Singer and Pabón et al. developed a Salmonella typhimurium bacterial platform that delivered non-spreading, self-replicating viral RNA, even into cell types beyond the virus’s natural tropism. S. typhimurium “encapsidating” full-length oncolytic Senecavirus A delivered i.t. into s.c. engrafted tumors cleared treated and distal tumors in athymic mice, as did i.v. treatment of immunocompetent mice (even in the presence of pre-existing circulating viral-neutralizing antibodies), without adverse effects. Additional virus engineering aimed to control viral spread and persistence and to mitigate RNA mutational escape by requiring that virion maturation depend on bacterially delivered TEV protease.
Contributed by Paula Hochman
ABSTRACT: The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice. Finally, we engineer the virus to require a bacterially delivered protease to achieve virion maturation, demonstrating bacterial control over the virus. Together, we refer to this platform as 'CAPPSID' for Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery. This work extends bacterially delivered therapeutics to viral genomes, and shows how a consortium of microbes can achieve a cooperative aim.
Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2)
Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (3) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (4) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (5) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (6) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (7) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (9) Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (10) Department of Biomedical Engineering, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Data Science Institute, Columbia University, New York, NY, USA. tal.danino@columbia.edu.
