Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts

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Abstract

The mammalian microbiome has many important roles in health and disease1,2, and genetic engineering is enabling the development of microbial therapeutics and diagnostics3,4,5,6,7. A key determinant of the activity of both natural and engineered microorganismsin vivois their location within the host organism8,9. However, existing methods for imaging cellular location and function, primarily based on optical reporter genes, have limited deep tissue performance owing to light scattering or require radioactive tracers10,11,12. Here we introduce acoustic reporter genes, which are genetic constructs that allow bacterial gene expression to be visualizedin vivousing ultrasound, a widely available inexpensive technique with deep tissue penetration and high spatial resolution13,14,15. These constructs are based on gas vesicles, a unique class of gas-filled protein nanostructures that are expressed primarily in water-dwelling photosynthetic organisms as a means to regulate buoyancy16,17. Heterologous expression of engineered gene clusters encoding gas vesicles allowsEscherichia coliandSalmonella typhimuriumto be imaged noninvasively at volumetric densities below 0.01% with a resolution of less than 100 μm. We demonstrate the imaging of engineered cellsin vivoin proof-of-concept models of gastrointestinal and tumour localization, and develop acoustically distinct reporters that enable multiplexed imaging of cellular populations. This technology equips microbial cells with a means to be visualized deep inside mammalian hosts, facilitating the study of the mammalian microbiome and the development of diagnostic and therapeutic cellular agents.

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