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Dr Michele Brocard


Research Fellow in Virology

Academic and research departments

School of Biosciences and Medicine.

My publications

Publications

MICHELE BROCARD, Jia Lu, BELINDA SUZETTE HALL, KHUSHBOO BORAH, CARLA SOFIA MOLLER-LEVET, Iliana Georgana, Frederic Sorgeloos, DANY BESTE, Ian G Goodfellow, NICOLAS S LOCKER (2021)Murine Norovirus infection results in anti-inflammatory response downstream of amino acid depletion in macrophages, In: Journal of Virology American Society for Microbiology

Murine norovirus (MNV) infection results in a late translation shut-off, that is proposed to contribute to the attenuated and delayed innate immune response observed both in vitro and in vivo. Recently, we further demonstrated the activation of the eIF2α kinase GCN2 during MNV infection, which has been previously linked to immunomodulation and resistance to inflammatory signalling during metabolic stress. While viral infection is usually associated with activation of dsRNA binding pattern recognition receptor PKR, we hypothesised that the establishment of a metabolic stress in infected cells is a proviral event, exploited by MNV to promote replication through weakening the activation of the innate immune response. In this study, we used multi-omics approaches to characterise cellular responses during MNV replication. We demonstrate the activation of pathways related to the integrated stress response, a known driver of anti-inflammatory phenotypes in macrophages. In particular, MNV infection causes an amino acid imbalance that is associated with GCN2 and ATF2 signalling. Importantly, this reprogramming lacks the features of a typical innate immune response, with the ATF/CHOP target GDF15 contributing to the lack of antiviral responses. We propose that MNV-induced metabolic stress supports the establishment of host tolerance to viral replication and propagation.

Michele Brocard, Valentina Ladevaia, Philipp Klein, Belinda Hall, Glenys Lewis, Jia Lu, James Burke, Margaret Willcocks, Roy Parker, Ian G. Goodfellow, Alessia Ruggieri, Nicolas Locker (2019)Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation, In: PLoS Pathogens Public Library of Science

Viral infections impose major stress on the host cell. In response, stress pathways can rapidly deploy defence mechanisms by shutting off the protein synthesis machinery and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression, viruses need to evade these pathways to propagate. Human norovirus is responsible for gastroenteritis outbreaks worldwide. Here we examined how norovirus interacts with the eIF2α signaling axis controlling translation and stress granules. While norovirus infection represses host cell translation, our mechanistic analyses revealed that eIF2α signaling mediated by the stress kinase GCN2 is uncoupled from translational stalling. Moreover, infection results in a redistribution of the RNA-binding protein G3BP1 to replication complexes and remodelling of its interacting partners, allowing the avoidance from canonical stress granules. These results define novel strategies by which norovirus undergo efficient replication whilst avoiding the host stress response and manipulating the G3BP1 interactome.

Michele Brocard, Alessia Ruggieri, Nicolas Locker (2017)m6A RNA methylation, a new hallmark in virus-host interactions, In: Journal of General Virology98pp. 2207-2214 Microbiology Society

The role of m6A methylation of RNA has remained elusive for decades, however recent technological advances are now allowing the mapping of the m6A methylation landscape at nucleotide level. This has spurred an explosion in our understanding of the role played by RNA epigenetics in RNA biology. m6A modifications have been tied to almost every aspects of the mRNA life cycle and it is now clear that RNA virus genomes are subject to m6A methylation. These modifications play various roles in the viral replication cycle. This review will summarize recent breakthroughs concerning m6A RNA modification and their implications for cellular and viral RNAs.