‘Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells’. Nature Microbiology (2016) Vol. 2

‘Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells’. Nature Microbiology (2016) Vol. 2

Influenza A virus (IAV) causes annual epidemics and occasional pandemics, and is one of the best-characterized human RNA viral pathogens1. However, a physiologically relevant role for the RNA interference (RNAi) suppressor activity of the IAV non-structural protein 1 (NS1), reported over a decade ago2, remains unknown. Plant and insect viruses have evolved diverse virulence proteins to suppress RNAi as their hosts produce virus-derived small interfering RNAs (siRNAs) that direct specific antiviral defence by an RNAi mechanism dependent on the slicing activity of Argonaute proteins (AGOs). Recent studies have documented induction and suppression of antiviral RNAi in mouse embryonic stem cells and suckling mice. However, it is still under debate whether infection by IAV or any other RNA virus that infects humans induces and/or suppresses antiviral RNAi in mature mamma- lian somatic cells. Here, we demonstrate that mature human somatic cells produce abundant virus-derived siRNAs co-immunoprecipitated with AGOs in response to IAV infection. We show that the biogenesis of viral siRNAs from IAV double-stranded RNA (dsRNA) precursors in infected cells is mediated by wild-type human Dicer and potently suppressed by both NS1 of IAV as well as virion protein 35 (VP35) of Ebola and Marburg filoviruses. We further demonstrate that the slicing catalytic activity of AGO2 inhibits IAV and other RNA viruses in mature mammalian cells, in an interferon-independent fashion. Altogether, our work shows that IAV infection induces and suppresses antiviral RNAi in differentiated mammalian somatic cells. Link to the paper    ...
‘Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity’.  Immunology & Cell Biology (2015) Vol. 93, Issue 3.

‘Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity’. Immunology & Cell Biology (2015) Vol. 93, Issue 3.

The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body’s first line of defense against infection. Although signaling pathways and transcription factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary cell lineage as well as context-specific gene expression in diverse innate immune cell types. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental triggers also induce changes in histone modifications that can either promote tolerance or ‘train’ innate immune cells for a more robust antigen- independent secondary response. Here we review the important contribution of epigenetic factors to the initiation, maintenance and training of innate immune responses. In addition, we explore how pathogens have hijacked these mechanisms for their benefit and the potential of small molecules targeting chromatin machinery as a way to boost or subdue the innate immune response in disease. Link to the...
‘Suppression of inflammation by a synthetic histone mimic’. Nature (2010) Vol. 468, Issue 7327.

‘Suppression of inflammation by a synthetic histone mimic’. Nature (2010) Vol. 468, Issue 7327.

Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal- induced assembly of nuclear chromatin complexes that support mRNA expression1–4. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression5–10. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflam- matory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria- induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs. Link to the...

Paper published in Nature Microbiology- ‘Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells’

The latest paper from the Jeffrey Lab in Nature Microbiology. In the paper we show for the first time that RNA interference (RNAi) – an antiviral mechanism known to be used by plants and lower organisms – is active in the response of human cells to some important viruses. We document both the production of RNAi molecules in human cells infected with the influenza A virus and the suppression of RNAi defense by a viral protein known to block the process in a common animal...