All Publications

  • Intragenic DNA inversions expand bacterial coding capacity. Nature Chanin, R. B., West, P. T., Wirbel, J., Gill, M. O., Green, G. Z., Park, R. M., Enright, N., Miklos, A. M., Hickey, A. S., Brooks, E. F., Lum, K. K., Cristea, I. M., Bhatt, A. S. 2024

    Abstract

    Bacterial populations that originate from a single bacterium are not strictly clonal and often contain subgroups with distinct phenotypes1. Bacteria can generate heterogeneity through phase variation-a preprogrammed, reversible mechanism that alters gene expression levels across a population1. One well-studied type of phase variation involves enzyme-mediated inversion of specific regions of genomic DNA2. Frequently, these DNA inversions flip the orientation of promoters, turning transcription of adjacent coding regions on or off2. Through this mechanism, inversion can affect fitness, survival or group dynamics3,4. Here, we describe the development of PhaVa, a computational tool that identifies DNA inversions using long-read datasets. We also identify 372 'intragenic invertons', a novel class of DNA inversions found entirely within genes, in genomes of bacterial and archaeal isolates. Intragenic invertons allow a gene to encode two or more versions of a protein by flipping a DNA sequence within the coding region, thereby increasing coding capacity without increasing genome size. We validate ten intragenic invertons in the gut commensal Bacteroides thetaiotaomicron, and experimentally characterize an intragenic inverton in the thiamine biosynthesis gene thiC.

    View details for DOI 10.1038/s41586-024-07970-4

    View details for PubMedID 39322669

    View details for PubMedCentralID 452554

  • Engineered skin bacteria induce antitumor T cell responses against melanoma. Science (New York, N.Y.) Chen, Y. E., Bousbaine, D., Veinbachs, A., Atabakhsh, K., Dimas, A., Yu, V. K., Zhao, A., Enright, N. J., Nagashima, K., Belkaid, Y., Fischbach, M. A. 2023; 380 (6641): 203-210

    Abstract

    Certain bacterial colonists induce a highly specific T cell response. A hallmark of this encounter is that adaptive immunity develops preemptively, in the absence of an infection. However, the functional properties of colonist-induced T cells are not well defined, limiting our ability to understand anticommensal immunity and harness it therapeutically. We addressed both challenges by engineering the skin bacterium Staphylococcus epidermidis to express tumor antigens anchored to secreted or cell-surface proteins. Upon colonization, engineered S. epidermidis elicits tumor-specific T cells that circulate, infiltrate local and metastatic lesions, and exert cytotoxic activity. Thus, the immune response to a skin colonist can promote cellular immunity at a distal site and can be redirected against a target of therapeutic interest by expressing a target-derived antigen in a commensal.

    View details for DOI 10.1126/science.abp9563

    View details for PubMedID 37053311