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Biology subjects

Power, U. F.

Publications and source records attributed to Power, U. F..

2 recordsLinked to original sources
bioRxiv2018

The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses.

Respiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-{lambda}1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-{lambda}1 production. However, the role of TLR4 in RSV infection and concomitant IFN-{lambda}1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-{lambda}1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-{lambda}1 secretion, while JSH-23, an NF-{kappa}B inhibitor, reduced IFN-{lambda}1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-{lambda}1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- {kappa}B and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.\n\nImportanceThe role of TLR4 in RSV infection and IFN-{lambda}1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-{lambda}1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.

microbiology↗
bioRxiv2018

The Viral protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. Additionally, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta peptide (A{beta}42), a major constituent of amyloid plaques in Alzheimers disease, in-vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.

microbiology↗