Biology subjects

Jones, T. C.

Publications and source records attributed to Jones, T. C..

3 recordsLinked to original sources

bioRxiv2022

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism

Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.

microbiology↗

bioRxiv2022

Genetic variability, including gene duplication and deletion, in early sequences from the 2022 European monkeypox outbreak

Genome sequences from 47 monkeypox virus infections detected in a German university virology laboratory were analyzed in context of other sequences from the 2022 outbreak and earlier monkeypox genomes. Identical non-synonymous amino acid changes in six genes and the signature of APOBEC editing match other sequences from the European outbreak. Non-synonymous changes that were present in one to three sequences were found in 34 other genes. In sequences from two lesions of one patient, an 856 nucleotide translocation between genome termini resulted in the duplication of an initial 5 gene, and the disruption or complete deletion of four genes near the 3 genome end. Orthopoxvirus genome rearrangements of this nature are known to confer fitness advantages in the face of selection pressure. This change may therefore represent an early virus adaptation in the novel widespread and sustained human-to-human context of the current monkeypox outbreak.

bioinformatics↗

bioRxiv2022

Mapping SARS-CoV-2 antigenic relationships and serological responses

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection. One sentence summaryAntigenic Cartography of SARS-CoV-2 variants reveals amino acid substitutions governing immune escape and immunodominance patterns.

immunology↗