Ko, M. | Search bioRxiv

bioRxiv2018

An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 reported SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates.\n\nAuthor summarySevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea. This tick-borne virus has infected more than 5,000 humans with a 6.4% to 20.9% fatality rate. Currently, there are no prophylactic or therapeutic measures against this virus. Historically, antibodies from patients who recovered from viral infection have been used to treat new patients. Until now, one recombinant monoclonal antibody was approved for the prophylaxis of respiratory syntial virus infection. We selected 10 antibodies from a patient who recovered from SFTS and found that one antibody potently inhibited SFTS viral infection in both test tube and animal studies. We determined the binding site of this antibody to SFTS virus, which allowed us to predict that this antibody could bind 247 out of 272 SFTS virus isolates reported up to now. We anticipate that this antibody could be developed into a therapeutic measure against SFTS.

biochemistry↗

bioRxiv2018

Creating Standards for Evaluating Tumour Subclonal Reconstruction

Tumours evolve through time and space. Computational techniques have been developed to infer their evolutionary dynamics from DNA sequencing data. A growing number of studies have used these approaches to link molecular cancer evolution to clinical progression and response to therapy. There has not yet been a systematic evaluation of methods for reconstructing tumour subclonality, in part due to the underlying mathematical and biological complexity and to difficulties in creating gold-standards. To fill this gap, we systematically elucidated the key algorithmic problems in subclonal reconstruction and developed mathematically valid quantitative metrics for evaluating them. We then created approaches to simulate realistic tumour genomes, harbouring all known mutation types and processes both clonally and subclonally. We then simulated 580 tumour genomes for reconstruction, varying tumour read-depth and benchmarking somatic variant detection and subclonal reconstruction strategies. The inference of tumour phylogenies is rapidly becoming standard practice in cancer genome analysis; this study creates a baseline for its evaluation.

bioinformatics↗