Biology subjects

Wang, L.-F.

Publications and source records attributed to Wang, L.-F..

3 recordsLinked to original sources

bioRxiv2018

Deconvoluting Virome-Wide Antiviral Antibody Profiling Data

The ability to comprehensively characterize exposures and immune responses to viral infections will be critical to better understanding human health and disease. We previously described the VirScan system, a phage-display based technology for profiling antibody binding to a comprehensive library of peptides designed to represent the human virome. The previous VirScan analytical approach did not fully account for disproportionate representation of viruses in the library or for antibody cross-reactivity among sequences shared by related viruses. Here we present the AntiViral Antibody Response Deconvolution Algorithm ( AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection at species-level resolution by considering alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. By comparing acute and convalescent sera, AVARDA successfully confirmed or detected antibody responses to human herpesviruses 1, 3, 4, 5, and 6, thereby improving the rate of diagnosing viral encephalitis in this cohort by 62.5%. We further assessed AVARDAs utility in the setting of an epidemiological study, demonstrating its ability to determine infections acquired in a child followed prospectively from infancy. We consider ways in which AVARDAs conceptual framework may be further developed in the future and describe how its analyses may be extended beyond investigations of viral infection. AVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases.

bioinformatics↗

bioRxiv2017

Viral hijacking of the nucleolar DNA-damage response machinery: a novel mechanism to regulate host cell biology

Recent landmark studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing, implicated in Treacher-Collins syndrome. Here, using proteomics, confocal/super-resolution imaging, and infection under BSL-4 containment, we present the first report that this nucleolar DDR pathway is targeted by infectious pathogens. We find that Treacle has antiviral activity, but that matrix protein of Henipaviruses and P3 protein of rabies virus, highly pathogenic viruses of the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1-Treacle interaction during a DDR. These data identify a novel mechanism for viral modulation of host cells by appropriating the nucleolar DDR; this appears to have developed independently in different viruses, and represents, to our knowledge, the first direct intra-nucleolar function for proteins of any mononegavirus.

microbiology↗

bioRxiv2017

The IFN response in bat cells consists of canonical and non-canonical ISGs with unique temporal expression kinetics

Bats are reservoirs for a number of highly pathogenic zoonotic viruses, yet they remain relatively asymptomatic during infection. Whether this viral resistance is due to a unique innate immune system is unknown. An evolutionarily conserved feature of vertebrate antiviral immunity is the interferon (IFN) response, which triggers cellular defenses through interferon-stimulated gene (ISG) expression. While bats encode an intact IFN system, global ISG expression patterns in bat cells are not well characterized. Here, we used RNA-Seq to assess the transcriptional response to IFN in cells derived from the bat Pteropus alecto (black flying fox). We show induction of more than 100 transcripts, most of which are canonical ISGs observed in other species. Kinetic gene profiling revealed that P. alecto ISGs fall into two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast to bat ISGs, human ISGs generally remained elevated for longer periods following IFN treatment, suggesting host-based differences in gene regulatory mechanisms. Notably, we also identified a small group of non-canonical bat ISGs, including an enzymatically active RNASEL that plays a role in controlling viral infection. These studies provide insight into the innate immune response of an important viral reservoir and lay a foundation for studies into the immunological features that may underlie unique virus-host relationship in bats.\n\nSignificance StatementBats are considered unique in their ability to resist disease caused by viruses that are often pathogenic in humans. While the nature of this viral resistance is unknown, genomic data suggest bat innate immune systems may be specialized in controlling these disease-causing viruses. A critical cell intrinsic antiviral defense system in vertebrates is the interferon response, which suppresses viral infection through induction of hundreds of interferon-stimulated genes (ISGs). In this study, we report the repertoire of ISGs and several unique features of ISG induction kinetics in bat cells. We also characterize induction and antiviral activity of bat RNASEL, which is induced by IFN in bat, but not human cells. These studies lay the foundation for discovery of potentially new antiviral mechanisms in bats, which may spur research into development of therapies to combat viral infection.

immunology↗