Biology subjects

Iliopoulou, E.

Publications and source records attributed to Iliopoulou, E..

4 recordsLinked to original sources

bioRxiv2024

Correlative humoral and cellular immunity to genetically attenuated malaria parasites in humans

Malaria caused by Plasmodium falciparum remains one of the major infectious diseases with a high burden in Sub-Saharan Africa. In spite of the advancements made in vaccine development and implementation in endemic countries, sterile and durable protection has not been achieved. Recently, we have shown the superior protective capacity of whole sporozoites attenuated to arrest late but not early during the liver stage development in a controlled human malaria infection study. Here we report the breadth of antigens targeted by hitherto understudied parasite liver stage immunity and convey the coherence between humoral and cellular immunity observed in our clinical study. Our findings uncover the underlying immunogenic differences between early- and late-liver stage arresting parasites and identify key liver-stage antigens for future vaccine development focused on inducing sterile immunity to malaria.

immunology↗

bioRxiv2024

First report of astroviruses in Tanzanian bats

Emerging and re-emerging infectious diseases have posed significant global health threats, with many attributed to zoonotic RNA viruses. These pathogens can, under some conditions, cross species barriers, facilitating transmission from animal hosts to humans. Bats, characterised by unique physiological and ecological features, and remarkable species diversity, are recognized to host numerous viruses with cross-species transmission potential. This study aimed to investigate the presence of RNA viruses from a broad diversity of Tanzanian bats while valorising archived biological samples. RNA was extracted from 125 samples (28 faeces and 97 oral swabs) of 17 bat species, followed by PCR amplification targeting five distinct viral genera (Filovirus, Coronavirus, Hantavirus, Paramyxovirus and Astrovirus). Overall, 1.6 % (3/125) of the samples from two bat species (Scotophilus dinganii and Miniopterus fraterculus) tested positive for astrovirus, with the coinfection of one bat with two AstV strains. No samples tested positive for Filovirus, Coronavirus, Hantavirus and Paramyxovirus. Phylogenetic analysis based on RNA-dependent RNA polymerase sequences revealed these sequences are respectively clustering with astroviruses detected in other bat species from the genus Scotophilus from East Asia and with astroviruses detected in Miniopterus bats from Africa and Asia. Altogether, these results are the first report of astroviruses in Tanzanian bats.

molecular biology↗

bioRxiv2023

Extensive Loss and Gain of Conserved Non-Coding Elements during Early Teleost Evolution

Conserved Non-coding Elements (CNE) in vertebrates are enriched around transcription factor loci associated with development. However, loss and rapid divergence of CNEs has been reported in teleost fish, albeit taking only few genomes into consideration. Taking advantage of the recent increase in high-quality teleost genomes, we focus on studying the evolution of teleost CNEs, carrying out targeted genomic alignments and comparisons within the teleost phylogeny to detect CNEs and reconstruct the ancestral teleost CNE repertoire. This teleost-centric approach confirms previous observations of extensive vertebrate CNE loss early in teleost evolution, but also reveals massive CNE gain in the teleost stem-group over 300 million years ago. Using synteny-based association to link CNEs to their putatively regulated target genes, we show the most teleost gained CNEs are found in the vicinity of orthologous loci involved in transcriptional regulation and embryonic development that are also associated with CNEs in other vertebrates. Moreover, teleost and vertebrate CNEs share a highly similar motif and transcription factor binding site vocabulary. We suggest that early teleost CNE gains reflect a restructuring of the ancestral CNE repertoire through both extreme divergence and de novo emergence. Finally, we support newly identified pan-teleost CNEs have potential for accurate resolution of teleost phylogenetic placements in par with coding sequences, unlike ancestral only elements shared with spotted gar. This work provides new insight into CNE evolution with great value for follow-up work on phylogenomics, comparative genomics and the study of gene regulation evolution in teleosts.

genomics↗

bioRxiv2023

Co-inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription

Pancreatic carcinoma is one of the most lethal cancers and the absence of efficient therapeutic strategies results in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC impacts initiation, development, and survival of this tumor type. Using patient-derived xenografts of pancreatic carcinoma driven by KRAS and MYC oncogenic transcription, we show that co-inhibition of Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) synergistically induce tumor regression through targeting promoter pause-release, a rate-limiting step in transcription elongation. By comparing the nascent transcriptome with the recruitment of elongation and termination factors along genes, we found that co-inhibition of TOP1 and BRD4, while globally impairing RNA production, disturbs recruitment of proteins involved in termination. Thus, RNA polymerases continue transcribing downstream of genes for hundreds of kilobases leading to readthrough transcription. This pervasive transcription also occurs during replication, perturbing replisome progression and leading to DNA damage. The synergistic effect of TOP1 and BRD4 inhibition is specific for cancer cells leaving normal cells unharmed, highlighting the sensitivity of the tumor to these transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of high transcription and replication. One Sentence SummaryTOP1 and BRD4 inhibitors synergize to selectively kill pancreatic cancer in vivo via readthrough transcription without emergence of drug resistance

cancer biology↗