bioRxiv Science⌕ Search

Biology subjects

Lau, S.-Y.

Publications and source records attributed to Lau, S.-Y..

6 recordsLinked to original sources

A statistical framework for quantifying the nuclear export rate of influenza viral mRNAs.

Influenza A virus transcribes viral mRNAs from the eight segmented viral genome when it infects. The kinetics of viral transcription, nuclear export of viral transcripts, and their potential variation between the eight segments are poorly characterised. Here we introduce a statistical framework for estimating the nuclear export rate of each segment from a snapshot of in situ mRNA localisation. This exploits the cell-to-cell variation at a single time point observed by an imaging-based in situ transcriptome assay. Using our model, we revealed the variation in the mRNA nuclear export rate of the eight viral segments. Notably, the two influenza viral antigens hemagglutinin and neuraminidase were the slowest segments in the nuclear export, suggesting the possibility that influenza A virus uses the nuclear retention of viral transcripts to delay the expression of antigenic molecules. Our framework presented in this study can be widely used for investigating the nuclear retention of nascent transcripts produced in a transcription burst.

systems biology↗

Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination

BackgroundVaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal. MethodsSince mucosal immunity is critical for nasal prevention, we investigated an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2. FindingsSubstantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity. InterpretationOur results demonstrated that intranasal influenza-based boost vaccination is required for inducing mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems. FundingThis study was supported by the Research Grants Council Collaborative Research Fund (C7156-20G, C1134-20G and C5110-20G), General Research Fund (17107019) and Health and Medical Research Fund (19181052 and 19181012) in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program (JSGG20200225151410198); the Health@InnoHK, Innovation and Technology Commission of Hong Kong; and National Program on Key Research Project of China (2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); and donations from the Friends of Hope Education Fund. Z.C.s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).

immunology↗

Low dose inocula of SARS-CoV-2 B.1.1.7 variant initiate more robust infections in the upper respiratory tract of hamsters than earlier D614G variants

There is a lack of experimental evidence to explain how the B.1.1.7 variant spreads more quickly than pre-existing variants in humans. We found that B.1.1.7 displays increased competitive fitness over earlier D614G lineages in an in-vitro system. Furthermore,, we demonstrated that B.1.1.7 variant is able to replicate and shed more efficiently in the nasal cavity than other variants with lower dose and shorter duration of exposure.

microbiology↗

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

microbiology↗

SARS-CoV-2 spike D614G variant exhibits highly efficient replication and transmission in hamsters

SARS-CoV-2 causes disease varying in severity from asymptomatic infections to severe respiratory distress and death in humans. The viral factors which determine transmissibility and pathogenicity are not yet clearly characterized. We used the hamster infection model to compare the replication ability and pathogenicity of five SARS-CoV-2 strains isolated from early cases originating in Wuhan, China, in February, and infected individuals returning from Europe and elsewhere in March 2020. The HK-13 and HK-95 isolates showed distinct pathogenicity in hamsters, with higher virus titers and more severe pathological changes in the lungs observed compared to other isolates. HK-95 contains a D614G substitution in the spike protein and demonstrated higher viral gene expression and transmission efficiency in hamsters. Intra-host diversity analysis revealed that further quasi species were generated during hamster infections, indicating that strain-specific adaptive mutants with advantages in replication and transmission will continue to arise and dominate subsequent waves of SARS-CoV-2 dissemination.

microbiology↗

Pathogenicity, immunogenicity, and protective ability of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein

SARS-CoV-2 contains a PRRA polybasic cleavage motif considered critical for efficient infection and transmission in humans. We previously reported that virus variants with spike protein S1/S2 junction deletions spanning this motif are attenuated. Here we characterize a further cell-adapted SARS-CoV-2 variant, Ca-DelMut. Ca-DelMut replicates more efficiently than wild type or parental virus in cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut does not induce proinflammatory cytokines in hamster infections, but still triggers a strong neutralizing antibody response. Ca-DelMut-immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, demonstrating sterilizing immunity.

microbiology↗