Biology subjects

Tajeri, S.

Publications and source records attributed to Tajeri, S..

5 recordsLinked to original sources

bioRxiv2025

Epigenetic landscape of the H3K27me3 mark in macrophages transformed by Theileria annulata

Theileria annulata and T. parva are obligate intracellular parasites that induce bovine leukocyte transformation leading to uncontrolled proliferation and heightened dissemination of infected leukocytes. Early passage T. annulata-transformed macrophages are virulent, but with long-term culture, they become attenuated for dissemination. Loss of dissemination is restored when TGF-{beta}2-mediated signaling is re-established in attenuated macrophages, suggesting that epigenetic changes might be occurring that contribute to the attenuated phenotype. We focused on one of the important repressive histone marks, tri-methylated lysine 27 of histone H3 (H3K27me3) catalysed by the Polycomb Repressive Complex 2 and found that the global level of H3K27me3 is increased in attenuated macrophages. ChIP-seq revealed the genomic distribution of H3K27me3 is heavily remodeled from virulent to attenuated macrophages, where many genes transition from a focal peak of H3K27me3 around the transcription start site to larger chromatin domains. This transition is not paralleled by large-scale transcriptional downregulation. RNA-seq analysis following PRC2 inhibitor treatment reveals that fewer genes are derepressed in attenuated macrophages than in virulent macrophages, suggesting that broader H3K27me3 profiles do not systematically translate into increased gene silencing activity. Our findings shed light on the mechanisms underlying the dysregulation of epigenetic modifications in Theileria-induced leukocyte transformation. Significance statementTropical theileriosis is a major constraint to livestock production worldwide. Infection with Theileria annulata induces the transformation of bovine leukocytes, which subsequently exhibit similarities to human leukemia. Long-term in vitro culture of transformed leukocytes attenuates their tumorigenic properties. The molecular changes underlying this process are currently unclear. We focused on H3K27me3, a key histone tail post-translational modification that regulates chromatin structure and gene expression, and compared its genomic landscapes in virulent, highly disseminating macrophages versus attenuated macrophages with reduced dissemination potential that are used as a live vaccine against tropical theileriosis. Western blot and ChIP-seq revealed higher global levels of H3K27me3 and a striking broadening of its genomic distribution in attenuated macrophages. To our surprise, this reconfiguration is not associated with major changes in gene expression and attenuated cells appear to be less responsive to PRC2 inhibition, suggesting that large-scale broadening of H3K27me3 does not systematically translate into increased PRC2-mediated silencing activity. Despite these changes, H3K27me3 maintains the silencing of key tumor suppressor genes in both virulent and attenuated macrophages. These findings shed light on the interplay between infection, the evolution of oncogenic potential and reconfiguration of the chromatin landscape following attenuation of virulence.

microbiology↗

bioRxiv2022

Theileria annulata histone deacetylase 1 (TaHDAC1) initiates schizont to merozoite stage conversion

A fungal metabolite, FR235222, specifically inhibits a histone deacetylase of the apicomplexan parasite Toxoplasma gondii and TgHDAC3 has emerged as a key factor regulating developmental stage transition in this species. Here, we exploited FR235222 to ask if changes in histone acetylation regulate developmental stage transition of Theileria annulata, another apicomplexan species. We found that FR235222 treatment of T. annulata-infected transformed leukocytes induced a proliferation arrest. The blockade in proliferation was due to drug-induced conversion of intracellular schizonts to merozoites that lack the ability to maintain host leukocyte cell division. Induction of merogony by FR235222 leads to an increase in expression of merozoite-marker (rhoptry) proteins. RNA-seq of FR235222-treated T. annulata-infected B cells identified deregulated expression of 468 parasite genes including a number encoding parasite ApiAP2 transcription factors. Thus, similar to T. gondii, FR235222 inhibits T. annulata HDAC (TaHDAC1) activity and places parasite histone acetylation as a major regulatory event of the transition from schizonts to merozoites.

cell biology↗

bioRxiv2021

Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or A. afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of P. falciparum and the pre-erythrocytic (i. e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for P. vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

microbiology↗

bioRxiv2018

Theileria highjacks JNK2 into a complex with the macroschizont GPI-anchored surface protein p104

Theileria is a unique apicomplexan parasite capable of transforming its host cell into a disseminating tumour. Constitutive JNK activity characterizes bovine T and B cells infected with T. parva, and B cells and macrophages infected with T. annulata. Here, we show that T. annulata manipulates JNK activation by recruiting JNK2, and not JNK1, to the parasite surface, whereas JNK1 is found predominantly in the host cell nucleus. In silico analysis identified 3 potential JNK-binding motifs in the previously characterized GPI-anchored macroschizont surface protein (p104), and we demonstrate here that JNK2 is recruited to the parasite via physical interaction with p104. A cell penetrating peptide harbouring a p104 JNK-binding motif also conserved in T. parva p104 competitively ablated binding, whereupon liberated JNK2 became ubiquitinated and degraded. Sequestration of JNK2 depended on PKA-mediated phosphorylation of the conserved JNK-binding motif and upon disruption of the p104/JNK2 complex loss of JNK2 resulted in diminished matrigel traversal of T. annulata-transformed macrophages. Loss of JNK2 also resulted in upregulation of small mitochondrial ARF that promoted autophagy consistent with cytosolic sequestration of JNK2 sustaininf not only JNK2, but also nuclear JNK1 levels that combined contribute to both survival and dissemination of Theileria-transformed macrophages.\n\nAuthor SummaryTheileria annulata parasites infect and transform their host bovine leukocytes into tumourlike cells that disseminate throughout infected animals causing a widespread disease called tropical theileriosis. Virulence has been ascribed to the parasites ability to constitutively activate leukocyte c-Jun N-terminal Kinase (JNK) leading to permanent induction of Matrix Metallo-Proteinase 9 (MMP9) that promotes transformed macrophage dissemination. In attenuated live vaccines JNK-mediated AP-1-driven transcriptional activity is reduced so dampening dissemination. However, in leukocytes JNK exists as two isoforms JNK1 and JNK2 and here, we show for the first time that in T. annulata-transformed macrophages they have different subcellular localisations and perform separate functions. Surprisingly, JNK2 associates with the parasite and is not in the nucleus like JNK1. JNK2 is hijacked by the parasite and sequestered in a complex with a macroschizont surface protein called p104. Upon forced complex dissociation JNK2 gets degraded and its loss negatively affects infected macrophage survival and ability to disseminate.

microbiology↗

bioRxiv2018

GZMA and RASGRP1 are novel tumor suppressors that counter dissemination of Theileria annulata-transformed macrophages

Theileria annulata is a tick-transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumors that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed during Theileria-induced transformation. Dataset comparisons highlighted a small set of genes associated with Theileria-transformed leukocyte dissemination. The roles of Granzyme A (GZMA) and RAS guanyl-releasing protein 1 (RASGRP1) were verified by CRISPR/Cas9-mediated knock-down. Knocking down of GZMA and RASGRP1 in attenuated macrophages led to a regain in their dissemination in Rag2/{gamma}C mice confirming their role as dissemination suppressors in vivo. We further evaluated the roles of GZMA and RASGRP1 in human B-lymphoma cells by comparing the transcriptome of 934 human cancer cell lines to that of Theileria-transformed bovine host cells. We confirmed dampened dissemination potential of human B-lymphoma cells that overexpress GZMA and RASGRP1. Our results provide evidence that GZMA and RASGRP1 have a novel tumor suppressor function in both T. annulata-infected bovine host cells and in human B-lymphomas.\n\nSummaryWe compared the transcriptomes of Theileria annulata transformed B-lymphocytes to 934 human cancer cell lines and provide functional evidence for shared tumor suppressor roles for GZMA and RASGRP1 in controlling the dissemination phenotype of both human B lymphomas and Theileria-transformed leukocytes.

molecular biology↗