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Erdmann, M.

Publications and source records attributed to Erdmann, M..

7 recordsLinked to original sources

High-accuracy prediction of 5-year progression-free melanoma survival using spatial proteomics and few-shot learning on primary tissue

Emerging techniques in imaging-based spatial proteomics (ISP) enable in-depth insights into the architecture and protein abundance of tissue(s). Explainable machine learning (xML) models promise to yield substantial advances in ISP data-based diagnosis and prognosis. However, a clinical application of these new possibilities predicting the course of a tumor has not been suggested yet. Here, we use a few-shot learning workflow on histological multi-antigen images to predict 5-year progression-free survival (PFS) in melanoma. We address the problem of a relatively small cohort (n = 22), by utilizing a pre-trained convolutional neural network (CNN) model, which we further pre-train on a proxy task for which more samples were available (n = 39) before fine-tuning for PFS prediction. Our approach yielded a model achieving an accuracy of more than 90%, outperforming baseline models trained on clinical data by around 10%. Using an xML technique, we identified immune infiltration and proteins associated with tumor progression as crucial predictors. This indicated that our models PFS predictions are not only highly accurate but also grounded in a relevant biological background.

bioinformatics↗

Spatial cell graph analysis reveals skin tissue organization characteristic for cutaneous T cell lymphoma

Cutaneous T cell lymphomas (CTCLs) are non-Hodgkin lymphomas caused by malignant T cells which migrate to the skin. The cancerous T cells lead to rash-like lesions which can be difficult to distinguish from inflammatory skin conditions like atopic dermatitis (AD) and psoriasis (PSO). To characterize CTCL in comparison to these differential diagnoses, we carried out multi-antigen imaging on 69 skin tissue samples (21 CTCL, 23 AD, 25 PSO). The resulting spatially resolved protein abundance maps were then analyzed via scoring functions to quantify heterogeneity of the individual cells neighborhoods within spatial graphs inferred from the cells positions in the tissue samples (available as a Python package at https://github.com/bionetslab/SHouT). Our analyses reveal several characteristic patterns of skin tissue organization in CTCL, including a combination of increased local entropy and egophily as characteristic properties of spatial T cell neighborhoods in CTCL as compared to AD and PSO. These results could not only pave the way for high-precision diagnosis of CTCL, but may also facilitate further insights into cellular disease mechanisms.

bioinformatics↗

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on -dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of -dystroglycan (-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of -DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant -DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virus in vitro. This study establishes soluble recombinant -DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.

microbiology↗

Recombinant SARS-CoV-2 lacking initiating and internal methionine codons within ORF10 is attenuated in vivo

SARS-CoV-2 has been proposed to encode ORF10 as the 3 terminal gene in the viral genome. However, the potential role and even existence of a functional ORF10 product has been the subject of debate. There are significant structural features in the viral genomic RNA that could, by themselves, explain the retention of the ORF10 nucleotide sequences without the need for a functional protein product. To explore this question further we made two recombinant viruses, firstly a control virus (WT) based on the genome sequence of the original Wuhan isolate and with the inclusion of the early D614G mutation in the Spike protein. We also made a second virus, identical to WT except for two additional changes that replaced the initiating ORF10 start codon and an internal methionine codon for stop codons (ORF10KO). Here we show that the two viruses have apparently identical growth kinetics in a VeroE6 cell line that over expresses TMPRSS2 (VTN cells). However, in A549 cells over expressing ACE2 and TMPRSS2 (A549-AT cells) the ORF10KO virus appears to have a small growth rate advantage. Growth competition experiments were used whereby the two viruses were mixed, passaged in either VTN or A549-AT cells and the resulting output virus was sequenced. We found that in VTN cells the WT virus quickly dominated whereas in the A549-AT cells the ORF10KO virus dominated. We then used a hamster model of SARS-CoV-2 infection and determined that the ORF10KO virus has attenuated pathogenicity (as measured by weight loss). We found an almost 10-fold reduction in viral titre in the lower respiratory tract for ORF10KO vs WT. In contrast, the WT and ORF10KO viruses had similar titres in the upper respiratory tract. Sequencing of viral RNA in the lungs of hamsters infected with ORF10KO virus revealed that this virus frequently reverts to WT. Our data suggests that the retention of a functional ORF10 sequence is highly desirable for SARS-CoV-2 infection of hamsters and affects the viruss ability to propagate in the lower respiratory tract.

microbiology↗

SARS-CoV-2 NSP12 associates with the TRiC complex and the P323L substitution is a host adaption.

SARS-CoV-2 emerged into the human population in late 2019 and human to human transmission has dominated the evolutionary landscape and driven the selection of different lineages. The first major change that resulted in increased transmission was the D614G substitution in the spike protein. This was accompanied by the P323L substitution in the viral RNA dependent RNA polymerase (RdRp) (NSP12). Together, with D614G these changes are the root of the predominant global SARS-CoV-2 landscape. Here, we found that NSP12 formed an interactome with cellular proteins. The functioning of NSP12 was dependent on the T-complex protein Ring Complex, a molecular chaperone. In contrast, there was differential association between NSP12 variants and components of a phosphatase complex (PP2/PP2A and STRN3). Virus expressing NSP12L323 was less sensitive to perturbations in PP2A and supports the paradigm that ongoing genotype to phenotype adaptation of SARS- CoV-2 in humans is not exclusively restricted to the spike protein.

microbiology↗

Development of SARS-CoV-2 replicons for the ancestral virus and variant of concern Delta for antiviral screening.

SARS-CoV-2 is the aetiologic agent of COVID-19 and the associated ongoing pandemic. As the pandemic has progressed, Variants of Concern (VOC) have emerged with lineage defining mutations. Using a SARS-CoV-2 reverse genetic system, based on transformation associated recombination in yeast, a series of replicons were produced for the ancestral Wuhan virus and the SARS-CoV-2 VOC Delta in which different combinations of the Spike, membrane, ORF6 and ORF7a coding sequences were replaced with sequences encoding the selectable marker puromycin N-acetyl transferase and reporter proteins (Renilla luciferase, mNeonGreen and mScarlet). Replicon RNAs were replication competent in African green monkey kidney (Vero E6) derived cells and a range of human cell lines, with a Vero E6 cell line expressing ACE2 and TMPRSS2 showing much higher transfection efficiency and overall levels of Renilla luciferase activity. The replicons could be used for transient gene expression studies, but cell populations that stably maintained the replicons could not be propagated. Replication of the transiently expressed replicon RNA genomes was sensitive to remedesivir, providing a system to dissect the mechanism of action of antiviral compounds.

microbiology↗

Rapid selection of P323L in the SARS-CoV-2 polymerase (NSP12) in humans and non-human primate models and confers a large plaque phenotype

The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

microbiology↗