Biology subjects

Ku, K. B.

Publications and source records attributed to Ku, K. B..

4 recordsLinked to original sources

bioRxiv2026

De novo design of a safe and potent respiratory syncytial virus immuno-focusing antigen

Respiratory syncytial virus (RSV) remains the leading cause of severe respiratory infections in infants, the elderly, and the immunocompromised. Although stabilized full-length pre-fusion (pre-F) protein vaccines are promising, enhanced respiratory disease (ERD) remains a critical safety concern. Here, we used artificial intelligence to design a de novo immuno-focused antigen that structurally preserves the RSV F head region containing critical neutralising epitopes-- site O, II and V-while replacing the non-neutralising stem with a computationally designed scaffold to minimise immunopathological risk. The lead candidate, aRF6, elicited robust protective immunity against RSV in mice and similar immunogenicity in non-human primates without detectable toxicity. Importantly, in stringent ERD-promoting models, aRF6 induced minimal pulmonary pathology and markedly attenuated Th2-biased cytokine responses, outperforming formalin-inactivated RSV and full-length-stabilized pre-F. The results of cryoelectron microscopy confirmed that the aRF6 structure precisely matched the computational predictions. These results demonstrated that computationally designed de novo immuno-focused antigens can yield safe and effective RSV vaccines, thereby providing a rational framework for next-generation vaccine development.

microbiology↗

bioRxiv2026

Disruption of the hypothalamic orexin system links SARS-CoV-2 infection to persistent cortical neuronal pathology

Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infection induces lasting cortical neuronal injury and hypothalamic orexin (hypocretin) dysfunction in vivo. In K18-hACE2 and wild-type BALB/c mice, viral RNA persisted in the brain and coincided with focal loss of Neuronal Nuclei (NeuN)-positive cortical neurones beyond acute infection. SARS-CoV-2, but not the influenza A virus, triggered rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Considering the downregulation of orexin and focal cortical NeuN expression, we showed that augmenting orexin signalling using recombinant orexin-A/B restored NeuN expression in vitro and in vivo. Overall, these findings identify the orexin system as a selective neural vulnerability to SARS-CoV-2 and define orexinergic circuit disruption as a mechanistic axis underlying the neurological manifestations of Long COVID.

microbiology↗

bioRxiv2024

Differential Responses of Lung and Intestinal Microbiota to SARS-CoV-2 Infection: A Comparative Study of the Wuhan and Omicron Strains in K18-hACE2 tg Mice

The COVID-19 pandemic, caused by SARS-CoV-2, has led to the emergence of viral variants with distinct characteristics. We investigated the differential effects of the original Wuhan strain and the emergent Omicron variant of SARS-CoV-2 using a K18-hACE2 transgenic mouse model. We compared the mortality rates, viral loads, and histopathological changes in lung and tracheal tissues, as well as alterations in the lung and intestinal microbiota following infection. We observed significant differences in disease severity, with the Wuhan strain causing higher mortality and more severe lung damage than the Omicron variant. Furthermore, microbiome analyses revealed distinct shifts in microbiota associated with infection by each variant, suggesting that microbiome-related mechanisms might influence disease outcomes. This comprehensive comparison enhances our understanding of COVID-19 pathogenesis and highlights the importance of microbiome dynamics in viral infections, providing insights for future therapeutic and preventive strategies. ImportanceUnderstanding the differential impacts of SARS-CoV-2 variants is crucial for effective public health response and treatment development. This study provides insights into the pathogenesis of the original Wuhan strain and the Omicron variant of SARS-CoV-2, revealing significant differences in host mortality, viral load, and lung pathology. The use of the K18-hACE2 transgenic mouse model enables detailed examination of these differences in a controlled setting. Furthermore, this study highlights the importance of the microbiome in modulating disease severity and host responses to viral infections. By uncovering distinct microbial shifts associated with infection by different SARS-CoV-2 variants, this study suggests potential microbiome-related mechanisms that might be targeted to mitigate disease outcomes.

microbiology↗

bioRxiv2020

Robust and sensitive detection of SARS-CoV-2 using PCR based methods

The World Health Organization (WHO) has declared the Coronavirus disease 2019 (COVID-19) as an international health emergency. Current diagnostic tests are based on the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method, the gold standard test that involves the amplification of viral RNA. However, the RT-qPCR assay has limitations in terms of sensitivity and quantification. In this study, we tested both qPCR and droplet digital PCR (ddPCR) to detect low amounts of viral RNA. The cycle threshold (CT) of viral RNA by RT-PCR significantly varied according to the sequence of primer and probe sets with in vitro transcript (IVT) RNA or viral RNA as templates, whereas the copy number of viral RNA by ddPCR was effectively quantified with IVT RNA, cultured viral RNA, and RNA from clinical samples. Furthermore, the clinical samples were assayed via both methods, and the sensitivity of the ddPCR was determined to be significantly higher than RT-qPCR. These findings suggest that ddPCR could be used as a highly sensitive and compatible diagnostic method for viral RNA detection.

microbiology↗