ORCID Profile
0000-0003-2497-3862
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Society for Microbiology
Date: 25-04-2018
Abstract: We have uncovered that long-term circulation of seasonal influenza A viruses (IAV) in the human population resulted in the progressive acquisition of increased sensitivity to a component of the innate immune response: the type I interferon-inducible TRIM22 protein, which acts as a restriction factor by inducing the polyubiquitination of the IAV nucleoprotein (NP). We show that four arginine residues present in the NP of the 1918 H1N1 pandemic strain and early postpandemic strains were progressively substituted for by lysines between 1918 and 2009, rendering NP more susceptible to TRIM22-mediated ubiquitination. Our observations suggest that during long-term evolution of IAVs in humans, variants endowed with increased susceptibility to TRIM22 restriction emerge, highlighting the complexity of selection pressures acting on the NP.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2022
DOI: 10.1038/S41590-021-01077-Y
Abstract: Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.
Publisher: American Society for Microbiology
Date: 15-04-2013
DOI: 10.1128/JVI.02548-12
Abstract: Tripartite motif (TRIM) protein superfamily members are emerging as important effectors of the innate immune response against viral infections. In particular, TRIM22 was reported to exert antiviral activity against RNA viruses, such as hepatitis B virus (HBV), encephalomyocarditis virus (ECMV), and human immunodeficiency virus type 1 (HIV-1). We demonstrate here, for the first time, that TRIM22 is upregulated by influenza A virus (IAV) infection at both mRNA and protein levels in human alveolar epithelial A549 cells. Conversely, TRIM22 potently restricted IAV replication, in that prevention of TRIM22 expression by means of short hairpin RNA led to a 10-fold enhancement of IAV replication in these cells. Depletion of TRIM22 also reduced the anti-IAV activity of alpha interferon (IFN-α), suggesting that TRIM22 is an important IFN-stimulated gene that is required for maximal suppression of IAV by type I IFN. Furthermore, the IAV infectious titer decreased up to 100-fold in MDCK cells expressing exogenous human TRIM22. Restriction of IAV replication was accounted for by the interaction between TRIM22 and the viral nucleoprotein (NP), resulting in its polyubiquitination and degradation in a proteasome-dependent manner. Thus, TRIM22 represents a novel restriction factor upregulated upon IAV infection that curtails its replicative capacity in epithelial cells.
Publisher: Mary Ann Liebert Inc
Date: 04-2014
Abstract: The human tripartite motif (TRIM) family, composed of more than 77 members, encompasses an emerging group of innate antiviral factors. Most TRIM proteins are characterized by being E3 ubiquitin ligases, but also engage in specific interactions with a variety of cellular and viral partners. They are involved in many cellular processes, including cell differentiation, transcriptional regulation, cytoskeleton remodeling, intracellular trafficking, membrane repair, and oncogenesis. In regard to antiviral immunity, they restrict both retroviruses and lentiviruses as well as other DNA and RNA viruses. This review will focus on the TRIM members endowed with anti-retroviral and anti-lentiviral activities and, in particular, human immunodeficiency virus.
Publisher: The American Association of Immunologists
Date: 15-08-2018
Abstract: Lymphocyte differentiation and identity are controlled by signals in the microenvironment that ultimately mediate gene expression in the nucleus. Although much focus has centered on the strategic and often unique roles transcription factors play within lymphocyte subsets, it is increasingly clear that another level of molecular regulation is crucial for regulating gene expression programs. In particular, epigenetic regulation is critical for appropriately regulated temporal and cell-type–specific gene expression during immune responses. As such, mutations in epigenetic modifiers are linked with lymphomagenesis. Furthermore, certain infections can remodel the epigenome in host cells, either through the microenvironment or by directly co-opting host epigenetic mechanisms, leading to inappropriate gene expression and/or ineffective cellular behavior. This review will focus on how histone modifications and DNA methylation, and the enzymes that regulate the epigenome, underpin lymphocyte differentiation and function in health and disease.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2011
Publisher: Elsevier BV
Date: 12-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2011
Publisher: MDPI AG
Date: 19-10-2020
Abstract: During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and disease progression. Epstein–Barr virus (EBV) is an endemic herpesvirus that is associated with several malignant tumours, including B-cell related lymphomas. In EBV-infected cells, the epigenomic landscape is extensively reshaped by viral oncoproteins, which directly interact with epigenetic modifiers and modulate their function. This process is fundamental for the EBV life cycle, particularly for the establishment and maintenance of latency in B cells however, the alteration of the host epigenetic machinery also contributes to the dysregulated expression of several cellular genes, including tumour suppressor genes, which can drive lymphoma development. This review outlines the molecular mechanisms underlying the epigenetic manipulation induced by EBV that lead to transformed B cells, as well as novel therapeutic interventions to target EBV-associated B-cell lymphomas.
No related grants have been discovered for Andrea Di Pietro.