced an epithelial-mesenchymal transition, which led to the high abundance of basal cells and a mis-stratified epithelium. We confirmed the results in vitro using an air-liquid interface culture and validated TNF as the causal inflammatory cytokine. In summary, our results show that one mechanism for sustained PCS is not through continued viral load, but through the presence of immune cells in nasal tissue leading to impaired mucosal barrier function and repeated infections. These findings could be further explored as a therapeutic option akin to other chronic inflammatory diseases by inhibiting the TNF-TGF{beta} axis, restoring the nasal epithelium, and reducing respiratory tract-related infections.

genomics↗

bioRxiv2019

A personal and population-based Egyptian genome reference

The human genome is composed of chromosomal DNA sequences consisting of bases A, C, G and T - the blueprint to implement the molecular functions that are the basis of every individuals life. Deciphering the first human genome was a consortium effort that took more than a decade and considerable cost. With the latest technological advances, determining an individuals entire personal genome with manageable cost and effort has come within reach. Although the benefits of the all-encompassing genetic information that entire genomes provide are manifold, only a small number of de novo assembled human genomes have been reported to date 1-3, and few have been complemented with population-based genetic variation 4, which is particularly important for North Africans who are not represented in current genome-wide data sets 5-7. Here, we combine long- and short-read whole-genome next-generation sequencing data with recent assembly approaches into the first de novo assembly of the genome of an Egyptian individual. The resulting assembly demonstrates well-balanced quality metrics and is complemented with high-quality variant phasing via linked reads into haploblocks, which we can associate with gene expression changes in blood. To construct an Egyptian genome reference, we further assayed genome-wide genetic variation occurring in the Egyptian population within a representative cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genetic studies and corresponding genome references. The Egyptian genome reference represents a comprehensive population data set based on a high-quality personal genome. It is a proof of concept to be considered by the many national and international genome initiatives underway. More importantly, we anticipate that the Egyptian genome reference will be a valuable resource for precision medicine targeting the Egyptian population and beyond.

genetics↗